anesthesia for esophagectomy

P R O C E E D I N G NI[Š, APRIL 25-27, 2014

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ORGANIZERS: SECTION FOR ANESTHESIOLOGY, INTENSIVE CARE AND PAIN THERAPY OF THE SERBIAN MEDICAL SOCIETY IN COLABORATION WITH SERBIAN ASSOCIATION OF ANESTHESIOLOGISTS AND INTENSIVISTS

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ISBN 978-86-6233-045-1

6 t h A n n u a l Spring S c i e n t i f i c S ymposium i n A n e s t h esiology a n d I n t e n s ive Care PROCEEDING April 25-27, 2014 Ni{, Serbia

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SIXT H AN N UA L SP RIN G SC I EN TI FIC S Y M P O S I U M I N A N E S T H E S I O LO GY A N D I N T E N S I V E C A R E

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SCIENTIFIC PROGRAM IS ENDORSED BY: WORLD FEDERATION OF SOCIETIES OF ANESTHESIOLOGISTS, EUROPEAN SOCIETY OF ANESTHESIOLOGY, EUROPEAN AIRWAY MANAGEMENT SOCIETY AND CENTRAL AND EASTERN EUROPEAN SEPSIS FORUM

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Sixth Annual Spring Scien�fic Symposium in Anesthesiology and Intensive Care, April 25-27, 2014, Niš, Serbia

– SIXTH ANNUAL SPRING SCIENTIFIC SYMPOSIUM IN ANESTHESIOLOGY AND INTENSIVE CARE PROCEEDING SCIENTIFIC SYMPOSIUM April 25-27, 2014 Ni{, Serbia

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SIXTH ANNUAL SPRING SCIENTIFIC SYMPOSIUM IN ANESTHESIOLOGY AND INTENSIVE CARE PROCEEDING Scien�fic symposium April 25-27, 2014 Niš, Serbia Editorial board Assoc. Prof. Radmilo Janković, Ph.D. Assist. Prof. Biljana Stošić, Ph.D. Assist. Prof. Ivana Budić, Ph.D. Publisher "Galaksija" Niš For the publisher Mlađan Ranđelović, manager Editor Dubravka Ranđelović Technical editor Mile Ž. Ranđelović Printed by "Galaksija" Niš Curcula�on 500 ISBN 978-86-6233-045-1

CIP - Каталогизација у публикацији Народна библиотека Србије, Београд 616-089.5(082) 615.211/.216(082) ANNUAL Spring Scien�fic Symposium in Anesthesiology and Intesive Care (6 ; 2014 ; Niš) Proceeding / Sixth Annual Spring Scien�fic Symposium in Anesthesiology and Intesive Care, April 25-27, 2014. Niš, Serbia ; [editor Dubravka Ranđelović]. - Niš : Galaksija, 2014 (Niš : Galaksija). - 226 str. : ilustr. ; 30 cm Tiraž 500. - Bibliografija uz svaki rad. ISBN 978-86-6233-045-1 a) Анестезиологија - Зборници COBISS.SR-ID 206870284

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TABLE OF CONTENTS ANESTHESIA IN PATIENTS WITH PHEOCHROMOCYTOMA: A 15 YEARS OF EXPERIENCE Nevena Kalezić, Milena Kažić, Vera Sabljak, Sonja Grković, Željko Bradić, Vesna Antonijević, Ksenija Stevanović, Anka Tošković, Maja Milinić, Aleksandar Diklić, Vladan Živaljević, Goran Zorić, Nikola Slijepčević, Katarina Taušanović, Nataša Vujačić, Ivan Paunović ............... 9 MILITARY MEDICAL ACADEMY - HOME OF SERBIAN ANESTHESIA Zoran Slavković ........................................................................................................................ 13 MODULATING OUTCOME AFTER NON�CARDIAC SURGERY: EFFECTS OF PHARMACOLOGICAL INTERVENTIONS Stefan De Hert ......................................................................................................................... 15 ASSESSING OXYGEN DEBT IN THE CRITICALLY ILL Krisz�án Tánczos, Zsolt Molnár ............................................................................................... 16 CENTRAL VENOUS PRESSURE CAN NOT PREDICT THE FLUID RESPONSIVENESS Şerban Bubenek ...................................................................................................................... 20 PAIN MANAGEMENT IN A CHANGING WORLD Paul E. Carns ............................................................................................................................ 22 EPIDURAL IN JEOPARDY: ANTITHROMBOTIC AND ANTICOAGULATION THERAPY UPDATE Vojislava Nešković ................................................................................................................... 25 THE USE OF TRANEXAMIC ACID IN ELECTIVE TOTAL KNEE AND HIP ARTHROPLASTY Christopher Duncan................................................................................................................. 27 LOCAL ANESTHETIC TOXICITY - LAST UPDATE Darko Golić .............................................................................................................................. 30 TREATMENT OF HYPERTENSION IN PREGNANCY Vesna D. Garovic ...................................................................................................................... 36

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MANAGEMENT OF BLEEDING AND INTRAOPERATIVE BLOOD SALVAGE IN OBSTETRICS Tatjana Ilić Mos�ć, Radan Stojanović, Danka Mos�ć, Mirjana Kendrišić, Radmila Sparić, Miroslava Gojnić Dugalić ......................................................................................................... 41 THE SAFE USE OF REMIFENTANIL FOR LABOUR PAIN Mirjana Kendrisic, Borislava Pujic, Tatjana Ilic-Mos�c ............................................................. 46 STATE OF THE ART LABOR ANALGESIA Ivan Veličković ......................................................................................................................... 50 BETA BLOCKERS IN THE SEPSIS Svetlana Apostolović, Dragana Stanojević ............................................................................... 54 VENTILATORY STRATEGIES FOR MORBIDLY OBESE PATIENTS TO PREVENT ATELECTASIS Juraj Sprung, Toby N Weingarten ............................................................................................ 65 FAT EMBOLISM SYNDROME IN TRAUMA VICTIMS Malgorzata Mikaszewska-Sokolewicz ...................................................................................... 68 RENAL REPLACEMENT THERAPY: WHEN, WHY AND HOW? Zorica Dimitrijevic, Branka Mi�c.............................................................................................. 71 PULMONARY EMBOLISM Dragana Unic-Stojnovic ........................................................................................................... 76 TREATMENT OF HEMATOLOGICAL EMERGENCIES IN SURGICAL PATIENTS Vesna Marjanovic, Mirjana Mihajlovic, Ivana Budic, Radmilo Jankovic, Goran Marjanovic .... 79 DO WE STILL NEED EPINEPHRINE FOR CPR? Jasna Jevđić, Filip Žunić ........................................................................................................... 85 TRANSPORTATION OF MECHANICALLY VENTILATED PATIENT Miodrag Milenović, Zla�bor Lončar, Nataša Petrović, Dušica Simić ........................................ 88 ANTIBIOTIC RESISTANCE: SERBIAN PERSPECTIVE Radmilo Janković, Radmila Veličković-Radovanović, Teodora Božić ........................................ 90 PROCALCITONIN-ASSISTED ANTIBIOTIC TREATMENT IN SEPSIS Zsolt Molnár, János Fogas ........................................................................................................ 93 THE IMPORTANCE OF PCT KINETICS IN SEPTIC PATIENTS János Fazakas, Zsolt Becze ....................................................................................................... 96 ANESTHESIA ASSOCIATED AIRWAY TRAUMA (A MEA CULPA) Barry Harrison ....................................................................................................................... 100 PREDICTORS OF DIFFICULT PEDIATRIC AIRWAY Marijana Karišik ..................................................................................................................... 103 4


THE DIFFICULT AIRWAY: THE USE OF SUBGLOTTIC JET VENTILATION FOR ENDOLARYNGEAL SURGERY Dusanka Janjevic ................................................................................................................... 106 EXTUBATION OF A PATIENT WITH DIFFICULT AIRWAY Iljaz Hodzovic ......................................................................................................................... 109 CHALLENGES FOR INTERNATIONAL SCIENTIFIC RESEARCH IN EUROPE Stefan De Hert ....................................................................................................................... 110 EVIDENCE-BASED PRACTICE: A HELP FOR BEGINNERS? Massimo Lamper� ................................................................................................................. 111 INNOVATION IN REGIONAL ANESTHESIA EDUCATION Hugh MacGregor Smith ......................................................................................................... 114 CORONARY ARTERY DISEASE - THE VULNERABLE PLAQUE John C Sill............................................................................................................................... 116 ANESTHESIA FOR REPAIR OF RUPTURED ABDOMINAL AORTIC ANEURISM Dusica Stamenkovic, Aleksandar Tomic, Ivan Marjanovic, Zoran Bjelanovic ......................... 118 CONTROVERSIES IN THE MANAGEMENT OF CAROTID ARTERY DISEASE Jeffrey J. Pasternak ................................................................................................................ 122 ANESTHESIA FOR LEFT VENTRICULAR ASSIST DEVICE (LVAD) HEART MATE II Dejan Markovic, Emilija Nestorovic, Sonja Grkovic, Zeljko Bradic, Vladimir Tutus, Mladjan Golubovic, Nebojsa Ladjevic, Svetozar Putnik ......................................................... 124 CAN WE IMPROVE OUTCOME IN HIGH-RISK PATIENTS? INTRAOPERATIVE MANAGEMENT Daniel A. Reuter .................................................................................................................... 127 SEPSEAST SATELLITE MEETING: PERIOPRATIVE CRITICAL CARE CAN WE IMPROVE OUTCOME IN HIGH RISK PATIENTS - POSTOPERATIVE MANAGEMENT Bianca Tudor, Claus G. Krenn ................................................................................................. 129 A NEW CONCEPT IN HEMOSTASIS MANAGEMENT János Fazakas, Judit Szabó, Anikó Smudla ............................................................................. 131 HAEMOSTATIC AGENTS: PLASMA, PLATELETS, CONCENTRATES Miodrag Vučić........................................................................................................................ 134 DIAGNOSTIC TOOLS IN BLEEDING MANAGEMENT Zoran Stanojković, Ana An�ć ................................................................................................. 138 CARDIAC SURGERY - INTRAOPERATIVE BLOOD MANAGEMENT - DO WE NEED TO CHANGE STRATEGY? Miomir Jovic .......................................................................................................................... 142 5


BLEEDING MANAGEMENT IN LIVER TRANSPLANT SURGERY Eleni Katsika........................................................................................................................... 146 HIGH RISK CARDIAC PATIENTS FOR NON-CARDIAC OPERATIONS Amman Sarang ...................................................................................................................... 149 ANESTHESIA FOR INTERVENTIONAL GASTROENTEROLOGY PROCEDURES Ljiljana Gvozdenovic .............................................................................................................. 150 PERIPHERAL NERVE INJURIES ASSOCIATED WITH SURGERY AND OPERATIVE POSITIONING Julie E. Hammack................................................................................................................... 153 EYE BLOCKS Bazil Ateleanu ........................................................................................................................ 154 COMMON COMORBIDITIES RELEVANT TO PEDIATRIC ANESTHESIA Ivana Budić, Dušica Simić, Vesna Marjanović, Radmilo Janković, Dejan Novaković, Vladimir Grozdanović, Ana Kos�ć .......................................................................................... 155 IS SPINAL ANAESTHESIA SUFFICIENT FOR BONE OPERATIVE PROCEDURES IN SMALL CHILDREN? Jasminka Nancheva ............................................................................................................... 162 NEW GUIDELINES IN PEDIATRIC TRANSFUSION Dušica Simić, Selena Purić Racić, Marija Stević, Irina Milojević, Ivana Petrov, Miodrag Milenović, Ivana Budić ........................................................................................... 165 DIFFICULT PEDIATRIC AIRWAY MANAGEMENT Dušica Simić, Miodrag Milenović, Ivana Budić ...................................................................... 168 PERIOPERATIVE FLUID MANAGEMENT Gordana Jovanovic ................................................................................................................ 172 COLLOID VERSUS CRYSTALLOID Gurinder M Vasdev ................................................................................................................ 174 HEMODYNAMIC ASSESSMENT BEFORE FLUID LOADING IN CRITICALLY ILL PATIENTS Gorazd Voga .......................................................................................................................... 177 DO WE NEED ADVANCED HEMODYNAMIC MONITORING IN PATIENTS UNDERGOING CRANIOTOMY? Jasmina Markovič Božič ......................................................................................................... 179 STRATEGY FOR REDUCING ANTIMICROBIAL RESISTANCE IN INTENSIVE CARE UNITS Slavče Antanasković, Slađana Vasiljević, Ana Antanasković .................................................. 182 BAD BUGS NEED NEW DRUGS Srdjan Pesic ........................................................................................................................... 188 6


SEVERE VIRAL PNEUMONIA THERAPY Nada Popović, Marina Stojanović, Danijela Stojimirović ....................................................... 190 HOW TO MANAGE SEVERE CNS INFECTIONS Steva Stanišić, Maja Jovanović, Miodrag Vrbić ...................................................................... 195 ADVANCES IN BREAKTHROUGH CANCER PAIN MANAGEMENT Nebojsa Ladjevic, Mirko Grajic, Ivana Likic Ladjevic, Dejan Markovic, Ana Mimic, Natasa Denčić ..................................................................................................... 201 MULTIMODAL TREATMENT APPROACH TO THE COMPLEX REGIONAL PAIN SYNDROME Mirko Grajic, Nebojsa Ladjevic, Sanja Tomanovic-Vujadinovic, Slavica Rajevic, Ksenija Boskovic, Andjela Milovanovic, Ljubomir Djurasic .................................................... 203 SPECIFICITY OF TREATMENT OF NEUROPATHIC PAIN OF MALIGNANT AETIOLOGY Bra�slav Branković ................................................................................................................ 206 CHRONIC POSTOPERATIVE PAIN – PREVENTION IS THE BEST TREATMENT Ana Mimić ............................................................................................................................. 211 HYPOTENSIVE ANAESTHESIA AND PLASMA LEVEL OF NO Biljana Shirgoska, Jane Netkovski .......................................................................................... 213 ANESTHESIA FOR ESOPHAGECTOMY Biljana Stošić, Radmilo Janković, Danijela Stanković, Dragana Stanković Đorđević, Nenad Savić, Ines Veselinović ................................................................................................ 216 VISION LOSS IN THE OPERATING ROOM Shelley Cross.......................................................................................................................... 223 PAIN BLOCKS FOR THE NON PAIN PRACTITIONER Jesse J Muir ........................................................................................................................... 225

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ANESTHESIA IN PATIENTS WITH PHEOCHROMOCYTOMA: A 15 YEARS OF EXPERIENCE

Nevena Kalezić1,2,3, Milena Kažić2,3, Vera Sabljak2,3, Sonja Grković3, Željko Bradić3, Vesna Antonijević3, Ksenija Stevanović3, Anka Tošković2,3, Maja Milinić2,3, Aleksandar Diklić1,2, Vladan Živaljević1,2, Goran Zorić2, Nikola Slijepčević2, Katarina Taušanović2, Nataša Vujačić2, Ivan Paunović1,2 School of Medicine, University of Belgrade Center for Endocrine Surgery, Clinical Center of Serbia, Belgrade 3 Center for Anaesthesiology and Resuscita�on, Clinical Center of Serbia, Belgrade 1 2

Introduc�on Pheochromocytoma is a rare tumor of adrenal medulla, with an incidence between 0,8 - 2,3 per one million per year, in general popula�on. It can present in any age, in any circumstances, including neonates, pregnancy etc, but is more common in females between 20 and 50 years of age. (1) The diagnosis is based on typical symptoms, laboratory and localiza�on inves�ga�ons (echosonography, CT, NMR and MIBI). Gene�c screening is recommended if suspicion of hereditary forms is present. In 0,1-1% cases, the diagnosis is established by cardiologists. This data suggests that every new-onset hypertension must be evaluated in the direc�on of possibility of pheochromocytoma - induced hypertension. (2) A specific diagnosis of pheochromocytoma is made biochemically, based on the presence of elevated catecholamines or their metabolites in plasma or in urine. The current recommenda�ons state that ini�al screening for pheochomocytma should include the measurement of frac�onated metanephrines in urine and/or plasma. A�er biochemical diagnosis has been made, the localiza�on of the tumor must be established. CT iden�fies pheochromocytoma in the majority of cases, but NMR is a be�er choice for extra adrenal localiza�on and small ones. If there is a suspicion on mul�ple sites or metastasis, scin�graphy with I-MIBG has high specificity and sensi�vity for their detec�on. (3,4) Typical presenta�ons of hypertension implies hypertensive crises in stressful situa�ons. But, about 10-20% pa�ents have moderate hypertension, without hypertensive crisis. Except the paroxysmal hypertension, the classic symptoms such are headache, swea�ng, pallor, anxiety and palpita�ons occur in only 50% of pa�ents. Approximately 5% of pa�ents with pheochromocytoma are asymptoma�c. These circumstances may delay diagnosis. (3,5) [email protected]

Preopera�ve prepara�on Preopera�ve prepara�on has two main goals: to control blood pressure and to restore blood volume to normal ranges. Ini�al therapy is always alpha-adrenergic blockade.(6) Phenoxybenzamine is the most common used drug. It is a long-ac�ng agent, which produces blockade of both α1 - and α2-adrenergic receptors. The treatment usually starts with a dose of 10 mg twice daily, but it requires a total daily dose of up to 100 mg. (5) Doxazosin and prazosin have a selec�ve postjunc�onal α1 inhibitory ac�vity. Therefore they produce a fall in the arterial blood pressure with a less increase of heart rate than phenoxybenzamine. They also have a shorter dura�on �me than phenoxybenzamine and that is why they don’t cause prolonged hypotension a�er surgery. (7) There is no strict �me limit for preopera�ve prepara�on (usually 3 weeks), but the opera�on should be done as soon as following criteria are achieved: normal arterial blood pressure at least 48 hours before the surgery, heart rate lower than 85 beats per minute, VES less than 5 per minute, and the absence of fresh ischemic lesions on the ECG. (8)

Periopera�ve anesthe�c management Periopera�ve anesthe�c management is based on avoiding any histamine-liberator or sympa�co-mime�c agent during anesthesia, as well as agents which contribute to blood pressure rising, or precipitate cardiac dysrhythmias, such as atropine, thiopentone, ketamine, morphine, succinilholin, atracurium, pancuronium. Halothane and desflurane are also not recommended. (9) Intraopera�vely, there are two major problems which must be treated by anaesthesiologists: hypertension (during induc�on and resec�on) and hypotension following devasculariza�on of the tumor. In addi�on, cardiac dysrhythmias may be a big problem, especially in the presence of epinephrine-secre�ng pheochromocytoma. In 9


order to successfully treat these hemodynamic disorders, invasive monitoring of blood pressure and central venous pressure must be established before the surgical procedure, as well as ECG and another standard monitoring. (9,10) An�hypertensive and an�arrhythmic agents must be available immediately for infusion (preferably using a central line). Many drugs have been used successfully including sodium nitroprusside, glyceryl trinitrate, phentolamine, esmolol, labetalol, nicardipine, magnesium sulphate and urapidil. (11,12,13) Hypotension a�er liga�on of the tumor’s venous drainage may be severe and refractory, par�cularly in pa�ents with incomplete alpha blockade preopera�vely. The treatment of hypotension should include intraopera�ve volume loading and minimizing the infusion of an�hypertensive drugs, by avoiding long-ac�ng hypotensive agents. Some pa�ents may require a vasoconstrictor/inotropic infusion (norepinepinephrine) postopera�vely during a few hours. (14)

Postopera�ve care The main problem and the leading course of death in the postopera�ve period is a persistent hypotension following tumor ex�rpa�on. The reasons for such a state are: an inadequate preopera�ve prepara�on with not good-enough alpha-blockade achieved, long-term usage of alpha blocking agents (such as phenoxybenzamine), less than 24 hours prior to surgery, in par�cularly if surgery is accompanied with a great blood loss. Somnolence and edema may exist during the some �me. (2,14) In the light of these facts, in addi�on to rou�ne postopera�ve care, it is appropriate to place pa�ents in high dependency unit (HDU) se�ng (level 2). Intra-arterial pressure monitoring should be con�nued, in oder to detected any episodes of hyper- or hypotension. Central venous pressure monitoring should be used to direct fluid and inotropic therapy (if required). Blood glucose level should be monitored frequently because hypoglycemia is expected event, in an immediately postopera�ve period (insulin levels rises following removal of the suppression caused by catecholamine). (2,6)

A 15 years of experience in the surgical treatment of pheochromocytoma in the Center for endocrine surgery, Clinical Center of Serbia During the period from January 1st1999 un�l December 12th 2013, in the Center for Endocrine Surgery, Clinical Center of Serbia, 177 pa�ents 10

with pheochromocytoma have been surgically treated. Although literature data suggest that both sexes are affected equally, in our series, there were significantly more female pa�ents (112= 63.3%). The majority of our pa�ents had a tumor which predominantly secreted norepinephrine (78.1%), then epinephrine (19.5%), and dopamine was secreted in only 2.3 %, which is consistent with the literature data that suggest that the ra�o of norepinephrine and epinephrine tumors is 83%: 17%, while dopamine is rarely described. In the Center for Endocrine Surgery, Clinical Center of Serbia, during the last 15 years, we had even 32% of pheochromocytoma pa�ents without hypertension, 6.25% of pa�ents had a bilateral tumor which was simultaneously part of Mul�ple Endocrine Neoplasia Syndrome (MEN), only 3.1% of pa�ents had extra adrenal tumor localiza�on, and the same number of pa�ents had complex, mul�ple tumors (associated with hormonally ac�ve tumors of the adrenal cortex); 2.3% of pa�ents had a recurrent pheochromocytoma, which primarily was surgically treated in another hospital. According to the literature, with the pheochromocytoma pa�ents one can see the rule of 10%, which means that 10% of the tumors have extra adrenal localiza�on, 10% are bilateral, 10% are malignant, 10% are presented without hypertension, 10% occur in children and, 10% are hereditary. However, the development of sophis�cated diagnos�c abili�es put this rule under the ques�on mark. Recent data suggested that up to 30% of pheochromocytoma may have a hereditary basis. Hereditary forms have a higher incidence of bilateral tumors (20-50%), extra adrenal presenta�on (up to 20%) and risk of malignancy rises up to 40%. (2,6) Surgical treatment, in par�cularly surgical approach for the incision, which, mainly determines the hemodynamic response to surgical s�mula�on, in the majority of cases in our pa�ents was a unilateral subcostal laparotomy (70%), but other approaches were used, as well: midline laparotomy (14.2%), bilateral subcostal laparotomy (6.1%), dorsal lumbotomy (8.3%), and one pa�ent underwent laparoscopic surgery. Judging by our experience, despite the fact that it is not a small one, anaesthesia for pheochromocytoma remains one of the most stressful ones, because some�mes is very difficult to prevent and to deal with major hemodynamic fluctua�ons, although pa�ents are well prepared and have appropriate monitoring equipment, and team of doctors is well- trained. One of our pa�ents had an abrupt increase of arterial blood pressure of 372/150 mmHg, which is, by our knowledge the highest recorded pressure


Fig. 1. The value of the arterial blood pressure in a pa�ent with pheochromocytoma, who underwent adrenalectomy at the Center for Endocrine Surgery, Clinical Center of Serbia

increase during surgery of pheochromocytoma in the literature. So far, the maximum pressure rise was recorded in the case report from the 2002nd, which was 320/120 mmHg (15) (Fig. 1).

Is the pheochromocytoma an anaesthesiologist’s night mare? According to the prior data (1927-1951) mortality rate among pa�ents who underwent surgical treatment of pheochromocytoma was 27% during surgery. (16) Nowadays, due to preopera�ve prepara�on using alpha blocking agents, a lot of newly discovered agents for rapid control of hypertensive crisis as well of hypotensive states, and the development of surgical techniques and sophis�cated devices for vital parameters monitoring, intraopera�ve mortality rate reduces to less than 2-3%. However, in the cases of non-diagnosted pheochromocytoma, mortality rate is s�ll high (25-50%), usually during minor surgery. (17) Regardless of the technological, pharmacological and other scien�fic achievements, anaesthesia for pheochromocytoma surgery s�ll stays challenging and highly stressful, even for experienced anaesthesiologists who work in highly-specialized ins�tu�ons and have extensive experience in dealing with these pa�ents. (18,19) In order to minimize anaesthesiologist’s stress during pheochromocytoma surgery, every anaesthesiologist must know several key-points about pheochromocytoma: (1,2,6,8,9,10,11) – The pheochromocytoma always produces catecholamines, depending of size, localiza�on and malignancy of the tumor. – Invasive monitoring of arterial blood pressure and central venous pressure is necessary for opera�on. – There are two cri�cal moments before opera�on: induc�on to anaesthesia and insuffla�ons of carbon dioxide in order to create pneumoperitoneum (for laparoscopic approach).

– There are two cri�cal moments and during opera�on: surgical handling of tumor and ligaturing of the predominant venous which supplies tumor with blood. – Laparoscopic surgery of pheochromocytoma should be avoided for three reasons: the crea�on of pneumoperitoneum causes an increase of blood pressure, the opera�on takes longer and recurrences a�er this approach are more frequent (possible dissemina�on?). This approach should be applied only sporadically: for small, benign, well-localized (and easily accessible) tumors, when catecholamines are not significantly elevated. – The tumor is well-perfunded. Implica�on is: bleeding may be enormous. – Catecholamines produce hemodynamic response, depending of its kind. That response occurs 20 seconds a�er surgical manipula�on. – Norepinephrine-secre�ng tumors cause high blood pressure during handling tumor, while epinephrine-secre�ng tumors cause less hypertensive response, but severe tachycardia or other dysrhythmias. – Short-ac�ng an�hypertensive drugs, such as vasodilators, as well as an�arrhythmic (esmolol, labetalol, amiodarone) must be available immediately. Infusion is a be�er choice than boluses. – The first choice for the therapy of hypotension is a volume loading, but prolonged hypotension may be treated using vasoac�ve agents (norepinephrine is recommended). – Cardiological evalua�on and addi�onal prepara�on is usually needed for pa�ents with prior cardiovascular disease, when levels of catecholamines are enormously high and when the diagnosis is delayed. – Preopera�ve prepara�on must be adequate in regards of its dura�on; pa�ents must be normotensive at least for 48 hours prior to the opera�on. Long-ac�ng alpha-blocking agents must be excluded (at least) 24 hours prior to the surgery.

Conclusion A mul�disciplinary approach to the pa�ents with pheochromocytoma is a condi�o sine qua non, in order to achieve successful treatment and less stress, both to the pa�ents and physicians involved in their treatment. Anaesthesiologist, surgeon, endocrinologist and some �me - cardiologist, even psychiatrics, must communicate to achieve the best preopera�ve condi�ons. In our country, like in most other ones, a pheochromocytoma pa�ent is referred to a special centers for management, of this rare, but severe disorder.

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15.

16. 17. 18. 19.

žlezde), urednika N. Kalezić, Medicinski fakultet, Beograd, 2009; 35: 491–510. Marković D, Sabljak V, Antonijević V, Malenković V, Gvozdenović LJ, Kalezić N. Treatment of intraopera�ve hypertensive crisis during opera�on pheochromocytoma, Fourth annual spring scien�fic symposium in anaesthesiology and intensive care, Niš, Proceeding Scien�fic Symposium, 2012; p-90-2. Obrenović-Kirćanski B, Kalezić N. Lečenje intraopera�vnih hipertenzivnih kriza, u knjizi: Anesteziološki aspek� endokrinih i metaboličkih poremećaja (š�tasta žlezda, paraš�taste i nadbubrežne žlezde), urednika N. Kalezić, Medicinski fakultet, Beograd, 2009; 37: 521–9. Obrenović-Kirćanski B, Kalezić N. Lečenje intraopera�vnih akutnih poremećaja srčanog ritma, u knjizi: Anesteziološki aspek� endokrinih i metaboličkih poremećaja (š�tasta žlezda, paraš�taste i nadbubrežne žlezde), urednika N. Kalezić, Medicinski fakultet, Beograd, 2009; 38: 531–8. Janićijević A, Sabljak V, Antonijević V, Živaljević V, Marković D, Kalezić N. Protrahirana posteks�rpaciona hipotenzija posle operacije feohromocitoma. SJAIT, 2011; 33(3-4): 307–12. Baraka A, Siddik-Sayyid S, Jalbout M, Yaacoub C. Variable hemodynamic fluctua�ons during resec�on of mul�centric extraadrenal pheochromocytomas. Can J Anesth 2002; 49(7): 682–6 . Su�on J, Sheldon G, Lie JT. Prevalence of clinically unsuspected pheochromocytoma; review of a 50 years series. Mayo Clin Proc 1981; 56: 354–60. Plates JK. Drew PJ, Harvey JN. Death from pheochromocytoma: lesson from a post-mortem study. J R Coll Phys London 1995; 29: 299–306. Myklejord DJ. Undiagnosed pheochromocztoma: the anesthesiologist nightmare. Clin Med Res 2004; 2:59-62. Kalezić N, Sabljak V, Živaljević V, Diklić A, Marković D, Paunović I. Anestezija kod bolesnika sa feohromocitomom: anesteziološka noćna mora? Anestezija i intenzivna terapija, 2011; 33(1-2): 75–8.


MILITARY MEDICAL ACADEMY � HOME OF SERBIAN ANESTHESIA Zoran Slavković

Clinic for Anesthesiology and Intensive Care, Military Medical Academy, Belgrade, Serbia

Military Medical Academy is one of the oldest ins�tu�on of medical science and prac�ce in the region. It turned 170 years old this year, so I would like to tell you a few words about its developmental pathway. The first medical ins�tu�on was established as medical service of Serbian Army by the cons�tu�on "Sretenjski ustav" in 1835. A year later the first military hospital of Belgrade was established in Savamala. Serbian prolonged figh�ng for its freedom and independence made the military ambulance a forerunner of the organized health system in the Balkans. The official begining of medical service of Serbian Army is March 2nd, 1844 (February 19th - Julian calendar), witch is the date of Serbian prince Aleksandar Karađorđević's decree that approved work of 120 hospital beds capacity Central Military Hospital. Ever since this date has been celebrated righ�ully and proudly as the day of Military Medical Academy. Central Military Hospital was located in the building of today's Third High School of Belgrade and has tes�fied about many historically significant events and wars before the Congress of Berlin. In 1904 the hospital was moved to west Vračar and renamed Danube Military Hospital and then General Military Hospital in 1909. With six units of medical care and 400 hospital beds capacity it was the most modern hospital in the Balkans. Employed stuff has been remembered by unselfish heroic feats during the wars from 1912 to 1918. In 1922 General Military Hospital became Permanent Military Hospital of the First Army Region and then turned into Principal Military Hospital with 780 hospital beds capacity in 1930. Principal Military Hospital's stuff played an important role as a founder of Medical University of Belgrade and gave its first professors. A�er the libera�on, the hospital con�nued its ac�vity as Principal Military Hospital of People's Libera�on Army of Yugoslavia. Military Medical Academy (MMA) was established in july 24th, 1949 by acts issued by the government. It began to work April 30th, 1950 and it has been military ins�tu�on for medical prac�ce, scien�fic research work and educa�on of [email protected]

the highest order in our country un�ll today. On April 8th, 1960 Assembly of Federa�ve People's Republic of Yugoslavia declared higher rank and equivalency of the educa�on provided both by MMA and Medical School of Balgrade. A�er Second World War organiza�onal, professional, scien�fic, and technological development was carried out according to the highest world standards through collabora�on and comminica�on with similar ins�tu�ons in the country and worldwide. A long-las�ng hursh Balkan reality was survived with Serbian people and Army. MMA stuff con�nued inexorably forward to the last decade of the 20th century when new test of its service, professional ethics and power of patrio�sm came. Medical care had been provided for more then 10000 wounded and thousands soldiers with pos�rauma�c stress regardless of na�onality, idelogical orienta�on, religion, or social origin. MMA stuff again passed the exam of professional responsibility, competence and ethics. Scien�fic researches, educa�on and publishing ac�vi�es con�nued through the hard period for our country. MMA reorganized daily ac�vi�es on a way of progress and con�nued to invest in knowledge, personel strengthening and technological moderniza�on. MMA signed the contract with the Na�onal Health Insurance and became a part of the public health system of Serbia using 40% of its capacity January 1st, 2008. Year 2009 was very important in the history of MMA. The great dream of genera�ons of our predecessors came true. Serbian academic circle recognized and verified a great poten�al of MMA for educa�onal and scien�fic research ac�vi�es. After accredita�on, government issued the license and made MMA a part of University of Defence of Serbia. Furthemore, 20 cadets were enrolled in the first class of integrated studies of medicine at Medical Faculty of MMA of University of Defence of Serbia in school year 2009/2010. MMA has provided health care for Army and civilians conscien�ously and diligently for 170 years. Because of that MMA is a great witness of history and fate of na�ons in this region. 13


Vladan Đorđević, Mihajilo Mika Marković, Sava Popović, Iva Kralj, Isidor Papa are a li�le part of numerous military medical professionals who deserved a great respect making the basics and building the MMA's tradi�on. They contributed that MMA became an important place on the Europian medical map. MMA has been an important ins�tu�on in Serbian principality, kingdom, monarchy, republic, despite the changes of rulers, state systems and the turbulences of Balkans'life. The roots of Serbian anaesthesia were at the Second Surgical Department of Principal Military Hospital of Belgrade. For the first �me in Serbia (in that �me, there was Yugoslavia) general endotracheal anaesthesia was performed by a team of experts from England, led by anesthesiologist Shackleton in 1945. Dr Patrick Sherwood and dr

14

Davis Russell con�nued Shackleton's mission during 1946 – they educated our doctors (dr Sever Kovačev, dr Milan Jovanović, dr Rista Ivanovski, dr Ivezić and many others). The first Department for Anaesthesiology and Resuscita�on was formed at that �me by Colonel Sever Kovačev – our first anaesthesiologist. Dr Dragoljub Mihajlović and Dr Dimitrina Nemet were the only anaesthesiologists at MMA in 1962. Our famous professors of anaesthesia Marenović Tomislav, Šefer Stevan, Jovanović Branimir, and dr Živković began their specializa�ons during that year. Depertment for Anaesthesia started growing. Rapid development and moderniza�on built today's Clinic for Anesthesiology and Intensive Care of Military Medical Academy of Belgrade with 47 anaesthesiologist (2 professors, 3 assistant professors and 3 assistants).


MODULATING OUTCOME AFTER NON�CARDIAC SURGERY: EFFECTS OF PHARMACOLOGICAL INTERVENTIONS

Stefan De Hert

Scien�fic Commi�ee ESA Department of Anesthesiology, Ghent University Hospital, Ghent University, Belgium

Over the years increasing a�en�on has focused on improvement of periopera�ve outcome. Pre- and intra-opera�ve risk assessment allow to iden�fy pa�ents that are increased risk for developing periopera�ve complica�ons and therefore may benefit from op�miza�on. In addi�on, close postopera�ve monitoring and prompt treatment of complica�ons may help to minimize postopera�ve complica�ons. Pre-opera�ve pharmacological treatment has gained wide interest in the last 20 years with mostly conflic�ng data. The present presenta�on will discuss the different pharmacological interven�ons that have been proposed and applied in periopera�ve medicine. Pre-opera�ve beta-blocking therapy has been widely proposed as providing protec�on against periopera�ve stress. However, the ini�al enthusiasm about its protec�ve effects has been challenged and the recent POISE 1 study clearly demonstrated that the beneficial effect on incidence of periopera�ve myocardial infarc�on was counterbalanced by an increased mortality duet o stroke, provoked by intraopera�ve bradycardia and hypotension. Conflic�ng data from studies with preopera�ve beta-blocking therapy might in part be a�ributed to methodological issues such as bias, start and dura�on of therapy but also be related to pharmacological specifici�es and even gene�c profile. These different issues will be presented and discussed. In addi�on the poten�al role of drug like sta�ns, aspirin and alpha-2 agonists will be addressed. Finally, poten�al influence of choice of anesthe�c regimen will be addressed.

[email protected]

Sugested Literature Bangalore S et al. Lancet 2008; 372: 1962–76. Devereaux P et al. Lancet 2008; 371: 1839–47. Poldermans D et al. Anesthesiology 2009; 111: 940–5. Ellenberger C et al. Anesthesiology 2011; 114: 817–23. Wutke H et al. Clin Pharmacol Ther 2002; 72: 429–37. Rau T et al. Clin Pharmacol Ther 2009; 85: 269–72. Badge� RG et al. Anesthesiology 2010; 113: 585–92. Wallace AW et al. Anesthesiology 2011; 114: 824–36. Mashour GA et al. Anesthesiology 2013; 119: 1340–6. Ashes C et al. Anesthesiology 2013; 119: 777–87. Bea�e WS et al. Anesthesiology 2010; 112: 25–33. Le Manach Y et al. Anesthesiology 2012; 117: 1203–11. Bouri S et al. Heart 2014; 100: 456–64. Chopra V et al. Arch Surg 2012; 147: 181–9. Lura� Buse GAL et al. Circula�on 2012; 126: 2696–704. Devereaux PJ et al. N Engl J Med 2014; DOI: NEJMoa1401105 Devereaux PJ et al. N Engl J Med 2014; DOI: NEJMoa1401106

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ASSESSING OXYGEN DEBT IN THE CRITICALLY ILL Krisz�án Tánczos, Zsolt Molnár

Department of Anaesthesia and Intensive Therapy University of Szeged, Hungary

Introduc�on Oxygen is one of the major essen�als required for sustaining life. The primary goal of the cardiorespiratory system is to deliver adequate oxygen to the �ssues to meet their metabolic requirements. The adequacy of �ssue oxygena�on is determined by the balance between the rate of oxygen transport to the �ssues (oxygen delivery, DO2) and the rate at which the oxygen is used by the �ssues (oxygen consump�on, VO2) (1). Standard formulae to determine oxygen delivery and oxygen consump�on are: DO2= SV * HR * [Hb * 1.34 * SaO2 + 0.003 * PaO2] = CO * [CaO2]~1000ml/min VO2=CO*[CaO2-(Hb*1.34* SvO2 + 0.003 * PvO2)] = CO*[CaO2-CvO2]~250ml/min DO2 - oxygen delivery, SV – stroke volume, HR – heart rate, Hb – haemoglobin, SaO2 – haemoglobin arterial oxygen satura�on, PaO2 – arterial oxygen par�al pressure, CO – cardiac output, CaO2 – arterial oxygen content, VO2 – oxygen consump�on, SvO2 – haemoglobin mixed venous oxygen satura�on, PvO2 – venous oxygen par�al pressure, CvO2 – venous oxygen content

Oxygen extrac�on ra�o (O2ER) as calculated from these two equa�ons is therefore about 25-30 %. In the cri�cally ill and in the periopera�ve period there is o�en an imbalance between delivery and consump�on. Oxygen delivery may be inadequate considering arterial oxygen content and/or cardiac output may be reduced (2,3). The circula�on can compensate to some extent, but a�er a cri�cal threshold severe oxygen debt and shock may occur (4) . The principle task of acute cri�cal care is to avoid or correct oxygen debt by increasing DO2 and/or decreasing VO2. Furthermore, knowing when increasing DO2 has restored �ssue perfusion and no further increase is necessary is an important ques�on in order to avoid harm that can be caused by unnecessary over resuscita�on. Perhaps the most commonly used methods to assess global VO2 are mixed venous oxygen satura�on (SvO2) and its surrogate, central venous oxygen satura�on (ScvO2). According to the above specified physiological changes measurement of mixed venous oxygen satura�on can be an indirect index of �ssue oxygena�on in the en�re body (5). However, regard16

[email protected]

ing the risk/benefit of the placement of a pulmonary artery catheter remains controversial (6–7). In contrast, inser�on of a central venous catheter in the superior vena cava via the internal jugular or the subclavian vein is considered standard care in cri�cally ill pa�ents. Just like SvO2, the measurement of central venous oxygen satura�on has been advocated in order to detect global �ssue hypoxia (4). Monitoring of ScvO2 may be therefore an a�rac�ve alterna�ve to that of SvO2.

Central venous oxygen satura�on ScvO2 is an easily obtained parameter via the central venous catheter already in situ in most cri�cally ill pa�ents and it is o�en used as a marker of the balance between oxygen delivery and consump�on. Measurement of ScvO2 indicates the level of venous oxygena�on of the brain and the upper part of the body. The normal value varies between 73-82 % (8). Because of the different level of measurement (en�re body in the case of SvO2 ↔ brain and the upper part of the body with ScvO2) there has been a considerable debate on the interpreta�on of ScvO2 values as compared to SvO2. Most of the studies that have analyzed the rela�onship between ScvO2 and SvO2 have shown that ScvO2 is an average of 5 % higher than SvO2 and is considered a reasonable surrogate marker in the clinical se�ng (9–11). However, recent clinical trials, mainly on sep�c pa�ents, were unable to show sa�sfactory agreement between ScvO2 and SvO2. This could in part be explained by modifica�ons of blood flow distribu�on and oxygen extrac�on by brain and splanchnic �ssue (12). It seems that ScvO2 and SvO2 are not numerically equivalent but the varia�ons in these two parameters usually occur in a parallel manner (13). The main factors, which influence ScvO2, are haemoglobin, arterial oxygen satura�on of haemoglobin, cardiac output and oxygen consump�on. Theore�cally if three of these factors are kept constant the value of ScvO2 reflects the changes of the la�er (14). One of the important features of venous satura�ons is that it can be pathologic both if it is high and when it is low. In a recent

Reprinted from Proceeding of Fi�h Annual Spring Symposium in Anaesthesiology and Intensive Care, 19-21 April 2013: 28-31.


large cohort of sep�c pa�ents in the emergency department it was found that mortality was 40% in pa�ents admi�ed with an ScvO290% (15). Finally, one has to bear in mind that ScvO2 should be measured in the superior vena cava. In a heterogeneous pa�ent popula�on it was found that there were very wide limits of agreement between ScvO2 measured in the superior vena cava as compared to results from the inferior vena cava, therefore femoral venous oxygen satura�on should not be used as surrogate for central venous oxygen satura�on (16).

ScvO2 as a transfusion trigger

One of the most common causes of inadequate DO2 in the periopera�ve se�ng is anaemia requiring red blood cell transfusions (17). It has recently been suggested that haemoglobin level should not be the only factor on which the indica�on of the need for transfusion is based (18–19). According to the TRICC trial, pa�ents with haemoglobin level above 10 g/dl require rarely transfusion while red blood cell dona�on is usually necessary if haemoglobin is below 7 mg/dl (20). There is however a clear need for addi�onal parameters in pa�ents with haemoglobin level between 7 and 10 g/dl. Clinicians u�lize different tools from simple clinical signs (confusion, tachycardia, ST-segment eleva�on/depression, diuresis) to invasive hemodynamic measurements (central venous oxygen satura�on, oxygen extrac�on, central venous-toarterial carbon dioxide difference) in order to have informa�on on anaemia related altered oxygen extrac�on and hence the need for blood administra�on (21). One of the poten�ally useful physiological parameters is the ScvO2. It was found during haemorrhage in animal and human experimental models that ScvO2 may be useful for the iden�fica�on of pa�ents with occult or ongoing clinically significant blood loss (22–23). In bleeding condi�ons, an ScvO2 value of ~70% has been used as a goal to therapeu�c interven�on in a�empts at improving oxygen delivery (21). In a prospec�ve human interven�onal study it was found that in acute isovolaemic anaemia of haemoglobin 50 g/L in conscious healthy res�ng humans did not produce hemodynamic instability, but oxygen imbalance was accompanied by a significant drop in mixed venous satura�on (24). These results were reinforced by a retrospec�ve analysis of a prospec�ve observa�onal study in which ScvO2 was found to be a good indicator of transfusion (25). The results of our animal study on isovolaemic haemodilu�on gave further evidence that anaemia-induced change in oxygen balance can be monitored by ScvO2 (26).

According to the above men�oned studies it seems that ScvO2 be�er iden�fies the point when compensatory mechanisms fail and oxygen delivery begins to decline, as compared to the Hb concentra�on alone. A “low” level of Hb does not necessarily lead to oxygen debt in hemodinamically stable, anesthe�zed, ven�lated pa�ents, while oxygen imbalance may occur in agitated, pyrexial pa�ents with “normal” haemoglobin level. These findings are in accord with the idea that compensatory changes in cardiac output and other parameters of oxygen delivery make haemoglobin concentra�on alone a less sensi�ve marker of oxygen balance and for the need for therapeu�c interven�on to increase DO2. ScvO2 could therefore be important in helping to avoid hypoxia and �ssue injury under such circumstances, while helping to more accurately guide blood transfusions. Therefore we believe that not only the haemoglobin level, but ScvO2 and other physiological signs of oxygen debt (confusion, angina, low diuresis, serum lactate level etc.) should be taken into account before using red blood cells in order to reduce the number of unnecessary transfusion. Protocolising transfusion and adop�ng protocols for every pa�ent is therefore difficult, because of its mul�modal features. Nevertheless, applying the above men�oned approach of including physiological indicators of oxygen debt in the decision making may help us in individualizing transfusion therapy.

ScvO2 as an indicator of hypovolaemia

A common cause for decreased cardiac output in the intensive care unit is hypovolaemia. Diagnosing hypovolaemia is an everyday challenge in cri�cal care. Although diagnosis may prove difficult, early recogni�on of hypovolaemia is of utmost importance. By the �me macro-hemodynamic changes manifest, the microcircula�on may already be damaged (3). Furthermore, on the one hand fluid resuscita�on can save lives, but on the other hand a cumula�ve posi�ve fluid balance is an independent factor for mortality (27). Up un�l now, there has been neither consensus on the most accurate hemodynamic marker of hypovolaemia, nor on the endpoints for op�mal fluid therapy (28, 29). Many recent studies have suggested that fluid therapy should be based on dynamic (such as: cardiac output, pulse pressure varia�on, stroke volume varia�on) rather than sta�c hemodynamic variables (such as: CVP, pulmonary artery occlusion pressure), because they are be�er predictors of fluid responsiveness in ICU pa�ents. However, pulse pressure varia�on and stroke volume varia�on are limited to pa�ents who are fully ven�lated and have no arrhythmias (30,31). Although it is not strictly a hemodynamic variable but in certain clinical condi�ons a ScvO2 value of 17


~70% has been used as a therapeu�c end-point to improve oxygen delivery (23). In a recent study it was found that a 4% increase in ScvO2 a�er fluid challenge had >80% sensi�vity and specificity in predic�ng volume responsiveness at the bedside in cri�cally ill pa�ents (32).

ScvO2 and major surgery

Since the two most common complica�ons in the periopera�ve se�ng are bleeding/anaemia and hypovolaemia it seems logical to assume that ScvO2 may be a good resuscita�on end-point during and a�er major surgery. In a single centre study pa�ents in the ScvO2-directed therapy group have a fewer postopera�ve complica�ons and were hospitalized for shorter periods than the pa�ents in the control group (33). In a prospec�ve, randomized, controlled trial a therapeu�c strategy designed to detect and reverse �ssue hypoxia (diagnosed by an increase of oxygen extrac�on) was used a�er major abdominal surgery. The interven�on group received therapy to maintain O2ER15 mm Hg, (28) or a 25% decrease in lead II T-wave amplitude. (29) However, elderly pa�ents are less responsive to beta s�mula�on (30) as are those on beta-blocking agents. Low cardiac output can prolong drug circula�on and delay the clinical effect of the beta mime�c, and therefore, the sensi�vity of the test. Accordingly, the interpreta�on of the test result is not always as straigh�orward as one would wish. The significant propor�on of false nega�ve test results warrants a reevalua�on of the rou�ne use of this test as a sole determinant to detect inadvertent intravenous injec�on. ● Ultrasound guidance may reduce the frequency of intravascular injec�on, but actual reduc�on of LAST remains unproven. IIa;C 32

Diagnosing LAST ● Classic descrip�on of LAST depict a progression of subjec�ve symptoms of CNS excitement (agita�on, auditory changes, metallic taste or abrupt onset of psychiatric symptoms), followed by seizures then CNS depression (drowsiness ,coma or respiratory arrest). Near the end of this con�nuum, ini�al signs of cardiac toxicity (hypertension, tachycardia, or ventricular arrhythmias) are supplanted by cardiac depression (bradycardia, conduc�on block, asystole, decreased contrac�lity). However, there is substan�al varia�on in this descrip�on including: simultaneous presenta�on of CNS and cardiac toxicity, cardiac toxicity without prodromal signs and symptoms of CNS toxicity. Thus, the prac��oner must be vigilant for atypical or unexpected presenta�on of LAST (I;B). ● The �ming of LAST presenta�on is variable. Immediate (< 60s) presenta�on suggests intravascular injec�on of local anesthe�c with direct access to the brain, whereas presenta�on that is delayed 1-5 min suggests intermi�ent intravascular injec�on or delayed �ssue absorp�on. Because LAST can present > 15 min, pa�ent that receive poten�ally toxic doses of local anesthe�c should be monitored for at least 30 min a�er injec�on. (I;B) ● Case report associate LAST with underlying cardiac, neurologic, pulmonary, renal, hepa�c or metabolic disease. Heightened vigilance may be warranted in these pa�ent, par�cularly if they are at the extremes of age. (II a; B)

Treatment Early recogni�on of the toxicity and early discon�nua�on of the administra�on is of crucial importance. The administra�on of local anesthetics should be stopped immediately. The airway should be maintained at all �mes, and supplemental oxygen is provided while ensuring that the monitoring equipment is func�onal and properly applied. Neurologic parameters and cardiovascular status should be assessed un�l the pa�ent is completely asymptoma�c and stable. ● If signs and symptoms of LAST occur, prompt and effec�ve airway management is crucial to preven�ng hypoxia and acidosis, which poten�ate LAST. (I;B) ● If seizures occur, they should be rapidly halted with benzodiazepines. If benzodiazepines are not readily available, small doses of propofol or thiopental are acceptable. (I;B) ● Propofol should be avoided when there are the signs of cardiovascular compromise, because propofol depress cardiac func�on. If seizures


persist despite benzodiazepines, small doses of succinylcholine or similar neuromuscular blocker should be considered to minimize acidosis and hypoxemia. (I; C) ● Lipid emulsion therapy (IIa; B) – consider administering at the first signs of LAST, a�er airway management – dosing: 1, 50 mL/kg 20% lipid emulsion bolus – 0,25 mL/kg per minute of infusion,con�nued for at least 10 min a�er circulatory stability is attained – If circulatory stability is not a�ained, consider rebolus and increasing infusion to 0,5 ml/kg per minute. Approximately 10ml/kg lipid emulsion for 30 min is recommended as the upper limit for ini�al dosing. Based on the recent data in animal studies, (31–33) as well as moun�ng case reports, (34–38) star�ng an infusion of lipid emulsion (intralipid), especially in those cases where symptoms of cardiac toxicity are present, should be contemplated early. (39) Importantly, there is a moun�ng consensus that infusion of intralipids may be ini�ated early, to also prevent, rather then treat cardiac arrest. If available, arrangements for transfer to an operating room where cardiopulmonary bypass can be ins�tuted should also be contemplated in situa�ons where the response to early treatment is not favorable. (40–42)2 ● If cardiac arrest occurs, we recommended standard Advanced Cardiac Life Support with the modifica�ons: – If epinephrine is used, small ini�al doses (10100µg boluses in the adult) are preferred (IIa: C) – Vasopressin is not recommended (III: B) – Avoid calcium channel blockers and β-adrenergic receptor blocker (III; C) – If ventricular arrhythmias develop, amiodarone is preferred (IIa: B): treatment with local anesthe�cs ( lidocaine or procainamide) is not recommended (III:C) ● Failure to respond to lipid emulsion and vasopressor therapy should prompt ins�tu�on of cardiopulmonary bypass. (IIa; B) Malignant arrhythmias and asystole are managed using standard cardiopulmonary resuscita�on protocols, (43,44) acknowledging that a prolonged effort may be needed to increase the chance of resuscita�on. The ra�onale of this approach is to maintain the circula�on un�l the local anesthe�c is redistributed or metabolized below the level associated with cardiovascular toxicity, at which �me spontaneous circula�on should resume. Because the contrac�le depression is core factor underlying severe cardio toxicity, it would be intui�ve to believe that the use of sympathomime�cs should be helpful.

Nonetheless, epinephrine can induce dysrhythmia or it can exacerbate the ongoing arrhythmia associated with local anesthe�c overdose. (45,46) Consequently, in the se�ng of local anesthe�c toxicity, vasopressin may be more appropriate to maintain the blood pressure, support coronary perfusion, and facilitate local anesthe�c metabolism. (47) The appropriateness of phosphodiesterase inhibitors administra�on is not corroborated by published research results. Although these inhibitors can promote hemodynamic, there is no evidence of a be�er outcome. As potent vasodilators, phosphodiesterase inhibitors do no support blood pressure, (48) and they have been associated with ventricular arrhythmias. (49) The current advanced cardiac life support algorithm emphasizes amiodarone as the mainstay drug for treatment of arrhythmias. (50) Also, for ventricular arrhythmias prompted by local anesthe�c overdose, current data favor amiodarone. Published studies of using lidocaine to treat arrhythmias reveal conflic�ng results, but it is logical to think that trea�ng local anesthe�c-induced arrhythmias with just another local anesthe�c an�arrhythmic is likely to add to the cardio toxicity. The use of bretylium is no longer endorsed. Occurrence of Torsades des Pointes with bupivacaine toxicity may require overdrive pacing if that rhythm predominates. Calcium channel blockers and phenytoin are contraindicated because their co administra�on with local anesthe�cs may increase the risk of mortality. (51) Recovery from local anesthe�c-induced cardiac arrest can take enduring resuscita�on efforts for more than an hour. Propofol is not an adequate alterna�ve for treatment with intralipid, although judicious administra�on to control seizures when used in small divided doses is appropriate. (52) Administra�on of the lipid emulsion has become an important addi�on to the treatment of severe local anesthe�c toxicity. (53) Because it is s�ll an innova�ve therapy, future laboratory and clinical experiences are needed for a be�er understanding of the mechanisms and further refinement of the treatment protocols. (54)

References 1. Neal JM, Bernards CM, Bu�erworth JF, et al. ASRA prac�ce advisory on local anesthe�c systemic toxicity. Reg. Anesth. Pain Med 2010; 35(2): 152–61. 2. Ma�son JB. Cocaine poisoning. Med Surg Rep 1891; 115: 645–50. 3. Auroy Y, Benhamou D, Burgues L, et al. Major complica�on of regional anesthesia in France. The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97: 1274–80.

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Sixth Annual Spring Scien�fic Symposium in Anesthesiology and Intensive Care, April 25-27, 2014, Niš, Serbia 4. Goldfrank LR, Folmenbaum NE, Lewin NA, et al.15071517. In Goldfrank´s Toxicologic Emergencies 6th ed. New York: McGraw Hill; 1998: 897–903. 5. Sco� DB. Toxic effects of local anesthe�c agents on the central nervous system. Br J Anesth 1986; 58: 732–5. 6. Sco� DB. Evalua�on of toxicity of local anesthe�c agents in man. Br J Anaesth 1975; 47: 56–61. 7. Mather LE, Tucker GT, Murphy TM. Cardiovascular and subjec�ve central nervous system effects of long ac�ng local anesthe�c in man. Anaesth Intensive Care 1979; 7: 215–21. 8. Sco� DB. Evalua�on of clinical tolerance of local anesthe�c agents . Br J Anaesth 1975; 47 Suppl: 328–31. 9. Ru�en AJ, Nancarow C, Mather LE et al. Hemodynamic and central nervous system effects of intravenous bolus doses of lidocaine, bupivacaine and ropivacaine in sheep. Anaesth Analg 1989; 69: 291–99. 10. Huang YF, Pryor ME, Mather LE, et al.Cardiovascular and central nervous system effects of bupivacaine and levobupivacaine in shepp. Anaesth Analg 1998: 86: 797– 804. 11. Feldman HS, Arthur GR, Covino BG. Compara�ve systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine and lidocaine in the conscious dog. Anaesth Analg 1989; 69: 794–801. 12. Liu P, Feldman H, Giassi R, et al. Compara�ve CNS toxicity of lidocaine, e�docaine, bupivacaine end tetracaine in awake dogs following rapid administra�on. Anaesth Analg 1983; 62: 375–9. 13. Reiz S, Nath S. Cardiotoxicity of local anesthe�c agents. Br J Anaesth 1986; 58: 736–46. 14. Hogan Q. Local anesthe�c toxicity un update.Reg. Anesth 1996;21:43–50. 15. Feldman HS, Covino BM, Sage DJ. Direct chronotropic and inotropic effects of local anesthe�c agents in isolated guinea pig atria. Reg Anesth 1982; 7: 149–56. 16. Lynch C. Depression of myocardial contrac�lity in vitro by bupivacaine, e�docaine, and lidocaine. Anesth Analg. 1986; 65: 551–9. 17. Block A, Covino B. Effect of local anesthe�c agents on cardiac conduc�on and contrac�lity. Reg Anesth 1982; 6: 55–61. 18. Stewart D, Rogers W, et al. Effects of local anesthe�c on the cardiovascular system in the dog. Anaesthesilogy 1968; 24: 620–4. 19. Tanz RD, Heske� T, et al. Compara�ve cardio toxicity of bupivacaine and lidocaine in the isolated perfused mammalian heart. Anesth Analg 1984; 63: 549–56. 20. Pitkanen M, Feldman HS, Authur GR, Covino BG. Chronotropic and inotropic effects of ropivacaine, bupivacaine and lidocaine in the spontaneously bea�ng and electrically paced isolated, perfused rabbit heart. Reg Anesth Pain Med 1992; 17: 183–92. 21. Englesson S. The influence of acid- base changes on central nervous system toxicity of local anaesthe�c agents.An experimental study in cats. Acta Anaesth Scand 1974; 18: 79–83. 22. Burney R, DiFazio C, Foster J. Effects of pH on protein binding of lidocaine. Anesth Analg 1978; 57: 478–80. 23. de Jong RH, Heavner JE. Diazepam prevents local anaesthe�c seizures. Anaesthesiology 1971; 34: 523–31. 24. de Jong RH, Heavner JE. Diazepam preventes and aborts lidocaine convulsiones in monkeys. Aneaesthesiology 1974; 41: 226–31.

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25. de Jong RH, Bonin JD. Benzodiazepines protect mice from local anaesthe�c convulsiones and deaths. Anest Analg 1981; 60: 385–9. 26. Ausinsch B, Malagodi MH, Munson S. Diazepam in the profilaksis of lignocaine seizures. Br J Anaesth 1776; 48: 309–13. 27. Liquori G, Chimento GF, Borow L. Possible bupivacaine toxicity a�er intraar�cular injec�on for postarthroscopy analgesia of the knee. Anesth Analg 2002; 94: 1010–13. 28. Kanh RI, Quin TJ. Blood pressure, not heart rate, as a marker of intravascular injec�on of epinephrine in an epidural test dose. Reg Anesth 1991; 16: 292–5. 29. Tanaka M, Nishikawa T. A compara�ve study of hemodynamic and T-wave criteria for detec�ng intravascular injec�on of the test dose (epinephrine) in sevoflurane anesthized adults. Anesth Analg 1999; 16: 292–5. 30. Schoenwald PK, Whalley DG, et al. The hemodynamic responses to an intravenous test dose in vascular pa�ents. Anesth Analg 1995; 80: 32–6. 31. Weinberg G, VadeBoncouer T. et al. Pretreatment or resuscita�on with a lipid infusion shi�s the dose response bupivacaine induced asystole in rats. Anaesthesiology 1998; 88: 1071–5. 32. Weinberg G, Ripper R, Feinstein D, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine induced cardiac toxicity. Reg Anesth Pain Med 2003; 8: 198–202. 33. Weinberg G, Di Gregorio G, Ripper R, et al. Resuscita�on with lipid versus epinephrine in a rat model of bupivacane overdose. Anaesthesiology 2008; 108: 907–13. 34. Rosenbla� M, Abel M, Fisher G, et al. Successfull use of a 20% lipid emulsion to resuscitate a pa�ent a�er a pressumed bupivacaine related cardiac arest. Anaesthesiology 2006; 105: 217–8. 35. Litz R, Popp M, Stehr S, Koch T. Successfull resuscita�on of a pa�ent with ropivacaine induced asystole a�er axillary plexus block using lipid infusion. Anaesthesia 2006; 61: 800–1. 36. McCuthcen T, Gerancher J. Early Intralipid may have prevented bupivacaine associated cardiac arrest. Reg Anaesth Pain Med 2008; 33: 178–80. 37. Foxall G, McCahon R, Lamb J, Bedforth N. Levobupivacaine induced seizures and cardiovascular collapse treated with intralipid. Anaesthesia 2007; 62: 516–8. 38. Whiteside J. Reversal of local anaesthe�c induced CNS toxicity with lipid emulsion. Anaesthesia 2008; 63; 203–4. 39. Warren JA, Thoma RB, Georgescu A, Shah SJ. Intravenous lipid emulsion in the successful resuscita�on of local anaesthe�c induced cardiovascular collapse a�er supraclavicular brachial plexus block. Anesth Analg 2008; 106; 1578–80. 40. Tsai MH, Tseng CK, Wong KC. Successful resuscita�on og a bupivacaine induced cardiac arrest using cardiopulmonary bypass and mitral valve replacement. J Cardiothorac Anesth 1987; 1: 454–6. 41. Long WB, Rosenblum S, Grady JP. Successful resuscita�on of bupivacaine induced cardiac arrest using cardiopulmonary bypass. Anesth Analg 1989; 69: 403–6. 42. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity.J Cardiothorac. Anesth 2003; 17: 357–8. 43. Chazalon P, Tour�er JP, Villevieille T, et al. Ropivacaine induced cardiac arrest a�er peripheral nerve block: successful resuscita�on. Anesthesiology 2003; 99: 1449–51.

Sixth Annual Spring Scien�fic Symposium in Anesthesiology and Intensive Care, April 25-27, 2014, Niš, Serbia 44. Huet O, Eyrolle LJ, et al. Cardiac arrest and plasma concentra�on a�er injec�on of ropivacaine for posterior lumbal plexus blockade. Anesthesiology 2003; 99: 1451–3. 45. Heavner JE, Pitkanen MT, Shi B, Rosenberg PH. Resuscita�on from bupivacaine induced asystole in rats: comparison of different cardioac�ve drugs. Anesth Analg 1995; 80: 1134–9. 46. Bernards CM, Carpenter RI, Kenter ME, Brown DL. Effects of epinephrine on central nervous system and cardiovascular system toxicity of bupivacaine in pigs. Anesthesiology 1989; 71: 711–7. 47. Krismer AC, Hogan QH, Wenzel V, et al. The efficasy of epinephrine or vasopressin for resusscitaion during epidural anaesthesia. Anesth Analg 2001; 93: 734–42. 48. Arnold JM. The role of phosphodiesterase inhibitors in heart failure. Pharmacol Ther 1993; 57: 161–70. 49. Nolan JP, Deakin C, Scar J, Bo�ger BW, Smith G. Europe resuscita�on Council Guidelines for resuscita�on 2005

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51. 52. 53. 54.

Sec�on 4.Adult advanced life support. Resuscita�on 2005; 67S1: 539–86. 2005 American heart Associa�on Gidelines for Cardiopulmonary Resuscita�on and Emergency Cardiovascular Care. Part 7.3: Menagement of Symptoma�c Bradycardia and Tachycardia. Circula�on2005; 112:IV: 67–77. Tallman RD Jr, Rosenbla� RM, Weaver JM, Wang YL. Verapamil increased the toxicity of local anaesthe�cs.J Clin Pharmacol 1988; 28: 317–21. Heavner JE, Arthur J, Zou J, et al. Comparrison of propofol with thiopentone for treatment of bupivacaine induced seizures in rats. Br J Anaesth 1993; 71: 715–19. Weinberg GL. Lipid infusion therapy;transla�on to clinical prac�se. Anesth Analg 2008; 5: 1340–2. Cave G, Harvey M. Intravenous lipid emulsion as an�dote beyond local anesthe�c toxicity: a systema�c review. Acad Emerg Med 2009; 16: 815–24.

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TREATMENT OF HYPERTENSION IN PREGNANCY Vesna D. Garovic

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Introduc�on There are many factors to consider when contempla�ng the treatment of hypertension during pregnancy. These encompass maternal factors, including dura�on and severity of hypertension, and presence of end-organ damage, as well as fetal factors, such as safety of blood pressure medica�ons and the poten�al for compromised uteroplacental and fetal circula�on due to overzealous blood pressure control. The first decision regarding drug therapy is whether to ins�tute it at all. For purposes of treatment, it is useful to divide hypertension during pregnancy into two general categories. The first includes the acute hypertensive syndromes of preeclampsia/eclampsia/HELLP syndrome, which carry a high risk for maternal and fetal morbidity and mortality. The most important reason for the ini�a�on of an�hypertensive treatment in these pa�ents is to prevent maternal cerebrovascular and cardiac complica�ons. While hypertension in these se�ngs can be treated medically, the defini�ve treatment remains delivery. The second general category is chronic hypertension. Ideally, these women should be evaluated before pregnancy for target organ damage, such as le� ventricular hypertrophy, hypertensive nephropathy and re�nopathy, which will help establish blood pressure treatment goals. Pa�ents with clinical clues sugges�ve of secondary hypertension (e.g., hardto-control hypertension requiring more than three an�hypertensive agents, and/or indica�ve laboratory and clinical findings) should undergo a work up for secondary hypertension (primary hyperaldosteronism, pheochromocytoma, and renal artery stenosis). Therefore, pre-pregnancy counseling of women with chronic hypertension may require exper�se outside the realm of obstetrics. Some forms of secondary hypertension, and par�cularly pheochromocytoma and renovascular hypertension, may further increase the risk for adverse pregnancy outcomes beyond that of essen�al hypertension; thus, surgery (for pheochromocytoma) or revasculariza�on (for renal artery stenosis) should be considered before pregnancy. In this popula�on of young women of 36

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childbearing age, these interven�ons may result in cure of hypertension. Pre-pregnancy evalua�on further should address changes in medica�ons to those that have acceptable safety profiles in pregnancy, and counseling related to pregnancy risks. It is es�mated that as many as 25% of women with chronic hypertension may develop superimposed preeclampsia. These women are at a par�cular high risk for cerebral hemorrhage and placental abrup�on. It remains unclear whether early treatment of chronic hypertension in pregnancy prevents preeclampsia. In the absence of randomized prospec�ve trials adequately powered to address this important clinical ques�on, prac�cing physicians should treat chronically hypertensive women according to currently accepted na�onal guidelines, which are presented and discussed below. The treatment of gesta�onal hypertension, i.e., hypertension that occurs for the first �me in the second half of pregnancy, depends on whether proteinuria subsequently develops. In the absence of proteinuria, blood pressure either returns to normal by 12 weeks’ postpartum (transient hypertension) or fails to normalize, leading to the diagnosis of chronic hypertension. Women with gesta�onal hypertension who subsequently develop proteinuria are then considered to have developed preeclampsia and are treated accordingly.

Pregnancy and blood pressure measurement The diagnosis of hypertension during pregnancy requires accurate measurements of both the systolic and diastolic pressure. Ideally, this requires manual blood pressure measurements. Many automated machines have not been tested for use during pregnancy and therefore may return unpredictable readings. The manual blood pressure is the best approach, using Korotkoff phase V (disappearance) rather than Korotkoff phase IV (muffling of sounds) to determine the diastolic pressure. In the clinical se�ng, blood pressure should be measured in the si�ng posi�on. In recumbent hospitalized pa�ents, care


must be taken to measure the blood pressure in the le� lateral decubitus posi�on to abrogate the blood pressure change caused by the compression of the inferior vena cava by the gravid uterus. In all cases, the arm in which blood pressure is being measured should be maintained at the level of the heart to avoid spuriously low readings from eleva�on of the arm. Hypertension is diagnosed with a systolic pressure ≥ 140 mm Hg and/or a diastolic pressure ≥ 90 mm Hg.

Ini�a�on of therapy and treatment goals Hypertension in preeclamp�c pa�ents Most experts agree that therapy should be ini�ated for blood pressures of ≥160/110 mm Hg in order to decrease the incidence of maternal cardiac and cerebral events. It is common clinical prac�ce to ini�ate treatment as the diastolic blood pressure approaches 100 mm Hg. The medica�ons most commonly used for urgent control of hypertension include intravenous hydralazine

and labetalol. Oral agents may be considered if delivery is not expected within the next 48 hours. Medica�ons that may be used are discussed below, while their safety profiles and dosing schedules are summarized in Table 1 and Table 2, respec�vely. Control of blood pressure does not cure preeclampsia or prevent progression of preeclampsia: eclamp�c seizures can occur when the blood pressure is only mildly elevated. Therefore, in addi�on to an�hypertensive therapy, preeclamp�c pa�ents should receive seizure prophylaxis with intravenous magnesium sulfate that should be con�nued during labor and delivery, and for at least 24 hours a�er delivery. As magnesium is renally excreted, the rate of con�nuous infusion, but not the loading dose, should be adjusted, i.e., decreased in women with renal failure. Serum magnesium levels should also be checked more frequently (every 1-2 hours) in these women compared to women with normal renal func�on (every 4-6 hours). Non-pharmacological treatment should include bed rest, which has been demonstrated to promote diuresis, lower blood pressure, and reduce premature labor.

Table 1. Classes and specific medica�ons useful for hypertension in pregnancy Central agents Preferred Alterna�ve Beta blockers Preferred

Benefits

Risks

Methyldopa Clonidine

Proven safety and efficacy Efficacy similar to methyldopa

Neuro-depressant side effects Unproven safety

Labetalol

Safety and efficacy similar to methyldopa. May be used for hypertensive urgency. None compared to Labetalol

Fetal bradycardia, neonatal hypoglycemia, decreased uteroplacental flow Intrauterine growth retarda�on

Lowers blood pressure without affec�ng umbilical artery flow Similar efficacy to other oral agents

Fetal distress, profound hypotension with magnesium Untested safety profile, risk of interac�on with magnesium

Contraindicated Atenolol Calcium channel blockers Preferred Nifedipine Alterna�ve

Verapamil

Direct vasodilators Preferred Hydralazine Alterna�ve Diure�cs Preferred Contraindicated

Nitroprusside

Most efficacious oral agent

Maternal neuropathy, drug-induced lupus, neonatal thrombocytopenia and lupus Effec�ve in severe hypertension Cyanide and thiocyanate toxicity

Useful in chronic HTN, renal failure, CHF Spironolactone None Thiazide

Volume contrac�on, electrolyte abnormali�es Possible fetal an�androgen effects

Table 2. Specific management of acute and chronic hypertension during pregnancy Indica�on Specific drug Urgent blood Labetalol pressure control Hydralazine

Dose 20 to 80 mg IV every 10 minutes, maximum of 220 mg 5 to 10 mg IV or IM every 20 minutes, if no success by 30 mg total, consider alterna�ves Chronic blood Methyldopa Ini�al 250 mg oral TID, max 3000 mg daily 100 mg oral BID, �trate to 600 mg BID pressure control Labetalol Hydralazine Ini�ate 10 mg QID, �trate to 50 mg QID, maximum of 300 mg Hydrochlorothiazide 12.5 to 25 mg orally daily Nifedipine ER Ini�al 30 to 60 mg oral daily, max 120 mg daily 37


Salt restric�on is not rou�nely recommended for women with preeclampsia who frequently are volume-contracted; it may be advisable for women with histories of chronic hypertension who followed a low sodium diet before pregnancy.

Chronic hypertension in pregnancy For women with chronic hypertension, medica�ons prescribed before pregnancy can be con�nued during pregnancy, except angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and atenolol (for a detailed discussion, see below). For pregnant pa�ents with chronic hypertension, but on no treatment, therapy is usually ins�tuted for a systolic pressure ≥ 150 mm Hg and/ or diastolic blood pressure ≥ 100 mm Hg. Treatment thresholds are higher for pregnant than for non-pregnant pa�ents due to a lack of studies to support the benefit of treatment for mild diastolic hypertension (90-99 mm Hg), and concerns with respect to fetal safety, as treatment induced blood pressure drops were shown to be associated with impaired fetal growth in a meta-analysis of published studies. An excep�on is made in women with evidence of end-organ damage: in the presence of renal disease, proteinuria, le� ventricular hypertrophy and re�nopathy, an�hypertensive therapy is ini�ated for a diastolic blood pressure ≥ 90 mm Hg.

Timing of delivery The decision to proceed with delivery can be made only a�er a careful assessment of risks to fetus and mother. Considera�on should be given to postponing delivery in pregnancies affected by preeclampsia before 32 weeks’ gesta�on, since the fetus is s�ll immature and may suffer profound consequences due to incomplete respiratory development. This approach is only reasonable in cases where the maternal risk is rela�vely low, such as in mild hypertension without evidence of hepa�c or cerebral involvement. Outpa�ent management can be considered for mild preeclampsia: an asymptoma�c pa�ent with treatment-responsive hypertension in the absence of marked proteinuria (50% of these deaths occurring within 24 hours of delivery. Other morbidity results from coagulopathy, shock, adult respiratory distress syndrome, loss of fer�lity, and pituitary necrosis. (7) Uterine atony The ini�al treatment of uterine atony is medical. Fluid resuscita�on is aimed at restora�on of blood volume because an atonic uterus can lose up to 2 L of blood in 5 minutes. This degree of blood loss occurs because approximately 15% of the cardiac output perfuses the uterus at term. Oxytocin is an effec�ve first-line treatment for postpartum hemorrhage. When oxytocin fails, ergot alkaloids are commonly used as a second42

line treatment. Ergot alkaloids enhance uterine contrac�lity and cause vasoconstric�on. Analgesia or anesthesia is o�en necessary in cases of retained placenta because the obstetrician must explore a uterus that is o�en par�ally contracted. The choice of anesthe�c technique depends largely on the degree of hemorrhage. In some pa�ents who have not received a neuraxial block before delivery, IV analgesia with ketamine (0.1 mg per kg), benzodiazepines, and judicious administra�on of opioids (e.g., fentanyl) may be adequate. Spinal anesthesia is a reasonable choice for pa�ents who are hemodynamically stable with li�le evidence of hemorrhage. However in pa�ents with profound hemorrhage, GA is a be�er choice because of the risk of hypotension resul�ng from sympathe�c blockade in a pa�ent with hypovolemia who has just received spinal anesthesia. Placenta accreta The role of experienced anesthesiology personnal who are skilled in obstetric anesthesia cannot be overemphasized, and they should be involved in preopera�ve assessment of the pa�ent. In cases of unexpected placenta accreta during elec�ve CS, GA is o�en necessary to protect the pa�ent’s airway. In all cases of placenta accreta, the anesthesiologist should be prepared for massive hemorrhage with adequate IV access and large amounts of crystalloid, colloid, and blood products. In pa�ents who are hemodynamically stable and euvolemic but are at risk for placenta accreta and hysterectomy, a con�nuous catheter neuraxial technique has been shown to be a reasonable op�on. (8) Uterine inversion Management of uterine inversion has two important components: the immediate treatment of hemorrhagic shock and replacement of the uterus. Resuscita�on should begin immediately while a�empts are made to replace the uterus manually because hypotension and bradycardia may occur.

Management of obstetric hemorrhage

Basic understanding The ini�al assessment of the pa�ent with blood loss requires only basic clinical evalua�ons. Monitoring of BP, pulse, capillary refill, mental status, and urinary output is sufficient to judge the amount and the rate of blood loss and to plan therapy. Scrupulous a�en�on to these indices is important because visual es�mates of obstetric blood loss are notoriously unreliable, and the failure to recognize early signs of hypovolemia


can lead to irretrievable complica�ons. Pregnant pa�ents tolerate blood loss of up to 15% of their blood volume (~1 L in a 70-kg woman at term) without symptoms or altera�ons in vital signs. When blood loss exceeds approximately 1,500 ml, hemodynamic changes (e.g., tachycardia, hypotension) begin to occur. (9) Transfusion in obstetric hemorrhage The ASA Prac�ce Guidelines for Obstetric Anesthesia state that a rou�ne blood cross match is not necessary for vaginal or opera�ve delivery. The decision whether to order or require a blood type and screen, or cross match, should be based on maternal history, an�cipated hemorrhagic complica�ons and local ins�tu�onal policies. Transfusion thresholds/when to transfuse Determining the point when a parturient should be transfused is o�en difficult because blood loss during and a�er delivery is o�en underes�mated. In these situa�ons, blood loss arises from several areas and amnio�c fluid is also present. Vital signs, ongoing hemorrhage as well as coexis�ng disease should be considered. Signs and symptoms of inadequate perfusion resul�ng from hypovolemia include tachycardia, decreased pulse pressure, tachypnea, decreased urine output, and altered mental status. Although the physiologic changes of pregnancy help mi�gate the parturient’s response to hemorrhage and vital signs may not change un�l > 1,500 mL of blood loss has occurred, pa�ents should be transfused when there are signs of significant hypoperfusion. The purpose of PRBC administra�on is to increase the O2 carrying capacity of blood. In the past, the goal of transfusion therapy was a hemoglobin concentra�on of 10 mg per dL. Recently this threshold was challenged by a study reporting decreased mortality rates in cri�cally ill pa�ents who were transfused at lower thresholds (1 mcg/kg administered over 30-60 seconds or an infusion at a rate greater than 0.1 mcg/kg/min. Seda�on has also been reported during remifentanil analgesia, but it is rarely excessive. Nausea and vomi�ng are side effects of opioid analgesia. The incidence reported with remifentanil varied 0-60% (14).

Fetal and neonatal side effects Most studies of fetal and neonatal side effects of maternal systemic opioid analgesia have focused on meperidine since it has been used for several decades. Detrimental effects may last 72h or more a�er delivery and are a�ributed principally to accumula�on of normeperidine. However, remifentanil has been found to produce more reliable analgesia and usually be�er Apgar and neurobehavioural scores than with meperidine. Despite these apparent advantages, close monitoring of maternal and neonatal respira�on is recommended with remifentanil, but not as yet with meperidine (15).

Remifentanil and Caesarean delivery Remifentanil is effec�ve at obtunding responses to airway manipula�on and surgery under gen48

eral anaesthesia. Neonatal effects are more pronounced and 50% of neonates may need assisted ven�la�on, and occasionally naloxone. Studies are needed to establish a dose range under general anaesthesia that prevents neonatal respiratory depression at birth.

Conclusion Sa�sfactory analgesia is of paramount importance in labor. Although neuraxial block provides excellent analgesia, systemic analgesia is useful for parturients in whom neuraxial analgesia is contraindicated, refused or when skilled anesthesia providers are not available. Modest labour analgesia, par�cularly for the first stage, can be achieved using a pa�ent-controlled analgesia bolus of 40 µg of remifentanil with a 2min lockout interval. Neonatal effects are minimal with this regime. However, maternal desatura�on is a possibility and requires one-to-one supervision and appropriate monitoring. Background infusions can improve analgesia, but maternal desatura�on or even apnoea is more likely. Further studies are needed to confirm if background infusions are safe in addi�on to pa�ent-controlled analgesia.

References 1. Jones L, Othman M, Dowswell T, Alfirevic Z, Gates S.et al. Pain management for women in labour: an overview of systema�c reviews. Cochrane Database Syst Rev 2012; 3: CD009234. doi: 10.1002/14651858.CD009234.pub2. 2. Ismail MT, Hassanin MZ. Neuraxial analgesia versus intravenous remifentanil for pain relief in early labor in nulliparous women. Arch Gynecol Obstet 2012; 286(6): 1375-81. doi: 10.1007/s00404-012-2459-3 3. Anim-Somuah M, Smyth R, Howell C. Epidural versus non-epidural or no analgesia in labour. Cochrane Database Syst Rev 2005; (4):CD000331. 4. Ullman R, Smith LA, Burns E, Mori R, Dowswell T. Parenteral opioids for maternal pain management in labour. Cochrane Database Syst Rev 2011; 10: CD007396. 5. Lavand'homme P, Roelants F. Pa�ent-controlled intravenous analgesia as an alterna�ve to epidural analgesia during labor: ques�oning the use of the short-ac�ng opioid remifentanil. Survey in the French part of Belgium (Wallonia and Brussels). Acta Anaesthesiol Belg 2009; 60(2): 75–82. 6. Roelants F, De Franceschi E, Veyckemans F, Lavand'homme P. Pa�ent-controlled intravenous analgesia using remifentanil in the parturient. Can J Anaesth 2001; 48(2): 175-8. 7. Hinova A, Fernando R. Systemic remifentanil for labor analgesia. Anesth Analg 2009; 109(6): 1925–9. 8. Douma M, Verwey RA, Kam-Endtz CE, van der Linden PD, S�enstra R. Obstetric analgesia: a comparison of pa�entcontrolled meperidine, remifentanil, and fentanyl in labour. Br J Anaesth 2010; 104(2): 209–15. 9. Leong WL, Sng BL, Sia AT. A comparison between remifentanil and meperidine for labor analgesia: a systema�c review. Anesth Analg 2011; 113(4): 818-25. doi: 10.1213/ANE. 0b013e3182289fe9.

Sixth Annual Spring Scien�fic Symposium in Anesthesiology and Intensive Care, April 25-27, 2014, Niš, Serbia 10. Balki M, Kasodekar S, Dhumne S, Bernstein P, Carvalho JC. Remifentanil pa�ent-controlled analgesia for labor: op�mizing drug delivery regimens. Can J Anesth 2007; 54: 626–33. 11. Volmanen P, Sarvela J, Akural EI, Raudaskoski T, Kor�la K, Alahuhta S. Intravenous remifentanil vs. epidural levobupivacaine with fentanyl for pain relief in early labor: a randomised, controlled, double-blinded study. Acta Anaesthesiol Scand 2008; 52: 249–55. 12. Schnabel A, Hahn N, Broscheit J, Muellenbach RM et al. Remifentanil for labour analgesia: a meta-analysis of randomised controlled trials. Eur J Anaesthesiol. 2012; 29(4): 177-85. doi: 10.1097/EJA.0b013e32834fc260.

13. Kranke P, Girard T, Lavand'homme P, Melber A. et al. Must we press on un�l a young mother dies? Remifentanil pa�ent controlled analgesia in labour may not be suited as a "poor man's epidural". BMC Pregnancy Childbirth. 2013;13: 139. doi: 10.1186/1471-2393-13-139. 14. Evron S, Glezerman M, Sadan O, Boaz M, Ezri T. Remifentanil: A novel systemic analgesic for labor pain. Anesth Analg 2005; 100: 233–8. 15. Volikas I, Butwick A, Wilkinson C, Pleming A, Nicholson G. Maternal and neonatal side-effects of remifentanil pa�ent controlled analgesia in labor. Br J Anaesth 2005; 95: 504–9.

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STATE OF THE ART LABOR ANALGESIA Ivan Veličković

Obstetrical Anesthesiology, SUNY Downstate Medical Centre, Brooklyn NY, USA

Epidural anesthesia has been prac�ced for several decades and s�ll it remains difficult to find two prac��oners that will u�lize the same technique. The reasons why such differences exist are as follows: the advancements in epidural anesthesia have come from various parts of the world, there are numerous types of medica�ons and equipment, and the goals that are trying to be achieved vary amongst prac��oners. This ar�cle discusses the author’s preferences in performing labor epidural/combined spinal epidural for labor analgesia. The ini�al goal for placement of medica�on via an epidural was to provide surgical anesthesia, both a sensory and a motor block. However, since a motor block is not necessary for labor analgesia, the goal is to mainly provide analgesia for labor. In terms of needle placement in the epidural space, there should be no differences whether the goal is to provide surgical anesthesia or labor analgesia. However, what vary are the concentra�ons, dosages, and volumes of medica�on administered. The author has performed over 10, 000 neuroaxial anesthe�cs over past 16 years in USA and less than 50 in Serbia. While in Serbia, the author’s Serbian colleagues had numerous ques�ons about the epidural technique that is used in USA. This ar�cle will be an a�empt to answer most, if not all of their ques�ons. The author emphasizes both the differences and similari�es in epidural/combined spinal epidural techniques and what can be learned from each other.

Pa�ent posi�oning The vast majority of epidurals in USA are performed in a si�ng posi�on. The following argument can be made when there are two or more ways to perform the same procedure; “it is easier if you do it my way”. However, from a pa�ent safety perspec�ve, advocates of the lateral posi�on are arguing that it is more comfortable for the pa�ent to lie on her side, especially if it takes a substan�al amount of �me to complete the epidural. Also, the baby may not tolerate when the 50

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mother is in the si�ng posi�on for a long period of �me. The author performs 99.99% of his procedures in a si�ng posi�on and argues that the lateral posi�on causes the pa�ent to bend either toward or away from the physician, which adds another dimension of difficulty during placement and has the poten�al to significantly complicate the procedure. Another very important part of the procedure is making sure the pa�ent understands exactly what the prac��oner is asking. For example, the author con�nuously ques�ons the pa�ent about the loca�on of their pain by asking, “do you feel the needle on the right side of your body or the le�?” in order to determine where their midline is located. From the author’s experience it is more difficult to understand this ques�on if pa�ent is in lateral posi�on vs. the sit�ng posi�on. The author also believes that while the pa�ent is in the lateral posi�on the following ques�on should be asked, “is the needle more toward the upper side of your body or the lower?” as asking right vs. le� may be too confusing. Author’s preference: si�ng posi�on

Sterile drape Clear, see-through sterile drapes have been available in USA since the late nine�es. Although, the author has experience with the blue, nontransparent drape in the beginning of his career, he has a strong preference towards the clear drape. The author believes it is essen�al to be able to look at the pa�ent’s hips and shoulders in order to determine where the pa�ent’s midline is located as well as to see if the epidural needle is at the correct angle (le� or right) of. In the absence of the clear drape, the author prefers to use a drape that covers only the first couple of cen�meters of the pa�ent lower back. The author also prefers wide margins when cleaning the pa�ent's back. Author's preference: Clear, see-through drape


Anesthe�zing the skin before epidural placement The majority of anesthesiologist in the USA use 2-3 ml of 1% lidocaine to anesthe�ze both the skin and subcutaneous �ssue before epidural placement. The author prefers to use a 25 G, 4 mm needle for the injec�on of lidocaine. He believes the rela�vely long needle has the added advantage of being able to “probe” for the bone. In some pa�ents, the spinous processes can be felt with the “lidocaine” needle. If the needle contacts the bone, the author sugges�on is to withdraw it and redirect either upwards or downwards un�l the inter-spinous space is found. When the �me comes for the placement of the epidural needle, it should follow the same pathway of the previous "lidocaine" needle. In order to avoid the complica�ons of a needle s�ck, the author suggests that the provider never holds one of their fingers on the pa�ent‘s back while simultaneously anesthe�zing the skin with the needle. Every finger should always be behind the �p of the needle, no ma�er if the needle is 25 G skin needle or an epidural needle. In the case of an accidental needle s�ck in a pa�ent with an unknown HIV status, all health care workers in USA are placed on an� HIV therapy un�l results of HIV tes�ng of the pa�ent are known. Author's preference: 3 ml of lidocaine before epidural placement

Size of the epidural needle Epidural needles in the USA are either 17 G or 18 G in diameter and may vary in length, with the most common length being 100mm. The 17 G needles are used for placement of 19 G epidural catheters. The 18 G needles are used for placement of 20 G epidural catheters. The author has no�ced no difference between the two types of needles in terms of ease of iden�fica�on of the epidural space. Some limited data exists that suggests 18 G needles result in less post dural puncture headaches when compared to 16 G epidural needles. The author has successfully performed epidural placement for several morbidly obese pa�ents weighing between 400-450 Lbs (180-205 kilograms) with a regular 100 mm epidural needle. The author does not recommend extra long needles for Serbian physicians, as the pa�ent popula�on in Serbia weighs far less than in the USA. A common reason why the needle may seem it is advanced too far or feel too short, is simply because the needle is off midline. When the needle is off midline the pa�ent will usually complain of pain on one side of her body. Author's preference: Author prefers 18 G, 100 mm Tuohy epidural needles.

Saline versus air for iden�fica�on of the epidural space Many review ar�cles have been wri�en on this topic and can easily be found online. US physicians are divided 50:50 when comparing air vs. saline. Advocates for saline argue that pneumocephalus is impossible if saline is used for the iden�fica�on of the epidural space and that the damage of the spinal cord may be less if saline is injected into spinal cord vs. air. They also argue that air can form a “pocket” in the epidural space that will prevent equal spread of the local anesthe�c and increase the chance of failure of the epidural block. Advocates for air argue; if air is used to iden�fy the epidural space, a pneumocephalus can only occur if air is injected into the intrathecal space. If a case arises where a dural puncture with 18 G needle occurs, CSF (cerebro spinal fluid) would be seen and this should prevent the provider from injec�ng air intrathecally and causing a pneumocephalus. Another advantage of using air to iden�fy the epidural space is that any fluid coming from the epidural needle can easily be iden�fied as CSF. Even minimal damage of dura can therefore be detected. A final advantage of using air is the ability to perform a “gravity test”. For example, a�er placement of the epidural catheter into the epidural space, the open end of the epidural catheter can be held below the level of inser�on and any fluid coming out of it can easily be iden�fied as a CSF. If saline is used to iden�fy the epidural space and a “gravity test” is performed, fluid coming out of the epidural catheter could be either saline or CSF. To summarize, using air to iden�fy epidural space will give us a chance to easily exclude intrathecal placement of epidural catheter by use of a "gravity test". Author's preference: air

Epidural versus Combined spinal epidural (CSE) Some US physicians exclusively use an epidural technique for labor analgesia, some prefer either an epidural or a CSE, while others perform only the CSE technique. Advocates for the epidural technique argue that the only way to confirm that the epidural catheter is in the epidural space is to bolus the catheter and wait for the block to develop. If a successful block develops with an epidural dose of medica�on then the catheter is definitely in the epidural space. However, advocates for the CSE technique would argue that pure epidurals, in the lumbar space, are a thing of the past for a mul�tude of reasons. 51


First they would argue that the rate of failure for a CSE is less than 5%, while the rate of failure for epidurals may be up to 30%. The higher rate of success is mainly because a spinal needle is used to iden�fy the intrathecal space, which is in the midline. For example, the intrathecal space is only 2 cm in diameter; therefore a�er successful placement of the catheter through the epidural needle, the epidural catheter must be within 1 cm from a midline. This is also one of the reasons why CSEs have less of an incidence of a unilateral block. A second reason to argue for a CSE is because the incidence of an uninten�onal dural puncture is also less. For example, if the provider encounters a ques�onable loss of resistance, the spinal needle can be used to confirm the space. If fluid is flowing from the spinal needle, the epidural needle is likely in the epidural space. However, if fluid isn't flowing from the spinal needle, then the epidural needle can be advanced another 711 mm without danger of accidentally puncturing dura. A third reason one would argue for a CSE is speed of block onset, 2-3 minutes vs 10-20 minutes for pure epidurals. A final reason to advocate for a CSE is because it provides be�er analgesia with far less medica�on leading to fewer complica�ons. For example, if an epidural catheter is accidentally placed intrathecally and an epidural dose of medica�on is given, total spinal can develop. This is simply not possible with CSE technique due to amount of medica�on that is used. Author's preference: CSE

Dosing of epidural catheter Although most physicians administer a dose that they have both experience and feel comfortable with, some recommenda�ons can be given. Boluses of fentanyl (50-100 mcg) should be avoided because of its potent analgesic proper�es. For example it will be difficult to differen�ate whether a catheter is in the epidural space or in a blood vessel since the pa�ent will not feel pain in either situa�on. Bupivacaine, levobupivacaine and ropivacaine will all have similar effects as fentanyl if catheter is in the epidural space. The concentra�on of the drug rather than the type of drug administered will actually have more of an impact on the speed of the block. For example, the higher the concentra�on used, the faster the onset. For ini�al dosing, the author recommends using smaller concentra�ons such as 0.1%, 0.2%, 0.25% of the above men�oned local anesthe�cs with or without small doses of fentanyl. However, when lower concentra�ons of the drug are administered, higher volumes need to be given. For instance, when using bupivacaine 0.1%, up to 20 ml should be administered or if bupiva52

caine 0.25% is used, up to 10 ml should be given. The ini�al amount should always be administered in divided doses up to 5 ml per �me and given in intervals of 5 minutes between doses. Otherwise, rare but fatal complica�ons such as total spinal anesthesia and local anesthe�c toxicity (cardiovascular collapse) can occur. These complica�ons are consequences of the epidural catheter being misplaced into either the spinal space or a blood vessel and the provider administers either one large dose of medica�on or several doses over a short �me period of �me. Author's preference: 5-10 ml of 0.25% bupivacaine in 5 minute intervals

Dosing of CSE The spinal component of a CSE should provide pain relief without significantly decreasing the blood pressure or cause itching. Many variables, such as the pa�ent's level of cervical dila�on or their body habitus, prevent one ideal dose that could work for every pa�ent. Most pa�ents will be able to tolerate and feel comfortable with 2-4 mg of ropivacaine, 1.5-2.5 mg of bupivacaine, or 1.5-3 mg of levobupivacaine along with 4-10 mcg of fentanyl added to each local anesthe�c dose respec�vely and given in a volume of 2-4 ml. Pure narco�c intrathecal doses, such as, 20-25 mcg of fentanyl can be jus�fied only if the pa�ent presents at the earliest stages of cervical dila�on (2 cm) and a walking epidural is desired. Author's preference: 3 ml 0.1% ropivacaine + fentanyl 6 mcg (USA) 2.5 ml 0.1% bupivacaine + fentanyl 5 mcg (Serbia) or 3 ml 0.1% levobupivacaine + fentanyl 6 mcg (Serbia)

Test dose For the past 30 years a test dose containing 5 ml of 1.5% lidocaine plus epinephrine (adrenaline) 1:200000 has been provided in most epidural trays sold in the USA. There are two main reasons for a test dose to be administered, one, to determine if the epidural catheter is misplaced into the intrathecal space and two if the catheter is misplaced into a blood vessel. If the catheter is mistakenly placed into blood vessel, the pa�ent should experience both a metalic taste in their mouth and ringing in their ears due to the local anesthe�c as well as a fast heart rate from the epinephrine (adrenaline). If the catheter is placed in the intrathecal space, the pa�ent should have both an intense motor and sensory block due to the 5 ml of lidocaine within the test dose. The strength of the test dose block would actually be


sufficient enough for a Cesarean Sec�on and can clearly be differen�ated from a mild block that would develop if the catheter is placed in the epidural space. However, a test dose in the same formula�on is not available in Serbia. The author does not rou�nely use a test dose a�er the labor CSE if both the gravity test is nega�ve and there was no blood in the epidural catheter. In the case of a pure epidural block, the author prefers to use 5 ml of the described test dose, followed by 5 ml of 0.25% bupivacaine. This combina�on should produce complete pain relief in the laboring pa�ent. Should the labor epidural need to be converted to surgical anesthesia for a Cesarean Sec�on the author prefers to use 5 ml of a test dose before epidural local anesthe�c. The author takes the same approach if for any reason the epidural is chosen for an elec�ve Cesarean Sec�on. Since doses of local anesthe�c used for surgical anesthesia can cause the catastrophic complica�ons as stated above, the author believes that the test dose significantly reduces the chance of these complica�ons. Since the USA formula�on test dose is not available in Serbia, the author recommends 25 mcg of epinephrine (adrenaline) if the goal is to exclude intravascular placement and 40-75 mg of lidocaine if the goal is to exclude intrathecal placement. Author's preference: no rou�ne test dose a�er labor CSE mandatory test dose for surgical anesthesia

PCEA regimen PCEA (Pa�ent Controlled Epidural Anesthesia) pumps have been available in USA since the late nine�es. The advantage of pa�ent control regimens is that the pa�ent immediately addresses her pain and relieves it by pressing the analgesic demand bu�on. Numerous studies have shown

that the lower the basal rate, the lower the total amount of medica�on that will be used. However, the lower the basal rate, the more boluses pa�ent will require. It is very difficult to show any difference in pa�ent sa�sfac�on no ma�er what regimen is used. The author is well aware of the lack of PCEA pumps in Serbia. However, many advantages of the PCEA program can be achieved by having the anesthesia provider administer medica�ons in a similar regimen to the one delivered by the pump. For example, con�nuous infusions of 10-15 ml of 0.1% bupivacaine along with bolus doses of 5-10 ml every 10-20 minutes, up to 3 blouses per hour will provide sufficient pain relief for nearly all pa�ents. Another op�on would be for the physician to give both a con�nuous infusion and supplement with boluses upon pa�ent request. Either op�on should obtain similar results. The overall conclusion is that the effects of a PCEA regimen can be achieved with or without PCEA pumps. Author's preference: 10/10/10/3 (con�nuous infusion, bolus, lock-out interval, number of boluses per hour) in USA; 10/10/10/3 (con�nuous infusion, bolus, lock-out interval, number of boluses per hour) in Serbia, administered by physician.

Conclusion Current clinical literature has enabled numerous clinicians to provide their experience and recommenda�ons on these topics. It has also enabled the authors of the literature to develop many different medica�ons regimens. However, we should never forget that every pa�ent is different and that any advice from the textbooks should be adjusted accordingly for each individual pa�ent.

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BETA BLOCKERS IN THE SEPSIS Svetlana Apostolović, Dragana Stanojević University Clinic of Cardiology, Niš, Serbia

Sepsis (called sep�caemia in the past) is the systemic response to infec�on, usually caused by bacterial infec�on (both Gram-posi�ve and Gram-nega�ve). The incidence of sepsis is con�nuing to rise although the case fatality rate has slowly fallen over the last 20 years. Hence, it is a common condi�on with an overall mortality of about 30% even when treated appropriately. Sep�c shock is the most severe form of sepsis and is associated with marked hypotension and organ failure. It is best viewed as a state of profound �ssue hypoperfusion. Shock increases the mortality to 60% or more. Sepsis and sep�c shock are characterized by mul�-organ failure, caused chiefly by a dysregulated immune response to the infec�on. Effec�ve management depends on early ini�a�on of treatment. All pa�ents should be given oxygen and intravenous fluids. Most will require a vasopressor. An�bio�cs should be given as quickly as possible and usually be broad-spectrum, bearing in mind the likely causa�ve organisms and the possibility of an�microbial resistance. The term "systemic inflammatory response syndrome" (SIRS) is used to describe the early response to injury, which may be infec�ve or non-infec�ve. Sepsis, the systemic inflammatory response to infec�on, is a mul�system disorder (1–3). When pathogens invade the hosts, inflammatory defense mechanisms are ac�vated resul�ng in immune, hormonal, metabolic, bioenerge�c, and autonomic nervous system modifica�ons. The �me-dependent interplay between these systems ideally eradicates the invading organisms, but can also result in mul�ple organ dysfunc�on (MODS) (4). Cardiac depression with impaired le� ventricular ejec�on frac�on is a well-described manifesta�on of this syndrome and can be diagnosed in up to 60% of pa�ents with sep�c shock (5). However, sepsis-induced myocardial depression can be viewed as adap�ve and, at least par�ally, protec�ve process. Early sepsis is characterized by elevated catecholamine levels, which derive from the autonomous nervous system, the gut, lymphocytes, 54

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macrophages, and neutrophils (6–14). This adrenergic response augments cardiac contrac�lity and heart rate, hence increasing cardiac energy demands (15,16). As sepsis progresses, circulatory derangements and mitochondrial dysfunc�on lead to �ssue hypoxia, respec�vely. On a subcellular level, this reduces adenosine-5-triphosphate forma�on and energy supply (17). When energy demand outweighs supply, the cardiac myocytes are at risk of cell death. Elevated troponin levels are indica�ve for such injury (18,19). To prevent further damage, the cells have to reduce their energy requirements. It can be hypothesized that they do so by reducing their cell-specific func�ons, hence crea�ng a new balance between energy produc�on and demand (Fig. 1).

Fig. 1. Balance between energy expenditure and energy genera�on. In condi�ons of reduced energy genera�on (such as sepsis), the cells are at risk for cell death. By reducing their cell-specific func�ons, the cells reduce their energy expenditure and create a new balance between energy supply and demand. This state with noncontrac�ng but viable myocytes can be viewed as a form of hiberna�ng myocardium. When the bioenerge�c crisis is overcome, the surviving cells have the poten�al for full func�onal recovery.

Reprinted from Rudiger A. Beta-block the sep�c heart. Crit Care Med 2010;38(Suppl):S606-S612.


Several underlying mechanisms of sepsis-induced myocardial depression have been iden�fied (20). Of major importance is the a�enua�on of the adrenergic response at the cardiomyocyte level resul�ng from down-regula�on of adrenergic receptors and depression of postreceptor signaling pathways (21–26). These changes are mediated by cytokines from ac�vated immune cells (27,28). Clinically, this adrenergic down-regula�on leads to a reversible hyporesponsiveness to dobutamine in pa�ents with sep�c shock for up to 10 days (29). These effects are probably enhanced by neuronal apoptosis in the cardiovascular autonomic centers and by inac�va�on of catecholamines through reac�ve oxygen species (30,31). Although the overall cardiac func�on is markedly reduced, the cardiomyocytes survive in a hiberna�on-like state. Once the sep�c insult is overcome and cellular energy supply reestablished, the cardiomyocytes start contrac�ng again. Clinicians will note a normaliza�on of the cardiac func�on in sepsis survivors, typically occurring between days 7 and 10 (32). Using portable radionuclide cineangiography, Calvin et al, were the first to demonstrate myocardial dysfunc�on in adequately volume-resuscitated sep�c pa�ents with decreased ejec�on frac�on and increased end-diastolic volume index (33). Adding pulmonary artery catheters to serial radionuclide cineangiography, Parker and colleagues extended these observa�ons with the 2 major findings that (1) survivors of sep�c shock were characterized by increased end-diastolic volume index and decreased ejec�on frac�on, whereas non survivors typically maintained normal cardiac volumes, and (2) these acute changes in end-diastolic volume index and ejec�on frac�on, although sustained for several days, were reversible (34). More recently, echocardiographic studies have demonstrated impaired le� ventricular systolic and diastolic func�on in sep�c pa�ents (35-37). These human studies, in conjunc�on with experimental studies ranging from the cellular level to isolated heart studies and to in vivo animal models, have clearly established decreased contrac�lity and impaired myocardial compliance as major factors that cause myocardial dysfunc�on in sepsis (38–43). Notwithstanding the func�onal and structural differences between the le� and right ventricle, similar func�onal altera�ons, as discussed above, have been observed for the right ventricle, which suggests that right ventricular dysfunc�on in sepsis closely parallels le� ventricular dysfunc�on (44–47). However, the rela�ve contribu�on of the right ventricle to sep�c cardiomyopathy remains unknown. Myocardial dysfunc�on in sepsis has also been analyzed with respect to its prognos�c

value. Parker et al, reviewing sep�c pa�ents on ini�al presenta�on and at 24 hours to determine prognos�c indicators, found a heart rate of 110/min Fever >38, 5C Jaundice Renal mptoms Re�nal symptoms New onset thrombocytopenia Drop in hemoglobin Elevated ESR Fat macroglobulinemia

Fat embolism syndrome is diagnosed if 2 major criteria are present or 1 major and 4 minor criteria are present. Schoenfeld suggested scoring system for diagnosing fat embolism syndrome: Table 3. Schoenfeld scoring system Sign/Symptom Petechial rash Diffuse infiltrates on chest X-ray Hypoxemia Fever Tachycardia Tachypnoe Confusion

Score 5 4 3 1 1 1 1 69


The score > 5 suggests diagnosis of fat embolism syndrome (FES). Respiratory distress is the most significant clinical feature of FES. This is why Lindeque proposed criteria for diagnosing fat embolism syndrome based only on respiratory changes: Table 4. Lindeque's criteria for FES Criteria pO2 < 8 kPa (60mmHg) pCO2 > 7,3 kPa ( 55mmHG) or pH35 despite of adequate seda�on Dyspnea, tachypnea, anxiety, tachycardia, increased work of breathing

Respiratory distress in FES is indis�nguishable from ARDS. White says that FES is ARDS with addi�onal organ involved due to fat microglobules deposits. There is no diagnos�c test that is sufficiently sensi�ve or specific to be useful for confirming or excluding FES. Laboratory and radiological tests are not specific. Chest x-ray is normal in majority of cases or may show diffuse inters��al infiltrates due to focal oedema or alveolar hemorrhage. Opaci�es are located in periphery and bases of lungs. Lung CT scan will show diffuse areas of vascular conges�on and pulmonary edema usually described as ground glass opaci�es and septal thickening. Ven�la�on-perfusion scan may demonstrate sca�ered spots of subsegmental perfusion defect with normal ven�lator pa�ern. The neuroradiological diagnosis of cerebral fat embolism is challenging. Computer tomography scans are usually nega�ve. MRI is more sensi�ve. One must remember however that MRI findings are not specific and develop a�er several days. On T2 weighted MRI scans mul�ple small, scattered, hyperintense intracerebral lesions can be seen. Signal abnormali�es appear in gray and white ma�er. MRI results correlates with the Glasgow Coma Scale. Lesions gradually disappear within several weeks. In laboratory sputum, blood, cerebrospinal fluid and urine are usually checked for presence of fat globules to confirm diagnosis. Biologic markers such as lipase, free fa�y acids, and phospholipase A2 can increase in blood in pa�ents with FES; however. But these findings are nonspecific in pa�ents with lung injury. Examina�on of bronchoalveolar lavage (BAL) fluid may detect fat droplets in macrophages.

70

Treatment There is no specific therapy for fat embolism syndrome. The most important is preven�on, early diagnosis, and adequate symptoma�c treatment. Early opera�ve stabiliza�on of fractures reduces the incidence of fat embolism syndrome. During orthopedic procedures me�culous care should be taken to limit the rise in intraosseous pressure in order to reduce the penetra�on of medullary fat to the circula�on. Suppor�ve care includes maintenance of adequate oxygena�on and ven�la�on, stable circula�on, adequate hydra�on and oxygen delivery. Various drugs have been tried but with inconclusive results. Cor�costeroids are given profilac�cally since several studies reported decreased incidence and severity of fat embolism in pa�ents receiving cor�costeroids (methylprednisolone 7.5 mg/ kg every 6 h for 12 doses) due to an� -inflammatory proper�es of steroids and reduc�on in perivascular hemorrhage and edema. Oral aspirin is advocated since it was describe effec�ve in normaliza�on of blood gases, coagula�on and platelets. Heparin ac�vates lipase and can clear lipemic serum but it can also increase level of circula�ng free fa�y acids and increase bleeding in polytrauma pa�ents. Acetylocysteine is given o some pa�ents with FES. It reverses the detrimental changes case in hypoxia-reperfusion syndrome.

Summary Fat embolism syndrome (FES) may complicate many different clinical condi�ons. It manifests clinically 24-72 hours a�er insult. Symptoms are very nonspecific and diagnosis is usually based on symptoms and clinical exclusions. Specific therapy for FES does not exists. Symptoms resolve in several weeks in majority of cases.

References 1. Bederman S, Bhandari M, McKee MD, Schemitsch EH. Do cor�costeroids reduce the risk of fat embolism syndrome in pa�ents with long-bone fractures? A metaanalysis. Can J Surg 2009; 52: 386–93. 2. Georgopoulos D, Bouros D. Fat embolism syndrome clinical examina�on is s�ll the preferable diagnos�c method. Chest 2003; 123: 982–3. 3. White T, Petrisor BA, Bhandari M. Preven�on of fat embolism syndrome. Injury 2006; 37: S59–67.


RENAL REPLACEMENT THERAPY: WHEN, WHY AND HOW? Zorica Dimitrijevic, Branka Mi�c

Nephrology Clinic, Clinical Center Nis, Serbia

Acute kidney injury (AKI) is a common complica�on in cri�cally ill pa�ents. In recent years emerged concept that AKI is not just a disease of a single organ because it is frequently part of the dysfunc�on of many diseases and nowadays, the term AKI is used for the spectrum of renal disease, from a minimal eleva�on of serum crea�nine (sCr), up to renal insufficiency that requires renal replacement therapy. Among those with severe AKI, 50 to 70% will receive dialy�c support which increases the complexity and costs of care and is associated with death, with case-fatality rates commonly exceeding 60% (1), and dialysis dependence among survivors (2). In the absence of any effec�ve pharmacologic therapies for AKI, its management remains suppor�ve, focused on op�mizing fluid balance, maintaining nutri�on, preven�ng or trea�ng electrolyte and acid-base disturbances, adjus�ng the dosing of medica�ons that are excreted by the kidney, and avoiding secondary hemodynamic and nephrotoxic renal injury. Although these conserva�ve therapies provide the ini�al underpinning of AKI management, renal replacement therapy using one or more of the mul�ple modali�es of dialysis and hemofiltra�on is o�en required.

Modality of renal replacement therapy There is a mul�tude of acronyms that have been generated to to describe all of the currently available approaches to "ar�ficial" mechanical support of renal func�on (3). A consensus statement recommends term "renal replacement therapy" (RRT). RRT may be Intermi�ent or Con�nuous and is differen�ated by the prefix I (IRRT) or C (CRRT), respec�vely (4). To maintain a steady state, the two main physical processes used to carry out the kidney func�ons of solute and water elimina�on are hemofiltra�on and hemodialysis. Hemofiltra�on This is a convec�ve process in which a hydrosta�c pressure gradient is used to filter plasma water and solute across a membrane. This fluid is [email protected]

then discarded. The proper�es of the membrane determine the size and charge of the solute that can be removed and the rate at which water will be filtered for any given driving pressure. This process mimics the func�on of the glomerulus. Hemodialysis This is a diffusive process where blood is passed over a semipermeable membrane which separates it from an electrolyte solu�on flowing in the opposite direc�on. The purpose of this counter current flow (contraflow) system is to maintain a waste solute concentra�on which is always lower on the dialysate side of the membrane, thus ensuring that a gradient persists along the en�re length of the membrane.

Intermitent or con�nues replacement therapy during AKI? Over the past three decades, the use of various forms of con�nuous and prolonged intermittent RRT in the management of cri�cally ill pa�ents with AKI has increased drama�cally. These modali�es are characterized by a "go slow" approach, prolonging the daily dura�on of therapy while reducing the rate of solute clearance and net ultrafiltra�on, based on the ra�onale that slower, gentler treatment will be be�er tolerated in hemodynamically compromised pa�ents. Several factors may determine the choice of modality. These include which technique is available, the exper�se of the clinician and nursing staff, hemodynamic stability, vascular access and whether the primary need is for fluid and/or solute removal. However, comparing outcomes between modali�es is complicated. Pa�ents treated with con�nuous or extended dura�on therapy are more likely to have greater severity of illness and be hemodynamically unstable. Comparing outcomes between con�nuous renal replacement therapy (CRRT) and conven�onal intermi�ent hemodialysis in observa�onal cohorts is therefore subject to selec�on bias. 71


Based on available data, the recent Kidney Disease Improving Global Outcomes (KDIGO) Clinical Prac�ce Guidelines for Acute Kidney Injury recommended that con�nuous and intermi�ent modali�es of RRT be used as complementary therapies, with the sugges�on to use CRRT preferen�ally for hemodynamically unstable pa�ents (5). In pa�ents with acute brain injury or increased intracranial pressure due to intracranial hemorrhage, fulminant liver failure or other causes, intermi�ent hemodialysis has been associated with greater decreases in cerebral perfusion than CRRT (6). In addi�on, convec�ve therapies are generally thought to provide be�er clearance of solutes with molecular weights greater than 1000 Daltons (7). It has therefore been suggested that convec�ve therapies might provide an added benefit in pa�ents with sepsis-associated AKI through enhanced removal of pro-inflammatory mediators (8).

Indica�ons for renal replacement therapy during AKI Whether or not to provide dialy�c support and when to start are two dilemmas for clinicians managing pa�ents with a sudden deteriora�on in renal func�on. There is no standard defini�on for the acute kidney injury that requires replacement therapy. Basically, replacement therapy is indicated when a clinical or biochemical state requires that AKI be corrected. The decision to ini�ate it should be based on the judgment of the physician, the organiza�on and available resources; therefore, renal replacement therapy is not uniform and its indica�on, �me and doses of dialysis will influence its efficacy and safety (Table 1) Tradi�onally, renal replacement therapy has been indicated to purify blood from urea and other uremic toxins along with regula�on of the extracellular Table 1. Factors influencing the decision to start RRT Pa�ent safety Unnecessary procedure • Possibility of pa�ent recovering renal func�on Risk associated with RRT procedure • Complica�ons associated with catheter placement • Hypotension and cardiac events during procedure • Fear of prolonging renal injury a�er ini�a�on of RRT Factors affec�ng implementa�on • Logis�cs • Vascular access availability • Availability of equipment and personnel • Time of decision to ini�a�on (Sundays, late night) 72

volume and of the electrolytes. In other words, RRT is needed to restore homeostasis. However, indica�ons such as metabolic abnormali�es, acidosis, oligo-anuria and volume overload are not sufficient to propose renal replacement therapy. Currently, only a small number of indica�ons are absolute. Most indica�ons are rela�ve and should be considered in the context of the complete clinical condi�on of the pa�ent. The absolute clinical indica�ons for renal replacement therapy are symptoma�c urea poisoning, severe metabolic acidosis (pH80% and replacement therapy should con�nue for ≥3 days. For children undergoing surgery, preopera�ve factor concentra�ons should generally be >80% and therapy should be maintained for 7–10 days a�er tonsillectomy, 3–4 days a�er circumcision, and ≥3 days a�er central venous access device inser�on. For dental extrac�ons, treatment with clot�ng factor concentrate is recommended to obtain a minimum factor concentra�on of 50%. FFP and cryoprecipitate have rela�vely low clo�ng factor concentra�ons and poten�al viral transmission risks. These products are indicated only if concentrates are not available (9).

Von Willebrand disease (VWD) is the most common hereditary bleeding disorder, caused by deficiency or dysfunc�on of VWF. The disease is Acquired von Willebrand syndrome comprises defects in VWF concentra�on, structure or func�on arising from medical disorders or treatments. Bleeding in VWD is due to impaired platelet adhesion and/or reduced levels of FVIII and is usually mild. VWF can be supplied by cryoprecipitate or human plasma-derived concentrates. Cryoprecipitate is not virus-inac�vated and its use is strongly discouraged, except in life-threatening situa�ons when concentrates are not available. Plasma-derived VWF concentrates may prevent excessive bleeding in over 90% of VWD pa�ents (10). The efficacy has been confirmed in surgical paediatric and adult pa�ents with VWD. For bleeding treatment/preven�on in major surgery, a loading dose of 40–60 U/kg is recommended, with 20–40 U/kg every 8–24 h for maintenance. For minor surgery, the doses are slightly lower, given less frequently and for a shorter dura�on. Periopera�ve monitoring of FVIII:C and VWF:RCo may help determine appropriate dosing. Adverse reac�ons to VWF concentrates include allergic and anaphylac�c reac�ons. VWF concentrates contain FVIII, and therefore carry a poten�al thromboembolic risk; an�thrombo�c prophylaxis should be considered. When haemorrhage persists despite increasedVWF/FVIII levels, administra�on of platelet concentrate can be helpful (11).

Management in pa�ents with polycythemia Polycythemia or erythrocytosis are terms to describe an abnormally elevated hematocrit. Even modest increases in the hematocrit level can have a major impact on whole blood viscosity. An increase in hematocrit can result from a reduc�on in plasma volume (rela�ve polycythemia) without a true increase in red cell mass. In addi�on, acute decreases in plasma volume, as may be seen with preopera�ve fas�ng, can convert an asymptoma�c polycythemia into one where hyperviscosity may threaten �ssue perfusion. When the hematocrit rises to levels much above 50% to 55%, whole blood viscosity increases exponen�ally, especially in small vessels with low flow/shear rates, such as capillaries (slower blood flow and decrease oxygen delivery). The cerebral circula�on in par�cular appears vulnerable to reduc�ons in flow with increased viscosity. The clinical signs and symptoms of an elevated hematocrit vary depending on the underlying disease process and the rate of onset. Pa�ents with modest chronic polycythemia, will complain of very few symptoms un�l the hematocrit rises above 81


55% to 60%, when headaches and easy fa�gability become commonplace. Hematocrit levels greater than 60% can be life threatening, as the increase in viscosity threatens organ perfusion. Pa�ents with hematocrits in this range are also at risk of venous and arterial thrombosis. Anesthe�c considera�ons remainded oxygen therapy, preopera�ve phlebotomy when indicated, periopera�ve hypercoagulability and poten�al for bleeding diathesis (12).

Management in pa�ents with causes of hypercoagulability Myeloprolifera�ve disorders, especially polycythemia vera, essen�al thrombocytosis are associated with an increased incidence of thrombophlebi�s, pulmonary embolism (PE), and arterial occlusions. Pa�ents with these condi�ons are also at risk of thrombosis of splenic, hepa�c, portal, and mesenteric vessels. The pathogenesis of the thrombosis in these pa�ents is not clear. Both the thrombocytosis and an abnormality in platelet func�on may play a role. Increased ac�va�on and aggrega�on of platelets has been postulated as a cause for the hypercoagulable state. Pa�ents with malignancies demonstrate a marked thrombo�c tendency. Adenocarcinomas of the pancreas, colon, stomach, and ovaries are the leading tumors associated with thromboembolic events. Pregnancy and oral contracep�ve use have been reported to increase the risk of thrombosis as well as pa�ents with nephro�c syndrome and an�phospholipid an�bodies. Current an�thrombo�c strategies range from simple management approaches like early ambula�on to the combina�on of subcutaneous heparin with elas�c stockings followed by conversion to outpa�ent warfarin with associated laboratory monitoring. Surgical pa�ents may present with a host of VTE risk factors, all of which must be considered when balancing the degree of thrombo�c risk and the costs (monetary and bleeding risk) of aggressive periopera�ve an�coagula�on. Prophylaxis strategies may take the form of pharmacologic or physical methods. Drugs that have proven to be suitable for VTE prophylaxis include UH, LMWH, the oral an�coagulant warfarin, direct thrombin inhibitors such as hirudin, and factor Xa inhibitors such as fondaparinux (13).

An�coagula�on and an�platelet therapy An�thrombo�c therapies have a range of indica�ons in anaesthesia and intensive care. 82

An�coagulant therapy Heparin is used in clinical prac�ce as unfrac�onated heparin (UFH) and low-molecular weight heparins (LMWHs) and it is necessary to dis�nguish between the two when making recommenda�ons. UFH binds an�thrombin, forming a complex which inac�vates thrombin and coagula�on factors Xa, IXa, XIa and XIIa. UFH may be administered intravenously or subcutaneously. With intravenous administra�on, the half-life is >1 h (70–100 min). With subcutaneous administra�on, the onset of an�coagula�on is delayed by approximately 1 h and peak plasma concentra�ons are reached at 3 h. Clearance occurs via binding to endothelial cells and macrophages, followed by renal metabolism. Indica�ons for UFH include periopera�ve thromboprophylaxis, deep vein thrombosis (DVT) or pulmonary embolism, an�coagula�on in CPB (extracorporeal pump) or haemodialysis, coronary pathology (unstable angina, myocardial infarc�on) and disseminated intravascular coagula�on. Rapid, effec�ve reversal of UFH can be achieved using intravenous protamine (1mg protamine neutralises 100 IU of UFH). When UFH has been infused con�nuously, the dose of protamine should be calculated from the UFH dose administered during the preceding 2–3 h. Also, in case of severe bleeding associated with subcutaneous UFH unresponsive to intravenous protamine at a dose of 1mg per 100 IU UFH, could be treated by con�nuous administra�on of intravenous protamine, with dose guided by aPTT (14). LMWHs are obtained from UFH by chemical or enzyma�c depolymerisa�on. They are widely employed in clinical prac�ce due to their favourable risk/benefit profile, once-daily dosing and reduced requirement for monitoring. LMWHs bind to and ac�vate an�thrombin. Unlike UFH, not all LMWH molecules can inhibit thrombin. The an�coagulant ac�on of LMWH is therefore based mainly on FX inhibi�on. Unlike UFH, LMWHs have low platelet interac�on. LMWHs have almost 100% bioavailability a�er subcutaneous administra�on. Peak plasma concentra�on is reached approximately 3–4 h a�er administra�on and the elimina�on half-life is around 4–6 h. Monitoring the an�coagulant effects of LMWHis usually unnecessary and can be achieved by measuring plasma an�-FXa ac�vity. Protamine administra�on does not completely reverse LMWH an�coagula�on; although it neutralises an�-FIIa ac�vity, it has limited effects on an�-FXa ac�vity. This is because protamine binds poorly to small LMWH fragments with 8–14 saccharides. In clinical prac�ce, protamine (1mg per 100 an�FXa units of LMWH administered; conversion of enoxaparin: 40mg = 4000 interna�onal an�-FXa


units) is suggested if haemorrhage occurs within 8 h of LMWH administra�on. A second dose of protamine (0.5mg per 100 an�-FXa units administered) may be administered if bleeding con�nues (15). Vitamin K antagonists (VKAs) are used in pa�ents with mechanical heart valves, atrial fibrilla�on or venous thromboembolic disease. VKA treatment is monitored by measuring INR. Before surgical interven�on, INR should be brought below 1.5. VKA treatment may be interrupted before elec�ve surgery and resumed a�er surgery (with the first meal). Postopera�ve heparin is given if the INR is < 2. For urgent surgery, prothrombin complex concentrate - PCC (25 IU/kg FIX) should be given, and addi�onal administra�on of 5 mg vitamin K1 (intravenous, subcutaneous or oral) is recommended. Vitamin K antagonists (VKAs) should not be interrupted for skin surgery, dental and other oral procedures, gastric and colonic endoscopies (even if biopsy is scheduled, but not polypectomy), nor for most ophthalmic surgery (mainly anterior chamber, e.g. cataract), although vitreore�nal surgery is some�mes performed in VKA-treated pa�ents. In low-risk pa�ents undergoing procedures requiring INR < 1.5, VKA should be stopped 5 days before surgery. Measure INR on the day before surgery and give 5mg oral vitamin K if INR exceeds 1.5. Subcutaneous LMWH should be given postopera�vely un�l the target INR is observed in two measurements. In case of high-risk pa�ents (pa�ents with recurrent VTE treated for 90% using an FiO2 of 1.0, and posi�ve pressure ven�la�on (PPV) via the mask on a pa�ent whose SpO2 was >90% prior to anesthe�c interven�on, or it is not possible for the unassisted anesthesiologist to prevent or reverse signs of inadequate ven�la�on during Posi�ve Pressure Mask Ven�la�on" ( ASA, 1993, p. 601). (5) Successful laryngoscopy occurs when "a view of the glo�c structures and laryngeal inlet can be achieved." Difficult laryngoscopy occurs when "it is not possible to visualize any por�on of the vocal cords with conven�onal laryngoscopy" (5). A difficult intuba�on is hard to define, with defini�ons ranging in regards to the number of unsuccessful a�empts and �meframes. A successful intuba�on is easier to define: according to a study by Poli�s et al. (6) induc�on �me and age group were both found to be predictors of successful intuba�on. The induc�on �me to achieve 80% successful intuba�on was 137 seconds for ages 1-4, and 187 seconds for ages 4–8. The main adult airway assessment tool Mallampa�’s classifica�on will be described, as pediatric tools, also, but Mallampa� test may not always be performed in pediatric pa�ents, because they are not coopera�ve as adults are.

Mallampa� classifica�on system Class I: so� palate, tonsillar fauces, tonsillar pillars, and uvula visualized - "easy" intuba�on. Class II: hard and so� palate, tonsillar fauces, and uvula visualized - "mildly difficult" intuba�on. Class III: hard and so� palate, base of uvula visualized - "much more difficult" intuba�on. Class IV: so� palate not visible - "near impossible" intuba�on. Modified Mallampa� classifica�on is to assess the structures with the pa�ent si�ng upright, with the tongue out, and no vocaliza�on. Mallampa� has proven to be aplicable to a popula�on of children 4 to 8 years of age without 104

anatomical malforma�ons and/or gene�c syndromes. The best oropharyngeal view (BOV) is the method of assessment similar to assessing MMP, mouth wide open but without tongue protrusion and be�er airway assessment tool than MMP classifica�on in children (7).

Cormack and Lehane grading System The Cormack and Lehane grading system is based on one’s ability to visualize certain structures upon direct laryngoscopy. Grade I: All or most of the glo�s is seen. Grade II: Only the posterior por�on of the glo�s can be seen. Grade II may not be considered "difficult" as defined by ASA if some part of the vocal cords is visible. Grade III: Only the epiglo�s can be seen. Grade III is considered difficult as defined by the ASA. Grade IV: Neither the epiglo�s nor the glot�s can be seen. Grade IV is considered difficult as defined by the ASA.

Thyromental distance The thyromental distance (TMD) is the distance from the lower mandible to the thyroid notch. The measurement is performed with the adult pa�ent's head fully extended. It helps determine how readily the laryngeal axis will fall in line with the pharyngeal axis when the atlanto-occipital (A/O) joint is extended. If the distance is short (less than 3 fingerbreadths or 6 cen�meters), it is difficult to achieve alignment of the airway axes, and less space is available for tongue displacement.

Atlanto-occipital joint Joint mobility is measured when the head is held erect and forward. Normal extension is 35 degrees. Almost all extension of the head on the neck takes place at the atlanto-occipital (A/O) joint. Flexion of the neck should also be checked by moving the chin down to the chest. When the A/O joint can’t be extended, a�empts to do so can cause the convexity of the cervical spine to bulge anteriorly, pushing the larynx anterior as well.

Temporal mandibular joint The temporal mandibular joint (TMJ) is assessed for the degree of opening, as the inability to open the mouth 3 fingerbreadths has been associated with a difficult intuba�on. If the opening is decreased, determine if this could be the result of pain. If so, the problem may disappear


with the medica�ons given for intuba�on. Addi�onally, when performing a TMJ assessment, an evalua�on of ability to move the lower jaw so that the teeth are in front of the upper incisors should be made. Wilson and colleagues developed another scoring system in which they took 5 variables – weight, head, neck and jaw movements, mandibular recession, presence or absence of buck teeth. Risk score was developed between 0 to 10. They found that higher the risk score, greater the accuracy of predic�on with a lower propor�on of false posi�ves. Arne and colleagues produced a new scoring system based on mul�factorial analysis. Apart from the above indicators by Wilson et al, it also included presence or absence of overt airway pathology. The sensi�vity and pecificity levels of this system was above 90%. This is LEMON pneumonic, a common airway assessment tool for the pediatric popula�on (8).

LEMON airway assessment method The score with a maximum of 10 points is calculated by assigning 1 point for each of the following LEMON criteria: L = Look externally (facial trauma, large incisors, beard or moustache, large tongue) E = Evaluate the 3-3-2 rule (incisor distance-3 finger breadths, hyoid-mental distance-3 finger breadths, thyroid-to-mouth distance-2 finger breadths) M = Mallampa� (Mallampa� score > 3). O = Obstruc�on (presence of any condi�on like epiglo��s, peritonsillar abscess, trauma). N = Neck mobility (limited neck mobility) Some prefer the COPUR scale for evalua�on of pediatric airway. This scale rates chin size, in-

terdental opening, previous intuba�on or OSA, uvula visualiza�on, and es�mated range of mo�on of neck on a 4-point scale (9). Scores above 10 predict difficult intuba�on. Securing a defini�ve airway will become easier with age. In conclusion: age, interincisor gap, neck circumference and sternomental distance are predictors of difficult mask ven�la�on (7). Age, best oropharyngeal view and thyromental distance are predictors of difficult laryngoscopy with intuba�on (7).

References 1. Vieira Santos APS , et al. Difficult intuba�on in children: applicability of the Mallampa� Index. Rev Bras Anestesiol 2011; 61(2): 156–62. 2. Gupta S, Rajes Sharma RKR, Jain D. Airway assessment: predictors of difficult airway. Indian J Anaesth 2005; 49(4): 257–62. 3. Benumof JL. Airway Management: Principles and Prac�ce. St. Louis, MO. Mosby Year book. 1996. 4. American Society of Anesthesiologists. Prac�ce guidelines for the management of the difficult airway: An updated report by the ASA Task Force on the Management of the Difficult Airway. Anesthesiology 2003; 98: 1269–77. 5. American Society of Anesthesiologists. Prac�ce guidelines for the management of the difficult airway: A report by the ASA Task Force on the Management of the Difficult Airway. Anesthesiology 1993; 78: 597–602. 6. Poli�s GD, Frankland MJ, James RL. ReVille JF, Rieker MP, Petree BC. Factors associated with successful tracheal intuba�on of children with sevoflurane and no muscle relaxant. Anaesth Analg 2002; 95(3): 615–20. 7. Aggarwal A, Sharma Rani K, et al. J Anesth Clin Res 2012; 3: 11. 8. Management of Unan�cipated Difficult Intuba�on. Pa�ent Saf Advis 2010; 7(4): 113–22. 9. Lane G. Intuba�on tehniques. Oper Tech Otolaryngol 2005; 16: 166–70.

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THE DIFFICULT AIRWAY: THE USE OF SUBGLOTTIC JET VENTILATION FOR ENDOLARYNGEAL SURGERY Dusanka Janjevic

ENT Clinic, Dept. of Anaesthesiology, Clinical Centre of Vojvodina, Novi Sad, Serbia

Direct examina�on and surgical procedures involving the larynx require close coopera�on between the laryngologist and the anaesthe�st as a balance must be achieved between adequate surgical access and safe, effec�ve ven�la�on. Endolaryngeal surgery with rigid laryngoscopes has an important place in solving various pathologic condi�ons of the larynx and trachea. Airway management during microlaryngeal surgery has evolved from apnoeic techniques through to the controlled methods rou�nely employed today. Over the last decades, several effec�ve jet techniques have been established for microlaryngeal and laryngeal laser surgery. Jet ven�la�on (JV) in the airway surgery provides the endoscopist with an unobstructed view on a quiet opera�on field, preserves the anaesthesiologist’s ability to control the pa�ent's ven�la�on and oxygena�on. High Frequency Jet Ven�la�on (HFJV) is an alterna�ve anaesthe�c technique with specific advantages when used for diagnos�c or surgical procedures in pa�ents undergoing end laryngeal surgery. Advantages offered by HFJV for intraopera�ve ven�la�on of anaesthe�zed pa�ents were reported as follows: posi�oning of small bore catheter or cannula in the presence of airway lesions with less effort than large tubes, performance of laser surgery with less risk, by avoiding the use of flammable plas�c materials, improvement of surgical access and viewing of the larynx due to the small-bore tubes, simplifying access to a near mo�onless surgical field and smoother process of surgery, reduced risk of aspira�on of blood and debris due to con�nuous ou�low of gases. Jet ven�la�on vs. Conven�onal ven�la�on. During JV gas from a high pressure source is delivered through a small-bore cannula posi�oned in the airway. Because of the narrow ou�low orifice, a jet effect is produced, entraining gas around the cannula. HFJV achieves gas exchange by using sub physiologic �dal volumes applied at extreme rates. The tradi�onal concepts of applied physiology to the mechanisms of normal or conven�onal mechanical ven�la�on (CV) are not completely 106

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applicable to JV. During the JV good gas exchange and the efficiency of CO2 elimina�on can be maintained with a �dal volume not larger than the dead space. The principles of oxygena�on during HFV are similar to those during (CV) and oxygena�on is dependent on an op�mal lung volume recruitment strategy and consequent reduc�on of intrapulmonary shun�ng of blood. In contrast to CV, where a bulk gas volume is rather slowly pushed forward into the airway via a large bore tube (an endotracheal tube) that is fi�ed air�ght to the trachea, JV consists of the rapid gas insuffla�ons with high velocity via a narrow nozzle into the open airway. While in CV gas flow in the delivery system is bidirec�onal and happens sequen�ally (alternating-inspira�on and expira�on), in JV the gas flow is mainly coaxial, par�ally simultaneous in both direc�ons (in and out) and the delivery system only allows insuffla�ons. Exhala�on happens completely outside of the delivery system. HFJV employs small-volume ven�la�on resulting in adequate gas exchange at lower peak and mean airway pressure than CV, it offers the poten�al benefit of genera�ng lower intrathoracic pressures thereby reducing the impedance of intrathoracic blood flow and minimizing cardiovascular depression. HFJV due to lower airway pressures offers the benefit of improved venous return, less bleeding, and improved opera�ng condi�on in ENT surgery. Subglo�c jet ven�la�on and difficult laryngeal exposure (DLE). HFJV with subglo�c approach can be used in all pa�ents including those with severe co-morbidi�es, obesity and difficult airway. Subglo�c je�ng may be safely employed in pa�ents with difficult airway. The requirements related to anaesthesiologist are delicate; it is necessary to provide a secure airway and ensure adequate ven�la�on and op�mum visibility of the opera�ve field. The direct rigid laryngoscope is placed transoraly and the larynx is easily exposed in most cases. However in some pa�ents a full or even par�al view of the larynx is not achieved by direct laryngoscopy. In this circumstance inadequate -


difficult laryngeal exposure is caused by inability to posi�on the rigid laryngoscope correctly because of the pathological anatomy of the larynx and inability of the pa�ent to hyperextend the neck. On the other hand subglo�c jet ven�la�on may be compromised in pa�ents with DLE due to incorrect gas stream in trachea and incorrect gas stream outside the trachea. Recent studies have been suggested the several parameters that could predict difficult laryngeal exposure (DLE). Possible factors that lead to exposure difficul�es during rigid laryngoscopy include difficul�es in opening the mouth, a short neck, a s�ff and muscular neck, macroglossia, retrognathia, obesity, various anatomical measurements and extension limita�on of the cervical spine have been suggested as possible, causes of DLE. These anatomical abnormali�es associated with difficult endotracheal intuba�on and obstruc�ve sleep apnoea (OSA) have also been implicated in DLE, and so these abnormali�es may also prove valuable in predic�ng DLE. Difficult laryngoscopy is synonymous with difficult intuba�on during surgery in most pa�ents. The incidence of DLE and difficult intuba�on are reported between 1.5 and 8.5%, 1-4% respec�vely, so preopera�ve evalua�on of DLE is important for the risk of difficult airway management in pa�ents undergoing endolaryngeal surgery.

Transtracheal jet ven�la�on and emergencies Transtracheal jet ven�la�on via a needle cricothyroidotomy. Transtracheal jet ven�la�on (TTJV) is included on most of difficult oxygena�on and difficult intuba�on algorithm. In the “can’t intubate, can’t ven�late“ (CICV) scenario cricothyroidotomy is recommended if all other methods of ven�la�on have failed, in order to rapidly restore oxygena�on. During transtracheal (puncture) jet ven�la�on (JV) it is essen�al that the expiratory pathway is unobstructed. In the cases of complete upper airway obstruc�on conven�onal TTJV is ineffec�ve and dangerous. The disadvantage of a small lumen cannula, however, is its high resistance to gas flow, and hence the need for a high driving pressure to achieve adequate flow. The occlusion of the expiratory pathway rapidly leads to hypoven�la�on, manifested by hypercarbia and hypoxemia, and interferes with cardiac output by increasing the intrathoracic pressure, with the risk of producing serious barotrauma to the lung. Recently reviews (Hamaekers at al.) suggested the ejectors capable of crea�ng suc�on by the Bernoulli principle, which facilitate expira�on

through small-bore catheters. Further research may confirm the clinical the clinical applicability Prophylac�c placement of cricothyroidotomy cannula. Transtracheal jet ven�la�on (TTJV) must be viewed as procedure providing adequate gasexchange and ensuring the patency of the airway un�l a defini�ve procedure such as oral intuba�on or surgical tracheotomy can be performed especially in laryngeal (upper airway) surgery. With transtracheal JV it is vital to keep the upper airway as open as possible with jaw thrust and to verify defla�on of the lungs and exhala�on through the upper airway. If the system is closed barotrauma becomes a real and serious risk.

Conclusion Subglo�c jet ven�la�on facilitates safe airway management during endolaryngeal surgery. Preopera�ve evalua�on of DLE, using the clinical predictors of the difficult airway, would be important for the successful applica�on of subglo�c high-frequency jet ven�la�on.

References 1. Ihra G, Gockner G, Kashanipour A, Aloy A. High-frequency jet ven�la�on in European and North American ins�tu�ons: developments and clinical prac�ce. Eur J Anaesthesiol 2000; 17(7): 418–30. 2. Bacher A, Lang T, Weber J, Aloy A. Respiratory efficacy of subglo�c low-frequency, subglo�c combinedfrequency, and supraglo�c combined-frequency jet ven�la�on during microlaryngeal surgery. Anesth Analg 2000; 91(6): 1506–12. 3. Hunsaker DH. Anesthesia for microlaryngeal surgery: the case for subglo�c jet ven�la�on. Laryngoscope 1994; 104(Suppl 65): 1–30. 4. Rezai-Majd A, Bigenzahn W, Denk D-M, et al. Superimposed high-frequency jet ven�la�on (SHFJV) for endoscopic laryngotracheal surgery in more than 1500 pa�ents. Br J Anaesth 2006; 96: 650–9. 5. Brooker CR, Hunsaker DH, Zimmerman AA. A new anesthe�c system for microlaryngeal surgery. Otolaryngol Head Neck Surg 1998; 118(1): 55–60. 6. Santos P, Ayuso A, Luis M, Mar�nez G, Sala X. Airway igni�on during CO2 laser laryngeal surgery and high frequency jet ven�la�on. Eur J Anaesthesiol 2000; 17(3): 204–7. 7. Lanzenberger-Schragl E, Donner A, Grasl MC, Zimpfer M, Aloy A. Superimposed high-frequency jet ven�la�on for laryngeal and tracheal surgery. Arch Otolaryngol Head Neck Surg 2000; 126(1): 40–4. 8. Leiter R, Aliver� A, Priori R, Staun P, Lo Mauro A, Larsson A, Frykholm P. Comparison of superimposed highfrequency jet ven�la�on with conven�onal ven�la�on for laryngeal surgery. Br J Anaesth 2012; 108(4): 690–7. 9. Ihra G, Aloy A. On the use of Venturi’s principle to describe entrainment during jet ven�la�on. J Clin Anesth 2000; 12(5): 417–9.

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Sixth Annual Spring Scien�fic Symposium in Anesthesiology and Intensive Care, April 25-27, 2014, Niš, Serbia 10. Janjevic D: Jet ven�la�on for difficult intuba�onsand Emergencies, joined Papers on Jet Ven�la�on. Edited by Baer GA. Tampere, Tampere University Press, 2011. 11. Henderson JJ, Popat MT, La�o IP, Pearce AC. Difficult Airway Society quidelines for management of the unan�cipated difficult intuba�on. Anaesthesia 2004; 59: 675–94. 12. Popet M, Dudnikov S. Management of the obstructed upper airway. In Current Anaesthersia and Cri�cal Care. Focus on Difficult Airway, ed Pollard BJ. Harcourt Publicher Ltd, London 2001; 12: 225–3. 13. Patel R. Percutaneous transtracheal jet ven�la�on:a safe, quick and temporary way to provide oxygena�on and ven�la�on when convencional methods are unsuccessful. Chest 1999; 116: 1689–94. 14. Mace SE, Khan N. Needle cricothyroidotomy. Emerg Med Clin Nort Am 2008; 26(4): 1085–101. 15. Ross-Anderson DJ, Ferguson C, Patel A. Transtracheal jet ven�la�on in 50 pa�ents with severe airway compromise and stridor. Br J Anaesth 2011; 106 (1): 140–4. 16. Schuh JR, Be�endorf R, Shapiro D, et al. Comfirma�on of needle cricothyroidotomy using an esophageal detector devices in a porcian model. Mil Med 2010; 275(9): 686–7. 17. Roh JL, Lee YW. Predic�on difficult laryngeal exposure in pa�ents undergoing microlaryngosurgery. Ann Otol Rhinol Laryngol 2005; 114: 614–20. 18. Pinar E, Calli C, Oncel S, Selek B, Tatar B. Preopera�ve clinical predic�on of difficult laryngeal exposure in suspension laryngoscopy. Eur Arch Otorhinolaryngol 2009; 266: 699–703.

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19. Hsiung MW, Pai L, Kang BH, Wang BL, Wong CS, Wang HW. Clinical predictors of difficult laryngeal exposure. Laryngoscope 2004; 114: 358–63. 20. Bourgain JL, Chollet M, Fischler M, Gueret M, Mayne A. Guide for the use of jet ven�la�on during ENT and oral surgery. Ann Fr Anaesth Reanim. 2010; 29(10): 720–7. 21. Bouldi M, Bearfield P. Techniques for emergency ven�la�on through a needle cricithyroidotomy. Anaesthesia 2008; 63: 535-9. 22. Gulleth Y. TTJV as an op�on in airway management in head and neck surgery. Arch Otolaryngol Head Neck Surg 2005; 131(10): 886–90. 23. Friedrich G, Kiesler K, Gugatschka M. Curved rigid laryngoscope: missing link between direct suspension laryngoscopy and indirect techniques? Eur Arch Otorhinolaryngol 2009; 266(10): 1583–8. 24. Chandradeva K, Palin C, Ghosh SM. Perccutaneous transtracheal jet ven�la�on as a guide in severe upper airway obstruc�on from supraglo�c oedema. Br J Anaesth 2005; 94: 683–6. 25. Cook TM, Alexander R. Major complica�ons during anaesthesia for elec�ve laryngeal surgery in the UK: a na�onal survey of the use of high-pressure source ven�la�on. Br J Anaesth 2008; 101: 266–72. 26. Mausser G, Friedrich G, Schwarz G. Airway management and anesthesia in neonatus, infants and children during endolaryngotracheal surgery. Paediatr Anaesth 2007; 17: 942–7.


EXTUBATION OF A PATIENT WITH DIFFICULT AIRWAY Iljaz Hodzovic Department of Anaesthe�cs and Intensive Care Medicine, Cardiff University, Cardiff , United Kingdom

There is increasing body of evidence to suggest that extuba�ng pa�ents with difficult airway may be more hazardous than when managing difficult intuba�on. The 4th Na�onal Audit Project reported that almost 30% of major airway disasters happened at the end of anaesthesia and during recovery. Closed Claims Study in the USA found that death and severe brain injury were more often associated with extuba�on and recovery. This talk will address the following issues: • Iden�fying pa�ents who are likely to be difficult to extubate – Pa�ents with pre-exis�ng difficult airway – Pa�ents who develop difficult airway during surgery due to • Oedema, blood in the airway • Restricted airway access due to surgery (cervical spine fusion, mandibular wiring) • Developing extuba�on strategy – Assess extuba�on risk – Ask: Can the pa�ent be extubated? – Prepare for extuba�on • 100% O2, Suc�on, Pa�ent posi�on, bite block • Methods used to remove the tube in a pa�ent 'at risk' – Awake (wait for full responsiveness, no s�mula�on, regular breathing, good TV) – Deep • Advanced techniques: – Laryngeal Mask inser�on prior to removing the tube – Use of Remifentanil infusion to aid extuba�on of pa�ents ‘at risk’. – Airway exchange catheter use

hodzovic@cardiff.ac.uk

The evidence base for extuba�on prac�ce is limited and is mostly based on expert opinion. Planning extuba�on, however, is likely to avoid airway difficul�es associated with end of anaesthesia and recovery in this group of pa�ents. Awake extuba�on of a well analgised pa�ent is the preferred technique for most pa�ents with difficult airway. Advanced techniques of extuba�on have their place but should be prac�ced on pa�ents with normal airways before they can be applied to pa�ents who are iden�fied to be at risk at extuba�on.

References 1. Cook et al. Royal College of Anaesthe�sts 4th Na�onal Audit Project: Major Complica�ons of Airway Management in the UK. Royal College of Anaesthe�sts London, 2011. 2. Peterson et al. Management of difficult airway: a closed claims analysis. Anesthesiology 2005; 103: 33–9. 3. Mitchell et al. Extuba�on guidelines. Anaesthesia 2012; 67: 318–40 4. Rassam et al. Pa�ent posi�on. Anaesthesia 2005;60:995– 1001 5. Richardson et al. Extuba�on technique. Acta Clin Croat 2012; 51: 529–36.

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CHALLENGES FOR INTERNATIONAL SCIENTIFIC RESEARCH IN EUROPE Stefan De Hert

Research Department of Anesthesiology, Ghent University Hospital, Ghent University, Belgium

This presenta�on will give an overview of the different issues that are encountered in the organiza�on of scien�fic research and exchange of knowledge in Europe. These issues relate to organizatonal, financial, social, and language differences. The different problems will be addressed and possible solu�ons will be presented for discussion.

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[email protected]

Suggested literature 1. Egger Halbeis CB et al. Eur J Anaesthesiol 2007; 24: 991– 1007


EVIDENCE�BASED PRACTICE: A HELP FOR BEGINNERS? Massimo Lamper�

Department of Neuroanaesthesia, Na�onal Neurological Ins�tute Besta, Milan, Italy

Introduc�on Evidence-based medicine (EBM) is the conscien�ous, explicit and judicious use of current best evidence in making decisions about the care of individual pa�ents. The prac�ce of evidence-based medicine means integra�ng individual clinical exper�se with the best available external clinical evidence from systema�c research. A good healthcare professional uses both individual clinical exper�se and the best available external evidence, and neither alone is enough. Without clinical exper�se, medical prac�ce risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual pa�ent. Without current best evidence, medical prac�ce risks becoming rapidly out of date, this could cause terrific damages to our pa�ents. Evidence-based medicine is not restricted to randomised controlled trials and meta-analyses. It involves tracking down the best external evidence (observa�onal studies, good retrospec�ve analysis) to answer our clinical ques�ons. The Five Steps of EBP Evidence-based prac�ce (EBP) is primarily based on five well-defined steps. The five steps of EBP were first described in 1992 and most steps have now been subjected to trials of teaching effec�vely it. The five steps are: 1. Asking Focused Ques�ons: transla�on of uncertainty to an answerable ques�on First, the ques�on should be directly relevant to the problem at hand. Next, the ques�on should be phrased to facilitate searching for a precise answer. To achieve these aims, the ques�on must be focused and well ar�culated for all 4 parts of its 'anatomy': a. the pa�ent or problem being addressed; b. the interven�on or exposure being considered; c. the comparison interven�on or exposure, when relevant; d. the clinical outcomes of interest.

[email protected]

2. Finding the Evidence: systema�c retrieval of best evidence available Training improves search performance and the quality of evidence retrieved. Searching the literature could improve the treatment of many medical inpa�ents, including those already receiving evidence-based treatment. 3. Cri�cal Appraisal: tes�ng evidence for validity, clinical relevance, and applicability Cri�cal appraisal is the process of assessing and interpre�ng evidence by systema�cally considering its validity, results and relevance to an individual’s work. Within the last decade cri�cal appraisal has been added as a topic to many interna�onal medical schools, and several con�nuing professional development ventures have been funded to provide further training. 4. Making a Decision: applica�on of results in prac�ce Many health professionals have recognized the need for instruc�on in evidence-based medicine. A curriculum intended to develop a resident-produced, evidence-based guideline for the care of pa�ents with a specific disease as diabetes. Each resident was supervised going through the steps of evidence-based medicine: asking a clinical ques�on, searching for the evidence to answer that ques�on, appraising that evidence, and producing an evidence-based answer. These answers were then compiled into a guideline distributed in the residency prac�ce. An evalua�on of this curriculum using focus group and survey data showed that learners appreciated the skills and knowledge gained in devising guidelines in an evidence-based manner but were uncertain that their searches were complete. The clinical evalua�on of the guideline implementa�on showed improvement in several clinical markers of diabetes care. 5. Evalua�ng Performance: audi�ng evidencebased decisions It appears logical that healthcare professionals would be prompted to modify their prac�ce if given feedback that their clinical prac�ce was inconsistent with that of their peers or accepted 111


guidelines. One such strategy, audit and feedback, con�nues to be widely used as a strategy to improve professional prac�ce.

Is EBM efficient? Evidence based medicine, s�ll young, faces challenges in integra�on into clinical prac�ce. A five year old Cochrane review by Parkes and colleagues found sparse evidence: just one randomised controlled trial showing that about six hours of journal club �me devoted to cri�cal appraisal increased knowledge of this. Two subsequent randomised controlled trials by Smith and Green, with broader teaching, showed a sustained educa�onal benefit across several of the processes of EBM. Another systema�c review by Coomarasamy shows that integra�ng the teaching of the steps of EBM with clinical prac�ce is vital to improving a�tudes, skills, and behaviour. Integra�on means applying the steps to real and current clinical problems. Thinking is not enough and doing is necessary for success.

How EBP has to be applied Role modelling may also be necessary. Unless students see their role models use EBM in prac�ce, they are unlikely to value it as clinically important. Therefore, specific content in their daily clinical educa�on must refer to relevant trials and cohort studies to show how research methods integrate with clinical prac�ce. Teaching EBM may need to focus as much on teachers as on students and registrars. In postgraduate environments, one useful modelling step is modified and ques�on driven journal clubs to enable registrars in hospital or general prac�ce to engage in a communal EBM ac�vity. Another way to improve the teaching of EBM in the postgraduate environment is to create evidence teams consis�ng of registrars and medical students to find evidence in everyday clinical se�ngs. Their evalua�on of the evidence can then be evaluated by the consultant on the team, who would be in the best posi�on to evaluate the use of that evidence for the pa�ent.

EBP in cri�cal care Demographics of the US and European popula�on ages predicts that by the 2020 the supply of intensivists will meet only 22% of the demand for their services. There will be a transi�on from the “old way” of teaching ("see one, do one, teach 112

one") and training to a modern and more objec�ve method of teaching supported by literature but applied to clinical prac�ce. EBM will be one of the solu�ons, together with new technologies for point-of-care diagnosis that will help future intensivist improving outcomes in their pa�ents. One excellent applica�on of EBM is the Surviving Sepsis Campaign (SSC) Guidelines for the management of severe sepsis and shock pa�ents. These guidelines are now adopted by 11 interna�onal Cri�cal Care socie�es and based on the GRADING system. A first ques�on answered by the SSC guideline was: what is the best ven�lator management of ARDS pa�ents? A low �dal volume strategy is the best prac�ce according EBM. The hypothesis that the classical prac�ce of Vt 10 to15 ml/kg could have adverse effects was confirmed by the ARDS-net trial published in 2000 that compared a 6ml/kg vs. a 12ml/kg ven�la�on strategy in a randomized mul�centre controlled trial. The result was a reduc�on in mortality of 22% using the low �dal volume strategy. In prac�ce, when ARDS is diagnosed, Vt has to be adjusted for ideal body weight and a permissive hypercapnea has to be allowed. The same networking group, four years later, demonstrated that low vs. high levels of PEEP have no difference in number of ven�lator free days or mortality rate. The use of steroids for late ARDS was abandoned as a placebo vs. steroids trial demonstrated that there was no value in use of steroids in late ARDS. Similar findings were analysed for other ARDS modali�es as prone posi�on, inhaled nitric oxide, surfactant and liquid ven�la�on that were no longer considered as beneficial for ARDS pa�ents. Another example of EBP in cri�cal care is glucose control in cri�cally ill pa�ents. In 2001 a single-centre randomized controlled trial published in the New England Journal of Medicine involving 1548 surgical pa�ents randomised pa�ents according a �ght vs. non �ght glycemic control (80-120mg/dl vs. 150mg/dl). The study revealed a 43% risk reduc�on in ICU mortality in the �ght glycemic control group. This study revealed also a 50% decrease of blood-stream infec�ons, acute renal failures requiring renal replacement treatment (RRT), cri�cal illness polyneuropathy, less transfusion requirement with a shorter dura�on of mechanical ven�la�on, ICU care and less mul�ple organ failure. The same intensive insulin therapy was applied in another single centre trial in 2004 with similar results although most of the benefits were found in sep�c pa�ents. Although these studies provide good evidence on the applica�on of the �ght glycemic control in sep�c pa�ents there should be some cri�cism before applying these results to all ICU pa�ents because those two studies were done in a single centre


and mainly with surgical pa�ents. For these reasons, the grading of these studies was considered low and the protocol cannot be generalized to all cri�cally ill pa�ents. The use of cor�costeroids in sep�c shock was widely studied. The old teaching was to avoid the use of high dose steroids in sep�c pa�ents while the new though in recent years was that pa�ents with sep�c shock who are unresponsive to pressor agents might have adrenal insufficiency. The incidence of adrenal insufficiency is 30-50% in cri�cally ill pa�ents and 50-60% in pa�ents with sep�c shock. Clinical presenta�on is resistant hypotension, hyponatriemia, and hyperkaliemia. This can happen with low or normal serum cor�sol levels. A mul�center randomized controlled trial published in 2002 in JAMA on 300 pa�ents with sep�c shock and vasopressor therapy demonstrated that with a baseline cor�sol level of 38.5◦C, bacterial superinfec�on); (e) Parental confirma�on of the child’s symptoms, parental belief, 'the child has a cold' (f) Passive smoke exposure.(1) [email protected]

The ques�ons of whether to cancel surgery and anesthesia for a child with an URI and how long to delay the procedure, if it is postponed, have not been ul�mately answered. However, there is a consensus that it is no longer mandatory to postpone surgery for a period of 6 weeks. Several authors have proposed a delay of at least 2 weeks when acute clinical signs of an infec�on are observed.(2,3) Overtly sick children who have fever >38°C, purulent nasal discharge, produc�ve cough and are ill-appearing with signs of pulmonary involvement should have elec�ve surgeries postponed for at least 4 weeks. Those with mild URI who have clear rhinorrhea, appear otherwise healthy, have clear lungs to ausculta�on and no fever, will not require ETT (endotracheal tube) and will not undergo surgery involving the airway can be safely anaesthe�zed without significant morbidity. Ul�mately the decision to proceed or postpone surgery in a child with URI rests on the anaesthe�st a�er consulta�on with surgeon and parents who should be fully informed of the risks. PRAEs can be prevented in many cases and thus rarely lead to serious periopera�ve morbidity and mortality. The preven�ve effects of salbutamol when given as a premedica�on agent were studied by von Ungern- Sternberg et al.(4), who showed in a prospec�ve observa�onal study that the premedica�on of children with a recent URI with high-dose inhala�onal salbutamol (2.5– 5mg) reduced the risk of PRAEs by at least 35%. Hence, salbutamol pretreatment should be considered in all children presen�ng with a URI or a moist cough. Combining salbutamol with inhaled cor�costeroids is more effec�ve in minimizing bronchoconstric�on due to intuba�on compared with inhaled ß2 agonist alone. Hamilton et al.(5) inves�gated more than 1000 children for elec�ve general anesthesia with endotracheal intuba�on and found a significantly higher rate of desatura�on in children treated with topical lidocaine compared with the placebo group. In this study, no difference in the incidence of laryngospasm was found. There is s�ll a lack of evidence for the preven�ve effects of 155


intravenous lidocaine on the incidence of PRAEs. von Ungern-Sternberg et al.(6) suggest that ‘intravenous anesthesia with propofol might be associated with lower incidence of PRAE with a be�er preven�ve effect when used as a maintenance drug compared to sevoflurane’, and Lerman(7) comments on the findings that ‘one should an�cipate a reduced frequency of PRAEs a�er intravenous induc�on of anesthesia than a�er inhala�onal induc�on, even when a minimally noxious agent such as sevoflurane is used’. A study found no difference between the laryngeal mask and the face mask with regard to the occurrence of periopera�ve bronchospasm, but the use of the laryngeal mask was associated with a significantly higher risk of laryngospasm, although to a lesser extent than with the use of tracheal tube.(6)

Asthma Asthma is the most common chronic disease in children. Asthma is defined by chronic inflamma�on of the airways, associated with airway hyperresponsiveness, which leads to recurring episodes of wheezing, coughing, breathlessness, and chest �ghtness and reversible airflow obstruc�on within the lung. ß-Adrenergic agonists are commonly used to provide rapid relief of acute bronchospasm (shortac�ng ß-agonists, SABAs) and are also used for chronic treatment (long-ac�ng ß-agonists, LABAs) but only in combina�on with inhaled cor�costeroids. Although they may be administered by oral or i.v. routes, inhala�on administra�on provides faster peak bronchodilata�on and fewer systemic side-effects. Inhaled cor�costeroids are the founda�on of treatment for asthma because they target the inflamma�on that characterizes the disease. Leukotriene modifiers are most commonly used as secondline controller medica�ons. Ipratropium bromide inhibits mucous hypersecre�on and decreases reflex bronchoconstric�on by targe�ng airway muscarinic cholinergic receptors.(8) Essen�al points to review in the preopera�ve evalua�on are the level of asthma control and the current medica�on regimen. Although otherwise healthy children can o�en be anaesthe�zed safely during an acute upper respiratory infec�on (URI), the risk of bronchospasm in asthma�cs is very high. They should ideally be postponed 4–6 weeks a�er such an event. Physical examina�on should include vital signs, assessment for wheezing, cough, type of breath sounds, use of accessory muscles, and level of hydra�on. The diagnoses of atopy/eczema and allergic rhini�s o�en go hand in hand with a diagnosis of asthma as they are all thought to be condi�ons of chronic inflamma�on. A family history of asthma and atopy also 156

contributes to intraopera�ve respiratory complica�ons. As in adults, significant gastro-oesophageal reflux disease can o�en be a trigger for asthma symptoms. Obese pa�ents present a variety of anaesthe�c challenges.(8) Preopera�ve prepara�on for a controlled asthma�c can include a use of an inhaled ß-2 adrenergic agonist 1–2 h before surgery. For moderately controlled asthma, addi�onal op�miza�on with an inhaled cor�costeroid and regular use of inhaled ß-2 agonists 1 week before surgery can be ins�tuted. Poorly controlled asthma�cs might need addi�on of one of the following: oral prednisone 1 mg/kg/day (60 mg max) 3–5 days before surgery, oral dexamethasone 0.6 mg/kg (16 mg max), or oral methylprednisolone 1 mg/kg for 48 h before surgery. Preopera�ve use of systemic cor�costeroids has been shown to suppress produc�on of inflammatory cytokines and mul�ple studies confirm the safety of a periopera�ve pulse of systemic cor�costeroids.(9) Pa�ents should con�nue all their controller medica�ons as normal on the day of surgery. Premedica�on with oral midazolam, 0.5–1 mg/kg, is safe in asthma�cs, and can be indicated since anxiety can precipitate acute bronchospasm. The use of systemic cor�costeroids in the last 6 months or high-dose inhaled cor�costeroids is an indica�on for stress dose coverage.(10) If indicated by the preopera�ve evalua�on, it is s�ll not too late to give i.v. cor�costeroids as their beneficial effect will extend into the postopera�ve period. If an i.v. catheter is in place before induc�on, several medica�ons can be given to diminish the response to tracheal intuba�on. Lidocaine can prevent reflex bronchoconstric�on and has li�le toxicity at a dose of 1–1.5 mg/kg i.v., 1–3 min before tracheal intuba�on. Direct spraying of the airway can trigger airway reac�vity, so the i.v. route is preferable. I.V. atropine given long with an i.v. induc�on or a�er an inhala�on induc�on may decrease secre�ons and provide addi�onal bronchodilata�on before tracheal intuba�on via their effect at muscarinic receptors. The choice between i.v. and inhala�on induc�on is o�en influenced by mul�ple clinical factors. There is li�le compelling evidence to suggest one technique over another in asthma�c children. If an i.v. induc�on is chosen, propofol is the i.v. induc�on agent of choice in haemodynamically stable asthma�c pa�ents. It has been shown in mul�ple studies to a�enuate the bronchospas�c response to tracheal intuba�on, both in asthmatic and non-asthma�c pa�ents.(11) Ketamine is the induc�on agent of choice in haemodynamically unstable asthma�c pa�ents. It likely produces smooth muscle relaxa�on and bronchodilata�on directly, via release of catecholamines and vagal-


ly mediated mechanisms, although its bronchoprotec�ve effect is not as pronounced as that of propofol.(12) Its mucous-s�mula�ng effects can be ameliorated by pretreatment with atropine. Vola�le anaesthe�cs have long been known to depress airway reflexes to tracheal intuba�on and cause direct airway smooth muscle relaxa�on. Sevoflurane seems to have the most pronounced effects of all the inhala�on anaesthe�cs and is the agent of choice for mask induc�on. As a word of cau�on: in children with asthma, tracheal intuba�on with sevoflurane as the sole anaesthe�c (even at 5% concentra�on) causes an increase in respiratory system resistance compared with non-asthma�c children. During maintenance of anaesthesia, children with asthma have shown low airway resistance with a propofol infusion, but in most asthma�c children, switching to sevoflurane further improved this effect.(8) The decision regarding airway management is likewise influenced by mul�ple clinical factors. As tracheal intuba�on is one of the most potent triggers for bronchospasm, choosing a laryngeal mask airway (LMA) or simple mask may be useful.When endotracheal intuba�on is performed, the use of uncuffed endotracheal tubes appears to be the first choice op�on in children, especially in smaller ones; anatomical features and an appropriate tube size ensure an adequate sealing.(13) The presence of asthma may represents a further indica�on to uncuffed tube usage. When a cuffed endotracheal tube is required (e.g. headneck surgery, neurosurgery, laparoscopic surgery) a perfect �ming of extuba�on is essen�al; indeed cuff defla�ng could represent a further irrita�ng factor. In order to avoid airway reflexes, extuba�on could be performed when the child is deep but with a spontaneous and valid respiratory ac�vity.(14) On the contrary, according to Taylor et al.(15) , and Weiss et al.(16) if tracheal intuba�on is required, the use of cuffed tracheal tubes allows for avoidance of mul�ple intuba�ons due to air leak, more reliable EtCO2 waveform monitoring, and the use of lower fresh gas flows. Intuba�on could be performed under deep inhala�on anesthesia and muscle relaxa�on drugs are not necessary during the majority of ambulatory and minor surgical procedures, especially for younger children.(14) Non-histamine-releasing neuromuscular blocking agents such as rocuronium, vecuronium, and cisatracurium are acceptable for use in children with asthma. Reversal of neuromuscular block with acetylcholinesterase inhibitors (e.g. neos�gmine) can be undertaken with cau�on in asthma�cs but carries the risk of residual neuromuscular block and muscarinic side-effects including bronchospasm. Synthe�c opioids like fentanyl and remifentanyl have not been associated with a significant

histamine release and therefore they have been used in asthma�c pa�ents.(14) Airway irrita�on should be minimized by humidifica�on of inspired gases. S�mula�on of the trachea by suc�oning should also be minimized and performed only with deep levels of anaesthesia. During mechanical ven�la�on, inspiratory pressures should be kept low and the expiratory �me lengthened. On a theore�cal basis, deep extuba�on should decrease the risk of bronchospasm evoked by coughing on the tracheal tube; however, li�le research has been done to answer this ques�on for asthma�c children. Regional anaesthesia should be considered whenever possible to avoid airway manipula�on.

Epilepsy Epilepsy has a prevalence of 1:200 in adults and is approximately twice as common in childhood. There is a U-shaped distribu�on, with the highest incidences in the first few months of life and in those aged more than 70 yr. Primary epilepsy has a gene�c predisposi�on with a 1.5–3% risk of paternal inheritance and a 3–9% risk of maternal inheritance. Secondary seizures may be caused by prenatal, perinatal, or post-natal events. Seizures may be par�al (focal), or generalized, or they may start as par�al and progress to generalized. Therapy is usually started with one an�epilep�c drug (AED) at a dose likely to result in therapeu�c plasma level, a�er which the dose can be op�mized as required. AEDs have mul�ple sideeffects and drug interac�ons which need to be considered when planning anaesthesia. Sodium valproate, carbamazepine, and ethosuximide can be associated with hepatotoxic effects as well as with thrombocytopenia and platelet abnormali�es.(17) The ketogenic diet (KD) is one treatment op�on for children with epilepsy whose seizures are not controlled with AEDs. Side-effects of KD include poor growth, especially in children ˂1 yr of age (typically below the 10th cen�le), kidney stones, skeletal fractures, dyslipidaemia, hypoprotenaemia, and elevated liver enzymes.(18) These effects, in addi�on to the ketoacidosis, need to be considered when planning anaesthesia. Febrile convulsions are probably the most common epilep�c seizure disorders; about 3–4% of all children below 5 years of age have presented at least one febrile seizure. The gene�c predisposi�on to febrile convulsions may be strong. In the interictal stage, the EEG records are usually normalized. The vast majority of febrile convulsions have an excellent prognosis. An�convulsive medica�ons are not necessary in this context.(19) Epilep�c children commonly present for surgical procedures not related to epilepsy or less 157


frequently, they may present for defini�ve neurosurgery to treat an epilep�c focus. Preopera�ve assessment (special focus on epilepsy and other coexis�ng medical problems) is important in neonates and infants, who are at a higher risk of periopera�ve morbidity. Epilepsy may be related to birth injury, perinatal hypoxia, or part of a syndrome or other disease (e.g. tuberous sclerosis, craniosynostosis, or microcephaly). These condi�ons may have other anaesthe�c implica�ons and that of epilepsy. Pa�ents on sodium valproate, carbamazepine, and ethosuximide should have their liver func�on, platelet count, and coagula�on indices checked. In poorly controlled epilepsy, plasma levels of AEDs should be measured and op�mized before opera�on. AEDs should be con�nued up to the �me of the surgery and should be restarted as soon as possible a�er opera�on. Fortunately, most have a long half life, so a delayed or even a missed dose is not usually cri�cal. However, in intractable epilepsy, or if the child is planned to be nil by mouth a�er opera�on, a periopera�ve an�epilep�c treatment plan should be agreed with the neurologist, as many AEDs are not available in parenteral prepara�ons.(17) Hyperven�la�on decreases seizure threshold, so anxious children may benefit from seda�ve premedica�on. However, one must consider the interac�on with AEDs. Enzyme induc�on may increase dose requirements, whereas phenobarbital and benzodiazepines may enhance seda�ve effects.(17) Midazolam has potent an�convulsant ac�vity and is commonly used in the treatment of status epilep�cus.(20) When planning induc�on of anaesthesia, one should consider the child's general condi�on and coexis�ng medical condi�ons. The theore�cal advantages of some agents are outweighed by the prac�cali�es of administering them to an uncoopera�ve child. Although sevoflurane may cause epilep�form EEG changes, inhala�on induc�on with sevoflurane and nitrous oxide in oxygen is s�ll an appropriate technique in epilep�c children. Older children and children with established i.v. access may opt for i.v. induc�on with propofol (3–4 mg/kg) or thiopental (5–8 mg/kg). Propofol in small doses also causes epileptogenic changes in the EEG, but in anaesthe�c doses, it suppresses EEG ac�vity.(17) In spite of the conflic�ng results in the literature, there is clinical evidence that propofol has an�convulsant effect and is considered a safe drug for seda�on, induc�on and maintenance of general anesthesia in children. In pa�ents with epilepsy, the occurrence of seizures of epilep�c origin is extremely rare with the use of propofol, and occurs frequently in the recovery from anesthesia. The an�epilep�c ac�vity of propofol is probably related 158

to inhibi�on of pre-and postsynap�c chloride channels mediated by GABA. Propofol can cause abnormal movements, as opisthotonus and myoclonia in both epilep�c and healthy pa�ents, but these changes do not seem to relate to epileptogenic ac�vity. Propofol is an effec�ve alterna�ve in the treatment of refractory epilep�c seizures to usual an�epilep�c drugs and in cases of status epilep�cus. Barbiturates, except for the methohexital, present a significant an�convulsant ac�vity in the EEG, and its use is considered safe for induc�on of anesthesia in epilep�c pa�ents, as well as treatment of status epilep�cus. Etomidate appears to have an�convulsant ac�vity at high doses and pro-convulsant characteris�cs in usual clinical doses. Threfore, it is recommended to avoid its use in epilep�c pa�ents. Most of the clinical evidence shows that ketamine, at usual doses, has significant epileptogenic poten�al, and should be, therefore, avoided in epilep�c pa�ents. It is recommended to avoid the use of high doses or rapid administra�on of opioids of the phenylpiperidine group (fentanyl, alfentanil, remifentanil and sufentanil) in epilep�c pa�ents.(20) Although nitrous oxide has excitatory effects on central nervous system, the epileptogenic poten�al of the drug is very low and can be used safely in epilep�c pa�ents. The epilep�form ac�vity of sevoflurane has been extensively studied. The depth of anesthesia with sevoflurane and/or the presence of hyperven�la�on (hypocapnia) were risk factors for the emergence of excitatory ac�vity of the central nervous system. It is recommended to avoid sevoflurane at concentra�ons above 1.5 MAC in epilep�c pa�ents in the presence of hypocapnia. In this context, hypocapnia should be especially avoided in the youngest pa�ent.(19) Enzyme induc�on caused by AEDs can cause resistance to nondepolarizing neuromuscular blockers (NMBs), and their dose and frequency may need to be increased. The use of a peripheral nerve s�mulator to monitor the effect of NMBs is recommended. If rapid sequence induc�on is required to secure the airway a�er a prolonged seizure or in status epilep�cs, succinylcholine should be avoided as it can cause a sudden catastrophic increase in serum potassium. In these circumstances, rocuronium can be used. Laudanosine, a metabolite of atracurium, has epileptogenic poten�al, so large doses and prolonged infusions of atracurium should be avoided. Hyperven�la�on reduces the seizure threshold and so normocapnia should be the aim during controlled ven�la�on.(17)


Regional anaesthesia is safe and can be used as the sole anaesthe�c technique in older children, as long as epilepsy is well controlled and factors known to precipitate seizures are avoided. However, many anaesthe�sts would not use a pure local anaesthe�c technique in epilep�c pa�ents, to avoid the possibility of intraopera�ve seizure, which can be precipitated by hypocapnia induced by the anxious child hyperven�la�ng.(17) It is essen�al to restart the an�epilep�c treatment in the postopera�ve period as soon as possible. Plasma levels of AEDs must be checked if there is any delay in restar�ng them or if periopera�ve seizures occur. Seizures are more common in the postopera�ve period.

Obesity The prevalence of childhood obesity is increasing. More than 90% of childhood obesity cases are primary, caused by excessive calorie consump�on. The remaining cases are secondary to underlying diseases like endocrine disorders, neurological dysfunc�on, and syndromes (e.g. Prader Willi). Childhood obesity is associated with numerous comorbidi�es. Pediatric obesity correlates with reduc�ons in func�onal residual capacity (FRC), expiratory reserve volume (ERV), forced expiratory volume in 1 s (FEV1), and diffusion capacity (DLCO). Childhood obesity may induce bronchial hyperreac�vity, and approximately 30% of obese 8–18-year-olds have asthma with increase in both incidence and severity with increasing BMI (body mass index).(21) Obstruc�ve sleep apnea (OSA) is reported in 13– 59% of obese children, compared to 1–2% of normal weight children. Children with OSA have a diminished ven�latory response to CO2 compared to other children. This has clinical implica�ons in spontaneously breathing anesthe�zed children and in the postanesthe�c care unit.(22) Use of systemic opioids in children with OSA increases the risk of postopera�ve respiratory depression. There is a posi�ve correla�on between incidence of hypertension and increasing BMI; 20–30% of obese children have hypertension. Furthermore, le� ventricular hypertrophy, hypercholesterolemia, and hyperlipidemia which are also cardiac risk factors are common in obese children. Blood pressure should be measured preopera�vely and a detailed history of physical ability which is highly consistent with actual physical performance in obese children should be obtained to determine the degree of cardiopulmonary compromise.(22) If cardiac disease is suspected, an echocardiography and electrocardiogram should be obtained.

Forty to fi�y percent of obese adolescents suffer from the metabolic syndrome with a high risk of insulin resistance and possibility to develop type 2 diabetes mellitus (DM). Previously, the typical presenta�on of diabetes in childhood was Type I or insulin-dependent diabetes. However, with the rise in obesity in childhood, there has also been a rise in NIDDM as well.(23) A preopera�ve fas�ng blood glucose level should be obtained, because undiagnosed type 2 DM is frequent.(24) As with adults, obese children have an increased incidence of gastroesophageal reflux disease (GERD) and may have delayed gastric emptying. But, a 2-h fas�ng period of clear liquid is sufficient even in obese children with gastroesophageal reflux.(25) Obtaining an intravenous catheter in obese children can be difficult. Highly lipophilic substances such as barbiturates and benzodiazepines tend to show significant increases in volume of distribu�on and less lipophilic drugs such as non-depolarizing muscle relaxants have minimal or no change in volume of distribu�on. Thus, assuming that a highly lipophilic drug should be dosed based on TBW (total body weight) can result in severe overes�ma�on. Hepa�c metabolism is usually only minimally affected, but renal clearance may actually be increased secondary to increased renal blood flow and GFR. However, with an increased volume of drug distribu�on, elimina�on half-life might be prolonged (e.g. diazepam). Monitoring the depth of anesthesia could be helpful in �tra�ng anesthe�cs in obese children. Succinylcholine is the only drug used in anesthesia prac�ce that has been fully pharmacokine�cally studied in obese children.(26) Despite its hydrophilicity, succinylcholine should be dosed according to TBW because of an increased pseudocholinesterase ac�vity in this popula�on. The vola�le anesthe�cs accumulate in adipose �ssue over �me, which may result in delayed recovery. Sevoflurane may be the inhala�onal drug of choice for obese children, but studies are performed on obese adults – not children. If tolerated by the pa�ent, N2O with its low fat solubility may allow faster �tra�on of anesthesia and shorter recovery �mes. However, the typical need for increased FiO2 in this pa�ent popula�on limits its use. Regional anesthesia is common in pediatric anesthesia. The reduced risk of postopera�ve respiratory depression and airway compromise makes both peripheral nerve blocks and neuroaxial blockade seemingly a�rac�ve for obese children, but there are no studies of this subject.(22) Obesity, age < 10 years, OSA, and procedures involving the airway were iden�fied as risk fac159


tors of periopera�ve respiratory complica�ons.(27) Alarming for the anesthesiologist is the correla�on between child obesity and increased reac�ve airway disease. Also, there has been shown an associa�on between increased respiratory infec�ons and increased BMI. Due to the increased work of breathing from obesity, the pa�ent can’t increase ven�la�on enough to normalize PaCO2 values. Owing to higher oxygen consump�on and less oxygen reserve, children develop hypoxemia faster than adults and obese children are more prone to intraopera�ve desatura�on than normal weight children.(28) A thorough and though�ul evalua�on of the airway of the obese child is mandatory during the pre-op visit. One must also consider whether there will be reduced compliance of the submental space from fa�y deposi�on, whether there will be collapse of so� �ssue structures into the oral cavity during induc�on, whether shoulder fat deposi�on will limit neck extension, or whether chest size will limit the placement of a laryngoscope handle. If available, review prior anesthe�c records for evidence of difficulty with mask ven�la�on or intuba�on. This must be viewed with respect to recent weight gain. Ques�ons to consider now include: Will there be difficulty with mask ven�la�on? Should atropine be given to dry secre�ons? Will I need addi�onal trained anesthesia help? What is my back up plan? The pa�ent should be evaluated for degree of pulmonary compromise. Is there baseline hypoxemia? Is there a history of obstructed sleep or breathing? Is there a component of reac�ve airway disease and does it respond to bronchodilators? Have there been recurrent episodes of upper respiratory tract infec�ons (URI’s) and when was the most recent? The pa�ent should have a room air pulse oximetry value recorded. A�er the evalua�on is complete, consider whether the pa�ent will need post-op respiratory support. If the pa�ent will need to remain intubated or will need a con�nua�on of CPAP or BiPAP support, arrange for the bed-space prior to star�ng the opera�on. Discuss these plans with the pa�ent and family.(29) The pa�ent’s home medica�ons should be reviewed including an�hypertensive medica�ons, bronchodilators, insulin, an�-diabe�c medica�ons, and weight loss medica�ons. See that there is a blood pressure cuff that is big enough. Obese children do not have an increased risk of pulmonary aspira�on when compared to normal weight children, and there is no evidence that rapid sequence induc�on (RSI) should be performed in all obese children. The risk of difficult mask ven�la�on is further increased in obese compared to normal weight children.(27) 160

Based on the circumstances involved, induc�on will be either an inhaled or IV induc�on. As discussed above, the decision will be made based on the age and maturity of the pa�ent, the airway examina�on, prior anesthe�c history, poten�al for IV access, and risk of aspira�on. The pa�ent should be preoxygenated for 3 to 4 minutes prior to induc�on as a decreased FRC and increased metabolic rate may lead to rapid O2 desatura�on during hypoven�la�on or apnea. Preoxygena�on may be best accomplished with the pa�ent in slight reverse Trendelenburg posi�on with a small amount of PEEP(30) that prevents atelectasis of lung �ssue and thereby oxygen desatura�on. Difficult laryngoscopy in obese compared to normal weight children has been evaluated.(27) The incidences seem to be the same, but results are heterogeneous. Laryngeal mask airway (LMA) may be reasonable for a short case not involving the abdomen in a lower risk obese pa�ents. However, given the risk of aspira�on and poten�al for hypoxemia, this should be considered with cau�on. On the other hand, an appropriate sized LMA should be readily available as part of the difficult airway algorithm.(29) When using LMA, choosing size according to TBW significantly increases the oropharyngeal leak pressure and gives be�er ven�la�ng condi�ons in overweight children.(31) Consider the use of an�-embolic stockings or sequen�al compression devices to prevent the development of deep venous thrombosis. Cisatracurium has been shown to be the most predictable non-depolarizer in obese pa�ents.(32) Any non-depolarizing muscle relaxant should be re-dosed with the use of a nerve s�mulator. Total IV anesthesia (TIVA) has been used effec�vely with combina�ons of propofol, remifentanil, sufentanil, fentanyl, and midazolam, but there would likely need to be a specific indica�on for its use. When opioids are given, it is recommended to use shorter ac�ng drugs and dose them on IBW. Obese pa�ents are at a greater risk for postopera�ve nausea and vomi�ng, especially those who receive neuroaxial opioids. An an�-eme�c should be administered based on IBW. Ketorolac dosed on IBW and the infiltra�on of local anesthe�cs into the incision site can also help with post-opera�ve pain management. The pa�ent should be extubated when fully awake(33) and in a semisi�ng posi�on, if possible, because reducing abdominal pressure on the diaphragm can increase FRC by up to 30%.


Conclusion In the case of upper respiratory tract infec�on (URI) blanket cancella�on as performed in the past is no longer indicated, and the literature supports selec�ve decisions on a case-by-case basis. Children with co-exis�ng pulmonary disease, such as asthma, have a wide range of clinical manifesta�ons with significant implica�ons for anaesthe�sts. Many anaesthe�c agents are reported to cause seizures, while also having an�convulsant effects in a dose-dependent fashion; low doses are usually proconvulsant, whereas higher doses are an�convulsant. Obese children not only have anaesthesia-relevant co-exis�ng diseases, that are, asthma and hypertension, but also have a higher incidence of anaesthesia-related complica�on.

References 1. Becke K. Anesthesia in children with a cold. Curr Opin Anesthesiol 2012; 25: 333–9. 2. von Ungern-Sternberg BS, Boda K, Schwab C, et al. Laryngeal mask airway is associated with an increased incidence of adverse respiratory events in children with recent upper respiratory tract infec�ons. Anesthesiology 2007; 107: 714–9. 3. Rachel Homer J, Elwood T, Peterson D, et al. Risk factors for adverse events in children with colds emerging from anesthesia: a logis�c regression. Paediatr Anaesth 2007; 17: 154–61. 4. von Ungern Sternberg BS, Habre W, Erb TO, et al. Salbutamol premedica�on in children with a recent respiratory tract infec�on. Pediatr Anesth 2009; 19: 1064–9. 5. Hamilton ND, Hegarty M, Calder A, et al. Does topical lidocaine before tracheal intuba�on a�enuate airway responses in children? An observa�onal audit. Pediatr Anesth 2012; 22(4): 345–50. 6. von Ungern-Sternberg, Boda K, Chambers NA, et al. Risk assessment for respiratory complica�ons in paediatric anaesthesia: a prospec�ve cohort study. Lancet 2010; 376: 773–83. 7. Lerman J. Periopera�ve respiratory complica�ons in children. Lancet 2010; 376: 745–6. 8. Lauer R, Vadi M, Mason L. Anaesthe�c management of the child with co-exis�ng pulmonary disease. Br J Anaesth 2012; 109 Suppl 1: i47–i59. 9. Su FW, Beckman DB, Yarnold PA, Grammer LC. Low incidence of complica�ons in asthma�c pa�ents treated with preopera�ve cor�costeroids. Allergy Asthma Proc 2004; 25: 327–33. 10. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and preven�on: GINA execu�ve summary. Eur Respir J 2008; 31: 143–78. 11. Eames WO, Rooke AG, Sai-Chuen Wu R, Bishop MJ. Comparison of the effects of etomidate, propofol, and thiopental on respiratory resistance a�er tracheal intuba�on. Anesthesiology 1996; 84: 1307–11. 12. Brown RH, Wagner EM. Mechanisms of bronchoprotec�on by anesthe�c induc�on agents: propofol versus ketamine. Anesthesiology 1999; 90: 822–8.

13. Weber T, Salvi N, Orliaguet G, et al. Cuffed vs non cuffed endotracheal tubes for pediatric anesthesia. Paediatr Anaesth 2009; 19: 46–54. 14. Dones F, Foresta G, Russo�o V. Update on periopera�ve management of the child with asthma. Pediatr Rep 2012; 4(2): e19. 15. Taylor C, Subaiya L, Corsino D. Pediatric cuffed endotracheal tubes: an evolu�on of care. Ochsner J 2011; 11: 52–6. 16. Weiss M, Dullenkopf A, Fischer JE, Keller C, Gerber AC. Prospec�ve randomized controlled mul�-centre trial of cuffed or uncuffed endotracheal tubes in small children. Br J Anaesth 2009; 103: 867–73. 17. Barakat AR, Mallory S. Anaesthesia and childhood epilepsy. Con�nuing Educa�on in Anaesthesia, Cri�cal Care & Pain 2011; 11(3): 93–98. 18. Vining EPG. Long-term health consequences of epilepsy diet treatments. Epilepsia 2008; 49(Suppl. 8): 27–9. 19. Constant I, Seeman R, Murat I. Sevoflurane and epilep�form EEG changes. Paediatr Anaesth 2005; 15(4): 266–74. 20. Maranhão MV, Gomes EA, de Carvalho PE. Epilepsy and anesthesia. Rev Bras Anestesiol 2011; 61(2): 232–41. 21. Lang JE, Feng H, Lima JJ. Body mass index-percen�le and diagnos�c accuracy of childhood asthma. J Asthma 2009; 46: 291–9. 22. Mortensen A, Lenz K, Abildstrøm H et al. Anesthe�zing the obese child. Paediatr Anaesth 2011; 21(6): 623–9. 23. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. Pediatrics 2005; 116: 473–80. 24. Gidding SS, Nehgme R, Heise C et al. Severe obesity associated with cardiovascular decondi�oning, high prevalence of cardiovascular risk factors, diabetes mellitus/ hyperinsulinemia, and respiratory compromise. J Pediatr 2004; 144: 766–9. 25. Cook-Sather SD, Gallagher PR, Kruge LE et al. Overweight/ obesity and gastric fluid characteris�cs in pediatric day surgery: implica�ons for fas�ng guidelines and pulmonary aspira�on risk. Anesth Analg 2009; 109: 727–36. 26. Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 2000; 90: 576–8. 27. Tait AR, Voepel-Lewis T, Burke C et al. Incidence and risk factors for periopera�ve adverse respiratory events in children who are obese. Anesthesiology 2008; 108: 375–80. 28. Setzer N, Saade E. Childhood obesity and anesthe�c morbidity. Pediatr Anesth 2007;17: 321–326. 29. Ross PA, Sco� GM. Childhood obesity: a growing problem for the pediatric anesthesiologist. J Crit Care 2006; 25(3): 142–8. 30. Dixon BJ, Dixon JB, Carden JR, et al. Preoxygena�on is more effec�ve in the 25° head-up posi�on than in the supine posi�on in severely obese pa�ents. Anesthesiology 2005; 102: 1110–5. 31. Kim HJ, Park MJ, Kim JT et al. Appropriate laryngeal mask airway size for overweight and underweight children. Anaesthesia 2010; 65: 50–3. 32. Leykin Y, Pellis T, Lucca M, et al. The effects of cisatracurium on morbidly obese women. Anesth Analg 2004; 99: 1090–4. 33. Smith HL, Meldrum DJ, Brennan LJ. Childhood obesity: a challenge for the anaesthe�st? Pediatr Anaesth 2002;12: 750–61.

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IS SPINAL ANAESTHESIA SUFFICIENT FOR BONE OPERATIVE PROCEDURES IN SMALL CHILDREN? Jasminka Nancheva

Clinic for Orthopaedic Surgery, Medical Faculty, Skopje, Macedonia

The biginig of regional anesthesia started as a pediatric regional anesthesia by Bier (1889) and Bainbridge (1899) who performed spinal anesthesia for hernioplasty on 3 months infant. This technique did not gain widespread un�l the 1980’s, when it was reintroduced as an alterna�ve to general anesthesia in high risk and former preterm infants for lower abdominal or extremity surgery. In this popula�on spinal anesthesia (SA) has been proposed as a means to reduce postopera�ve complica�ons, especially apnea, postopera�ve respiratory dysfunc�on and bradicardia (1). The efficacy and safety is also established in older children as an alterna�ve to general anesthesia with or without of seda�on (2,3).

Expanded indica�ons for spinal anesthesia Spinal anesthesia would be fundamentally useful in: — high risk and former preterm infants, a popula�on with an increased risk of respiratory complica�ons and postopera�ve apnea, especially when the hematocrit is bellow 30% and prior episodes of apnea exsisted; — children with chronic respiratory disease; — poten�ally difficult airway; — malignant hyperthermia; — congenital heart disease, to minimize hemodynamic fluctua�ons; — bullous epidermolysis, where manipula�on of the airway should be avoided whenever possible; — children who have difficul�es in sleeping; — neuromuscular disorders (4). Generally, spinal anesthesia in children is more frequently use for lower abdominal and limbs opera�ve procedures, but nowadays there are widely reported applica�ons of SA as a: • General surgical procedures: umbilical and inguinal herniorrhaphy, appendectomy, colostomy, pernioplasty, rectal biopsy, incision and drainage of rectal abscess, gastrostomy, closure of gastroschisis, exploratory laparotomy, bowel resec�on, extramucosal pylorotomy; (5) 162

[email protected]

• Urological procedures: orchidopexy, hydrocoelectomy, circumcision, cystoscopy, suprapubic catheter placement, vesicostomy, hypospadias repair, ureteral reimplant; • Orthopaedic and lower extremity procedures: hip or lower extremity incision and drainage, foot or lower extremity amputa�on, reposi�on sanguinea coxae, correc�ve foot opera�ve procedures, tendon lengthening, miotomy, lower extremity osteotomy, osteotomia innominata sec. Salter (pelvis osteotomy), muscule biopsy (6); • Miscellaneous applica�ons: meningomyelocele repair (7), cardiothoracic surgery (PDA liga�on, ASD/VSD closure), diagnos�c cardiac catheteriza�on (8), radia�on oncology, chronic pain management.

Contraindica�ons for spinal anesthesia Absolute contraindica�ons are the same as in adults and include: allergic reac�on to local anesthe�cs, local and systemic infec�on, coagulopathy, intracranial hypertension, hydrocephalus, intracranial hemorrhage and parental refusal. Hypovolemia and spinal deformi�es, such as spina bifida or myelomeningocele, could be considered rela�ve contraindica�ons for spinal anesthesia, however, this technique has been used in the repair of myelomeningocele in infants.

Anatomical and physiological differences in children

• The spinal cord ends at L3-L4 level at birth, and reaches L1-L2 by the end of first year. The dural sac is at S4 at birth and reaches S2 by the end of first year. That’s the reason why spinal anesthesia in neonates is administered at L4-L5, and in yearling and older children L3-L4 level; • SA technique itself is successful if you apply it for opera�ve procedures that do not last more than 2 hours. In neonates and infants breakdown of local anesthe�c is much faster than adults, and the amount of local anesthe�c is higher, because of double more produc�on of cerebrospinal fluid than in adults (neonates 10 ml kg-1, infants 4 ml kg-1, adults 2 ml / kg -1);


• In neonates and infants propor�ons of the structures of the nervous system in terms of muscle and bone mass is greater, and it requires the use of higher concentra�ons of local anesthe�c; • The greater medulla spinalis blood flow, increases the faster decomposi�on of local anesthe�c; • The children, hemodynamicaly are very stable up to six years of age, even if the block mounts to the T4 level (due to the smaller venous capacity of the lower extremi�es, less dependence on vasomotor tone in neonates, immature sympathe�c autonomic system, less compensatory vagal ac�vity). The children over 6 years haemodynamic changes were comparable those found in adults. Preloading before SA is not a rou�ne in children. • Myelinisa�on is incomplete at birth and con�nues to develop into the fourth year. Endoneurium is loose, presen�ng li�le barrier to drug diffusion, with faster onset and offset of block. Premedica�on protocols before performing a subarachnoid block The standard preopera�ve fas�ng guidelines are required to be followed before elec�ve spinal anaesthesia, 2-3 hrs fas�ng for clear fluids, 4 hrs for other fluids and 6 hrs for solids is usually followed in most centers. Adequate premedica�on is the key to a smooth regional procedure in children. Various drugs via different routes may be used to achieve a well sedated child who allows venous puncture, placement of monitors and even a lumbar puncture. Combina�on of midazolam, ketamine and atropine (performing oral,intramuscular or intravenously) are quite effec�ve and safe for premedica�on in most cases. Performing a subarachnoid block and maintenance of airway In neonates, infants and young children, for a safe perform of SA block, there are several important factors for maintain the airway. • In newborn, breathing is primarily diaphragma�c, and if the block goes higher, is required ven�latory support; • Ven�latory support is some�mes necessary in the course of giving spinal block due to respiratory depressive effect of seda�ves (ketalar + midazolam), which is necessary for maintaining the posi�on of the baby during delivery of SA; • Giving crystallized pacifier some�mes reduces the need for seda�v; • The tepmerature in oppera�ng room should be 25o or higher. Infants and babies react with apnea in low and high room temperatures;

• More confortable posi�on for infant and baby is lateral decubitus posi�on with easily hiperextension head, in order to avoid obstruc�on of the airway. • Commonly used anesthe�c is ropivacain and isotonic 0.5% bupivacain, which is an effec�ve agent for neonates at a dose of 1mg/kg-1 for infants, children up to 15 kg 0.6-0.8mg/.kg-1 and 0.4-0.6mg kg.-1 for 15-25 kg. Addi�on of adjuvants to local anesthe�c is not very popular in children’s SA, because of possibility of postopera�ve respiratory depression. Fentanyl (1mcg.kg-1) and morphine (30 mcg.kg-1) increases the dura�on of spinal block and provides prolonged postopera�ve analgesia without significant respiratory and hemodynamic altera�ons (9). Complica�ons Complica�ons associated with SA in children are extremely rare and therefore, it is a safe and efficient technique in this popula�on. Hypoxemia, intraopera�ve apnea and bradycardia are usually due to the prematurity of pa�ents amenable to this type of anesthesia. They can also be the consequence of an excessively flexed neck during the lumbar puncture, a too high block, or the addi�onal seda�on. The hemodynamic consequences of a high spinal block are usually not important in young children, but the respiratory effects may require ven�lator assistance. Postdural puncture headache (PDPH) is rare in paediatric pa�ents and some autors have even challenged its existence. Kokki et al (10) in his study on 200 children using two different sizes spinal needles of 25 G and 29 G Ouinke, found that 10 had PDPH with no difference regarding the type of needle used. Neuro - endocrine and metabolic response in children with bone opera�ve procedures under the spinal anesthesia Surgical trauma is a s�mulus over human body, which produces a series of neuro-endocrine, metabolic, immunological and haemodynamic changes in it. Children react equally as adults to surgical trauma. In children, the surgical stress response appears as a protec�ve machanisms, which aims to protect the disturbance of the body homeostasis, or more exactly to ease the wound healing and postopera�ve recovery. The stress response to surgical trauma can be reduced with regional anesthesia, general anesthesia and combina�on of both of them. In a study od 145 cases (Dg. Luxa�o coxae congenital) aged 1-6 years at the Clinic for Ortopae163


dic Surgery, Medical Faculty, Skopje, pelvic and correc�ve femoral osteotomy were performed under the subarachnoid block in 93 children and in 52 cases under the general anaesthesia, by Nancheva et al (11). The aim of this study was to evaluate the stress response free (analgesic) effect of spinal anaesthesia compare with general anaesthesia for pelvic (osteotomia innominata sec. Salter) and femoral correc�ve osteotomy in babies and small children with luxa�o coxae congenita. Severity of the surgical stress response in children, under spinal and general anesthesia, was followed through the level of stress hormones: cor�sol, prolac�ne, growth hormone and metabolites: glucose and lactates, in four checking �mes: preopera�vely, at the end of opera�on, 24 and 48 hours postopera�vely. The results showed that the children operated under spinal anaesthesia showed lower hormonal-metabolic responses comparing to the children operated under general anesthesia, which makes subarachnoidal block a method of choice in opera�ve procedures for pelvic and femoral bone opera�ve procedures. Subarachnoidal block is quick and easy for applica�on, with fast ac�on, good muscle relaxa�on, allows cardicirculatory and respiratory stability, a rare occurrence of nausea and vomi�ng, decreased postopera�ve morbidity and shortened recovalescensy, difficult urina�on occurs less frequently, less intraopera�ve and postopera�ve blood loss, a cost effec�ve less than general anesthesia, can be repeated many �mes, the ideal method for "day case surgery". In the hand of experienced regional anesthesist this advantages makes the spinal anaesthesia more frequently used than general anesthesia for lower abdominal and limb opera�ve procedures.

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References 1. Abajian JC, Mellish RW, Browne AF, Perkins FM, Lambert DH, Mazuzan JE Jr. Spinal anesthesia for surgery in the high- risk infant. Anesth Analg 1984; 63: 359–62. 2. Williams RK, Adams DC, Aladjem EV, Kreutz JM, Sartorelli KH, Vane DW, et al. The safety and efficacy of spinal anesthesia for surgery in infants: The Vermont Infant Spinal Registry. Anesth Analg 2006;102:67–71. 3. Kokki H. Spinal blocks. Paediatr Anaesth 2012;22:56–64. 4. Lopez T, Sanchez FJ, Garzon JC, Muriel C. Spinal anesthesia in pediatric pa�ents. Minerva Anesth 2012; 78-No1: 78–87. 5. Somri M, Gai�ni LA, Vaida SJ, Sabo E. The effec�veness and safety of spinal anesthesia in the pyloromyotomy procedure. Paediatr Anaesth 2003; 13: 32–7. 6. Aronsson DD, Gemery JM, Abajian JC. Spinal anesthesia for spine and lower extremity surgery in infants. J Pediatr Orthop 1996; 16: 259–63 7. Calvert DG. Direct spinal anesthesia for repair of myelomeningocele. Br Med J 1996; 2: 86–7. 8. William RK, Abajian JC. High spinal anaesthesia for repair of pa�ent ductus arterious in neonates. Paediatr Anaesth 1997; 7: 205–9. 9. Ganesh A, Kim A, Gasale P, Cucciaro G. Low dose intratechal morphine for postopera�ve analgesia in children. Anesth Analg 2007; 104: 271–6. 10. Kokki H, Heikkinen M, Turunen M, Vanamo K, Hendolin H. Needle design does not affect the success rate of spinal anaestheisa or the incidence of postpuncture complica�ons in children. Acta Anaesthesiol Scand 2000; 44: 210–3. 11. Nanceva J, Nojkov O, Ivanovska E,Vasilevska K. Endocrino stress response to surgical trauma in children under spinal anaesthesia during orthopaedic opera�ve procedures. Anaesthesiology and Intensive Care, 1,1,Sofia, Bulgaria, 2005.


NEW GUIDELINES IN PEDIATRIC TRANSFUSION Dušica Simić1,2, Selena Purić Racić1, Marija Stević1, Irina Milojević1, Ivana Petrov1, Miodrag Milenović5, Ivana Budić3,4 University Children’s Hospital, Belgrade, Serbia School of Medicine, University of Belgrade, Serbia 3 Centre for Anesthesia and Resuscita�on, Clinical Centre Niš, Serbia 4 School of Medicine, University of Niš, Serbia 5 Clinical Centre of Serbia, Belgrade, Serbia 1 2

Introduc�on One of the major causes of morbidity and mortality in pediatric surgical pa�ents is hypovolemia as a result of bleeding. (1) Failure to control bleeding at the surgical site and non-surgical or hemosta�c bleeding, are the two most important causes of periopera�ve blood loss. E�ology, in most cases, is: 1. Preopera�vely un-diagnosed coagula�on disorders (hemophilia, von Wilebrand disease, etc.). 2. Chronic diseases (chronic kidney disease, liver diseases, malignancies, etc.). 3. Coagula�on disorders caused by specific surgical interven�ons (liver transplanta�on, congenital heart defects with cardiopulmonary bypass, etc). 4. Massive bleeding in serious mul�ple trauma, major surgery in areas were bleeding cannot be stopped easily (craniosynostosis, or scoliosis). (2) It is the anesthesiologist’s responsibility to be knowledgeable of all key aspects during the periopera�ve period and in respect to that take adequate steps to prepare pediatric pa�ent for the surgery. (3) It is necessary to iden�fy high risk pa�ents and understand which hemosta�c mechanisms are in place during surgery. Adequately replace blood losses, prevent and early treat complica�ons from massive transfusion, and at the same �me prevent contribu�ng factors to the coagula�on cascade disorders, such as: hypothermia, acidosis and hemodilu�on. Pharmacological interven�ons to reduce periopera�ve bleeding are recommended, and it is crucial to understand usefulness and limita�ons of the coagula�on tests. Whenever possible it is necessary to reduce number of transfusions, using one of the blood preserva�on methods. (2)

Hemostasis in children Although there are mostly quan�ta�ve differences between coagula�on system of a child and adult, children have excellent, periopera�ve hemostasis. (4) Due to faster metabolism and higher [email protected]

oxygen consump�on, as well as the presence of fetal hemoglobin in the early age, normal hemoglobin (Hb) levels differ in children. (5) Table 1. Normal Hb values in term and preterm infants (5) At birth

Term Preterm g/dl g/dl 19,3 Somewhat lower 16,6 15,4 13,9 11,6 11,2 9,4

0,5m 1m Lowest physiological Hb 9-12wks term /6-10wks preterm 4m 12,2 6m 12,5

11,7 12,4

Coagula�on factors (CF) of the mother do not cross placental barrier. Fetus begins synthesizing CF during fi�h gesta�on week (GW) and their blood has the ability to coagulate around 11 GW. At birth all CF and inhibitors are present qualita�vely normal, compared to adults, although differ in terms of quan�ty. For example, vitamin K dependant factors are 50% reduced. Around six months of age they reach 80% of adult values. Consequently, in this period of life PT, PTT and INR are slightly extended. On the other hand F VIII and Von Willebrand factor (vWF) are elevated during first few months. (2) During first six months coagula�on inhibitors (AT III, protein C and S) are lowered, up to 50%. Platelet func�on in vitro is reduced. Fibrinogen is present in adult values, but it is dysfunc�onal �ll the end of first year. Plasminogen is reduced to a half �ll the end of sixth month, when it reaches adult values. At the same �me primary fibrinolysis inhibitor (PIF) is normal or elevated in neonatal period of life. As a result in neonates produc�on of plasmin is reduced and fibrinolysis is depressed. (6)

Iden�fica�on of high risk pa�ent Personal history, family history and physical examina�on preopera�vely are cri�cal in order to 165


iden�fy pa�ents at risk. Special a�en�on should be paid to previous bleeding history. If there is no alarming data and bleeding is not expected during surgery, no coagula�on tests are needed. If, however, surgery is more complicated, preopera�vely PT, PTT and platelet number should be done. If we obtain informa�on sugges�ng a history of bleeding, coagula�on tests are necessary, and hematologist should be consulted. (2) Most common congenital coagula�on defects in children are: hemophilia A and B (expressed during the first year of life), vW disease and platelet func�on disorders. Acquired disorders are caused mostly by vitamin K deficit in newborns, malabsorp�on, and platelet func�on disorders. They are present in severe chronic diseases (chronic kidney disease, chronic liver disease, cyanogenic heart diseases, malignancies, etc.). (7) In trauma pa�ents, causes of coagulopathies are mul�factorial (trombomoduline and protein C ac�va�on, increased fibrinolysis), acidosis and hypothermia are promo�ng it, and they should be prevented.

Prepara�on of pediatric pa�ent for elec�ve surgery Before surgery with high risk of bleeding it is necessary to check complete blood count (Hct, Hb, Plt) and to perform coagula�on tests. Volemic status and total blood volume should always be es�mated, beforehand, as well as allowable blood losses. Table 2. Es�mated blood volume in children Age Blood volume premature 90ml/kg 80-90ml/kg Term baby up to 3 m 70-80ml/kg 3m-2yr. 70ml/kg >2yr.

(8)

Monitoring of a pa�ent should be prepared according to the expected blood losses and in case of predicted blood volume loss between 30-50%, urinary catheter should be placed together with two peripheral venous lines. If bigger losses are expected arterial and central venous line should be placed. If massive blood loss is expected equipment for rapid blood replacement should be prepared, acid-base and electrolyte status monitored, coagula�on parameters controlled and hypothermia prevented. Communica�on with the blood bank and prepara�on of adequate quan��es of blood and blood products, as well as rethinking strategies for blood conserva�on are crucial. (3)

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Volume replacement If the bleeding occurs we have to be prepared for adequate replacement, having in mind restric�ve approach, pharmacological bleeding control, as well as preven�on and early therapy of eventual massive blood loss. (10)

Erythrocytes Well hydrated and hemodinamicaly stable infant, up to 4 months tolerates Hb up to 7g/dl, so no erythrocyte transfusion is necessary. (3) In massive bleeding threshold for erythrocyte transfusion is at 8g/dl. (4) At the same �me erythrocyte transfusion threshold in children younger than 4 months, children with cyanogenic congenital heart defects, chronic pneumonia and hemoglobinopathies is 12g/dl. (11) Maximal allowable blood loss is calculated based on the following formula: (5) [(pa�ents Hct-desirable Hct)/pa�ents Hct] x es�mated blood volume

It can be replaced with crystalloids (1.3:1) or colloids (1:1). Decision when to start erythrocyte transfusion is made based on bleeding speed, lowered oxygena�on and es�mated consequences of the blood loss. Usual dose is 10-15ml/kg erythrocytes, but there are several formulas for more precise calcula�on of the volume that should be transfused. One of them is: (4) TT(kg) x desired Hb(g/dl) rise x 5

If massive transfusion required ra�o of erythrocytes: fresh frozen plasma: platelets should be 1:1:1. If massive replacement is expected erythrocytes should be one week old, at most, and the maximal transfusion speed should be 1ml/ kg/min. (3) Potassium will progressively leave the erythrocytes. Erythrocyte dose right a�er collec�on has: 12mEq/l K+, on the 21st day: 32mEq/l, and on the 35th day: 50mEq/l. In order to prevent hypocalcemia, due to presence of citrate preserva�ves, it is recommended to give 5-10mg/kg Ca++ chloride or 15-30mg/kg Ca++ gluconate IV.

Platelets One unit of platelets on 10 kg BW or 5ml/kg should raise platelets level for 20000-50000mcg/l. Platelets should be transfused if their level is below 50000 in acute bleeding or invasive procedures. In neurosurgical interven�ons level for platelet transfusion is 100000mcg/l. (4)


Fresh frozen plasma Transfusion of FFP for treatment of severe bleeding is not supported by high quality evidence, although is recommended by several guidelines. Usual dose recommended is 10-15ml/ kg BW of FFP in acquired bleeding where PTT and PT >1,5 �mes normal. However, novel opinions suggest that this is not enough to stop the bleeding, while at the same �me larger volume can significantly overburden circulatory volume. Serious side effects are described, like TRALI, increased child mortality in children with ALI, sepsis in seriously burned pa�ents, immunomodula�on and mul�ple organ insufficiency. (4) Fresh frozen plasma is recommended only if fibrinogen is not available.

Coagula�on factors Fibrinogen concentra�on is the first to be reduced in serious blood losses. In children hemosta�c fibrinogen levels should be maintained (1,5-2,0g/l) applying fibrinogen concentrate (3050mg/kgBW) or cryoprecipitate (5ml/kgBW) if thromboelastography is available. It will provide informa�on of all coagula�on phases, cloth forma�on and retrac�on and fibrinolysis. There are no recommenda�ons for safe use of concentrated prothrombin complex, nor FXIII. rFVIIa is not recommended for use in children except in leukemia with an�bodies against FVIII. Rou�ne applica�on of desmopressin is also not recommended unless there is a proof of hemophilia type A or Von Willebrand disease. On the other hand preopera�ve use of an�fibrinoly�cs (e.g. tranexamic acid) is recommended in pediatric surgery, in order to reduce blood losses and need for transfusion. Op�mal dose is not precisely defined (10-100mg/kg at 1-10mg/kg/h).

Fluids Goal of the periopera�ve fluid replacement is to maintain fluid and electrolyte balance and consequently hemodynamic stability. Crystalloids should be the first choice for periopera�ve fluid replacement in children. A�en�on should be made not to overburden circulatory volume with fluids and to prevent dilu�on coagulopathy. (5) Nega�ve colloids effect on hemostasis is well known and should be carefully monitored. Hydroxyethyl starch (HES) causes extravasa�on

of plasma proteins inters��ally, lowers FVIII and VWF concentra�on, lowers platelet func�on and inhibits interreac�on FXIII – fibrin polymers, although new genera�ons of these solu�ons cause less disturbances. (2) Dextrans cause vW syndrome and enhance fibrinolysis so they should not be applied in doses bigger than 20ml/kg/day in children. Gela�nes disrupt coagula�on and should be replaced in children. Human albumine as well disrupts coagula�on by inhibi�ng platelet aggrega�on or affec�ng an�trombin III, which is similar to heparine, but in lesser extent than synthe�c colloids. (5)

Conclusion No ma�er age differences exists between children and adults, hemosta�c system of a child func�ons perfectly. It is vital to detect hemostasis disorders and bleeding, during periopera�ve period and to react promptly. At the same �me it is extremely important to prevent hypovolemia, hypothermia and acidosis.

References 1. Morray J, Habarkern CH, Geidusheck J. Anaesthesia related cardiac arrest in children: update from the pediatric periopera�ve cardiac arrest registry. Anaesth Analg 2007; 105: 344–50. 2. Giraldo MZ. Pediatric periopera�ve bleeding-Basic considera�on. Rev Colomb Anestesiol 2013; 41 (1):44–9. 3. Giraldo MZ. Management of periopera�ve bleeding in children. Step by step review. Rev Colomb Anestesiol 2013; 41(1): 50–56. 4. Tose�o A, Castaman G, Rodeghiero F. Bleeding scores in inherited bleeding disorders: clinical or research tools? Haemophilia 2008; 14 (3): 415–22. 5. ESA guidelines: managements of severe bleeding. Eur J Anaesth 2013; 30:270–382. 6. Arya VK. Basic of fluid and blood transfusion therapy in paediatric surgical pa�ents. Indian J Anaesth 2012; 56(5):454–62. 7. Guzze�a N, Miller B. Principls of hemostasis in children: models and matura�on. Pediat Anesth 2011; 21: 39. 8. Sarnaik A, Kamat D, Kannikeswaran N. DDiagnosis and management of bleeding disorder in a child. Clin Pediatr 2010; 49: 422–31. 9. Hemlata VA. Transfusion principles in children. Anesth Intens Care 2009; 10: 71–5. 10. Weber T, Hartlage G, Van Aken L. Anesthe�c strategies to reduce periopera�ve blood loss in pediatric surgery. Eur J Anesthesiol 2003; 20: 175–81. 11. Casino R, Luban N. Blood component therapy. Pediatr Clin North Am 2008: 421–45.

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DIFFICULT PEDIATRIC AIRWAY MANAGEMENT Dušica Simić1,2, Miodrag Milenović3, Ivana Budić4,5

University Children’s Hospital, Belgrade, Serbia Medical Faculty, University of Belgrade, Serbia 3 Emergency Center, Clinical Center of Serbia, Belgrade 4 Center for Anesthesiology and Resuscita�on, Clinical Center Nis, Serbia 5 Medical Faculty, University of Nis, Serbia 1 2

Introduc�on There are three broad causes of a challenging airway in children and infants – difficulty obtaining a mask seal, difficulty visualizing the vocal cords, and the third cause in which the larynx can be visualized but the difficulty lies at or beyond that level. The most feared challenge, 'cannot intubate, cannot ven�late' (CICV), is fortunately rare in children, but its management is poorly studied. (1) The incidence of difficult mask ven�la�on in adults is 1.4 – 5% (2,3) but is fortunately less common in the non-obese child. (4) This failure to achieve adequate mask ven�la�on is very important; evidence from closed claim studies suggests that the commonest cause of morbidity and mortality due to airway problems in paediatric pa�ents is due to inability to ven�late rather than to intubate. (5) Good preopera�ve assessment and prepara�on is therefore key to success of the management of the difficult airway in children. Many a�empts have been made to predict difficult laryngoscopy in paediatric pa�ents. These methods have variable sensi�vity in children. The Mallampa� score, described by Cormack and Lehane, is not prac�cal to use in infants and young children due to poor coopera�on. But in a number of large, single center studies, the incidence of poor visualiza�on of laryngeal inlet on direct laryngoscopy in children, as defined by Cormack and Lehane view equal to or greater than grade 3, varied between 0.06% and 1.34%. (6−8) Kopp et al (9) studied the use of the Mallampa� classifica�on to predict to the glo�c view on laryngoscopy in children and found that the Mallampa� score does not accurately predict a poor view of the glo�s during direct laryngoscopy in paediatric pa�ents. Standard values for thyromental and horizontal mandibular lengths do not exist for the paediatric popula�on. There are anatomical and physiological differences between the infant, child and adult that make even the normal paediatric airway difficult for the inexperienced anaesthe�st, par�cularly in children under one year of age. The presence of a congenital or acquired problem involving the airway increases the risk to the pa�ent and anxiety of the anaesthe�st. 168

[email protected]

Pediatric difficult airways are o�en associated with dysmorphic features and are easy to recognize during the preopera�ve assessment. However, in neonates and infants, subtle signs of mandibular hypoplasia can easily be missed if the child is not visualized in lateral profile. Other morphometric features such as limited head extension and large tongue, may also predict a difficult laryngoscopy. Children with large neck circumference are more likely to be loud snorers, but there is no associa�on between high neck circumference and difficult laryngoscopy. (10) Anesthesia providers with limited pediatric experience may find the normal airways of younger children difficult to manage. A rela�vely large occiput, redundant so� �ssue and a larger tongue of a child can make mask ven�la�on difficult. Similarly, in preschool and older children, adenotonsillar hypertrophy is common and the narrowest por�on of airway may be at the tonsillar level. The cephaloid posi�on of laryngeal inlet, a s�ff omega-shaped epiglo�s and larger tongue rela�ve to submandibular space creates an airway anatomy that makes the laryngeal inlet appear more anterior. Furthermore, high metabolic demands and low oxygen reserves shorten the �me to significant hypoxemia during apnea associated with tracheal intuba�on. (11)

Illustra�ve case A 4 year old child was admi�ed to a general hospital a�er a motor vehicle accident in which he suffered a skull base fracture, hemothorax, lung contusion, le� femur fracture and serial rib fractures (4-8) on the le�. The pa�ent was intubated with a cuffed no. 4 tube. Chest tube was placed and femur was immobilized. Child was transported to the University Children’s Hospital (UCH) in Belgrade12 hours a�er the injury. Chest X-ray, and complete skeletal X-ray were obtained, together with abdominal ultrasound, CT of the head and chest, standard biochemistry, complete blood count (CBC) and arterial blood gases (ABGs). On admission the child was hemodynamically and respiratory stable (vital parameters and ABGs were within reference


values). CBC was normal. Medical history was significant for prematurity. A conserva�ve management plan was chosen. Intuba�on indica�ons are the same in children and adults, i.e. airway protec�on or inadequate ven�la�on/oxygena�on. A child with polytrauma should be intubated by the most experienced team member. An anesthesiologist has 80% success rate a�er performing 90 intuba�ons. Tube number may be approximated by the thickness of the distal phalange of the fi�h digit. It may be calculated by dividing child’s age by 4 and adding 4 or 3 if a cuffed tube is used. Depth of placement should be roughly equal to the tube no. mul�plied by 3. It should always be checked if the air leaks back between the tube and trachea on posi�ve pressure applica�on, which is necessary to prevent mucosal injury. Tube should always be manually held in place un�l it is carefully secured, which should be done as soon as possible. A backup plan for the case of unsuccessful intuba�on should always be kept in mind. There is a simple ABC guide for that situa�on: • Alterna�ve posi�on, size and type of the blade • Blind intuba�on: Mask, oropharyngeal or nasopharyngeal tube Laryngeal mask Combitube Retrograde intuba�on • CRIC- needle cricothyroidotomy or tracheotomy On admission to the PICU of the UCH the child was intubated with no. 5 uncuffed tube, with seda�on and muscle relaxa�on. During the interven�on, lacerated vocal cords were noted. Although the anesthesiologist supported opinion that children under 6 should be intubated with uncuffed tube, this has been recently challenged. Certain studies suggest that cuffed tube intuba�on of children is safe in the hospital set�ng, but the cuff pressure should be kept below 20cmH2O. Cuffed tube is also useful because the ven�la�on of pa�ents with decreased lung compliance or increased airway resistance may be performed. However, further studies are required to prove safety of cuffed tube applica�on in young children. Ques�on regarding the need for muscle relaxant administra�on prior to intuba�on in the ICU is also brought up. Relaxa�on will certainly make the intuba�on easier, but it should be performed only a�er determining if the mask ven�la�on is feasible. Succinylcholine is s�ll the golden standard, although it has some adverse effects which some non-anesthesiologist intensivists might be unaware of. Prior to intuba�on in the ICU seda�ve/analgesic which does not cause hemodynamic in-

stability should be administered (etomidate, ketamine). Children under 10 should receive atropine (0,02mg/kg) 3 min before the intuba�on, due to increased vagal tone in this group of pa�ents. Lately, it has been recognized that cricoid pressure during intuba�on does not decrease the risk of aspira�on of regurgitated gastric content, but it makes the visualiza�on more complicated. Pressure regulated volume controlled ven�la�on (PRVC) was applied in our pa�ent. While an inexperienced junior doctor a�ended the ICU, an accidental extuba�on occurred, with laryngeal spasm following it. Muscle relaxa�on and reintuba�on were performed. The most common causes of laryngeal spasm are secre�ons, anxiety and vagal irrita�on. It is up to 3 �mes more common in children under 6 years of age. In 4% of children the spasm is followed by lung edema. The younger a pa�ent, the great is associated mortality, so it is be�er to prevent laryngeal spasm than having to treat it. Literature data indicate that 38% of pa�ents respond to chin li�/jaw thrust with CPAP, and 62% to neuromuscular relaxa�on and endotracheal intuba�on. Certain number of pa�ents responds to the pressure on the malleolus, tragus or upper part of the trapezius muscle. Weaning our pa�ent from the mechanical ven�la�on was associated with a number of complica�ons. The pa�ent had to be reintubated three �mes, and developed laryngeal spasm in 2 of these occasions. During weaning, care should be taken about the nutri�onal state, electrolyte balance, respiratory muscle strength and psychological condi�on of the pa�ent. Problems have to be iden�fied and addressed, and ven�lator triggering should be adjusted to maximum sensi�vity. Complica�ons of the unnecessarily prolonged ven�la�on or premature weaning are numerous, e.g. nosocomial pneumonia or cardiac complica�ons may develop. Mortality a�er reintuba�on is around 40%. Difficult extuba�on is an independent predictor of mortality. Cor�costeroids administered 12 h before extuba�on diminish the need for reintuba�on and decrease incidence of postextuba�on stridor. On the other hand, these medica�ons may have adverse effects, especially on the CNS and developing lungs. Addi�onal diagnos�c tests were ordered to determine the cause of complicated weaning in our pa�ent. Subglo�c stenosis was diagnosed. This condi�on develops in 90% of prolonged intuba�ons. It is less common in newborn and premature babies, due to immaturity of the cricoid car�lage. Pathogenesis includes ischemia induced by the tube pressing on the airway wall, which leads to edema, necrosis and ulcera�on of the mucosa. Granula�on �ssue appears a�er few hours, leading to scarring and stenosis in 48 hours. 169


When to perform a tracheotomy in a child? There are no strict indica�ons or �me frame. For tracheotomy in adults, guidelines from the 1989 consensus conference s�ll apply. General indica�ons for tracheotomy in children are prolonged ven�la�on, congenital malforma�ons, laryngomalacia, severe acquired airway obstruc�ons, severe swallowing disorders and large amount of tracheal secre�ons. On the other hand, tracheostomy has many complica�ons, both early (pneumothorax, bleeding, decannula�on, obstruc�on, infec�on), and late (granuloma, necrosis in the pressure site, subglo�c stenosis, tracheocutaneous fistula, difficult decannula�on). Stenosis was repaired surgically. With support from the mother and staff, our pa�ent was successfully extubated on the day 28 a�er the admission.

Discussion Regarding difficult airway no single method or available device has been shown to succeed in all pa�ents. A clear stepwise approach to manage the difficult or failed airway, customized according to local resources and exper�se, should be formally established at all sites that provide anesthesia or airway interven�ons in children. (11) An algorithm, based on Difficult Airway Society guidelines, has been recently proposed for unexpected difficult airway in children. (12) It stresses avoiding unnecessary trauma by limi�ng the number of direct laryngoscopy a�empts, earlier use of alterna�ve technologies, incorpora�on of extra-glo�c devices (laryngeal mask airway) for rescue ven�la�on, and considera�on for using laryngeal mask airway as a conduit for tracheal intuba�on under fiberop�c guidance. Indirect laryngoscopes are a new category of intuba�ng aids that allow to ‘see around corners’. They incorporate a video camera or coherent fiberop�c bundle mounted on a fixed or malleable intuba�ng blade, and display the image of the laryngeal inlet on a screen. Several of these devices are suitable for use in children and have been recently reviewed (e.g. Airtraq, Bullard Infant Elite Laryngoscope, Glidescope). (13) But, a comprehensive background paper to inform the Australian and New Zealand College of Anaesthe�sts guideline on equipment for management of difficult airway during anesthesia makes the following statement: 'Evidence is s�ll lacking to support the replacement of standard laryngoscopes with nonstandard devices for rou�ne or difficult intuba�ons, and the results of large mul�centre clinical trials of new airway devices are required'. (14) If the proce-

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dure is elec�ve and above men�oned resources are not available on site, waking the pa�ent and transfer to an opera�ng room with an experienced pediatric anesthesiologist and otolaryngologist is the most prudent op�on. (11) The pediatric airway has certain dis�nct anatomic features that reduce the efficacy of transtracheal catheters to secure the obstructed airway par�cularly neonates and infants. In the se�ng of ‘cannot ven�late and cannot intubate’ invasive emergency measures are high risk and may take too long to prevent irreversible hypoxic injuries. The small size of the crico-thyroid membrane with a mean length of 2.6 ± 0.7 mm and width of 3 ± 0.63 mm, limits the size of the trans-tracheal device. (15) Secondly, this technique has an unacceptably high complica�on rate in children under 5–6 years when used as an emergency adjunct. (16) When acceptable oxygena�on can be maintained with an oro-pharyngeal airway and two hands–two person ven�la�on technique, a surgical tracheostomy performed by a surgeon experienced in pediatric airway may be a preferred over percutaneous cricothyroid puncture. (11) A difficult airway con�nues to be a problem, and perhaps be more difficult during extuba�on and emergence. With the introduc�on of guidelines for management of difficult airway, there has been a reduc�on in airway claims arising from injury at induc�on of anesthesia. There is a paucity of literature focusing on airway complica�ons during extuba�on in pediatric pa�ents. Many pa�ents with a difficult airway are extubated in the ICU. Such extuba�on should only be performed when the child is completely awake, and a team of providers with advanced airway skills are available for reintuba�on.

Conclusion Rescue op�ons for infants and children who cannot be ven�lated or intubated are very limited and management is very challenging. Extuba�on of pediatric pa�ents with a known difficult airway may also be fraught with the peril of airway obstruc�on. The approach to manage the difficult or failed airway should be customized according to local resources and exper�se. It is important to remember that a tool is not a plan. Having sophis�cated equipment available is not sufficient; every pa�ent should be carefully and pa�ently observed and a clear management strategy should be discussed in advance with the team.


References 1. Sims C, von Ungern-Sternberg BS. The normal and the challenging pediatric airway.Paediatr Anaesth 2012; 22(6): 521–6. 2. Kheterpal S, Han R, Tremper KK et al. Incidence and predictors of difficult and impossible mask ven�la�on. Anesthesiology 2006; 105(5): 885–913. 3. Langeron O, Masso E, Huraux C et al. Predic�on of difficult mask ven�la�on. Anesthesiology 2000; 92(5): 1229–36. 4. Tait AR, Voepel-Lewis T, Burke C et al. Incidence and risk factors for periopera�ve adverse respiratory events in children who are obese. Anesthesiology 2008; 108(3): 375–80. 5. Jimenez N, Posner KL, Cheney FW et al. An update on pediatric anesthesia liability: a closed claims analysis. Anesth Analg 2007; 104: 147–53. 6. Henrich S, Birkholz T, Ilmsen H et al. Incidence and predictors of difficult laryngoscopy in 11,219 pediatric anesthesia procedures. Pediatr Anesth 2012; 22: 729–36. 7. Ohkawa S. Incidence of difficult intuba�on in pediatric popula�on. Annual mee�ng of American Society of anesthesiologists. Anesthesiology 2005; 103: A1362. 8. Mirghassemi A, Soltani A, Abtahi M. Evalua�on of laryngoscopic views and related influencing factors in a pediatric popula�on. Pediatr Anesth 2011; 21: 663–7.

9. Kopp VJ, Bailey A, Valley RD et al. U�lity of the Mallampa� classifica�on for predic�ng difficult intuba�on in paediatric pa�ents. Anesthesiology 1995; 83: A1146. 10. Naifu O, Burke C, Gupta R et al. Associa�on of neck circumference with periopera�ve adverse respiratory events in children. Pediatrics 2011; 127: e1198–205. 11. Sunder RA, Haile DT, Farrell PT, Sharma A. Pediatric airway management: current prac�ces and future direc�ons. Paediatr Anaesth 2012; 22(10): 1008–15. 12. Engelhardt T, Weiss M. A child with a difficult airway: what do I do next? Curr Opin Anaesthesiol 2012; 25: 326–32. 13. Holm-Knudsen R. The difficult pediatric airway – a review of new devices for indirect laryngoscopy in children younger than two years of age. Pediatr Anesth 2011; 21: 98–103. 14. Baker PA, Flanagan BT, Greenland KB et al. Equipment to manage a difficult airway during anaesthesia. Anaesth Intensive Care 2011; 39: 16–34. 15. Navsa N, Tossel G, Boon JM. Dimensions of the neonatal cricothyroid membrane - how feasible is a surgical thyroidotomy? Pediatr Anesth 2005; 15: 402–6. 16. Cote CJ, Hartnick CJ. Pediatric transtracheal and cricothyrotomy airway devices for emergency use: which are appropriate for infants and children? Pediatr Anesth 2009; 19(Suppl1): 66–76.

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PERIOPERATIVE FLUID MANAGEMENT Gordana Jovanovic

University of Novi Sad, Faculty of Medicine Novi Sad Clinic for Anaesthesia and Intensive Care Therapy, Clinical Centre of Vojvodina, Novi Sad, Serbia

Introduc�on As a clinicians, we administer intravenous fluids in everyday prac�ce, but o�en we do not think about ra�onale behind fluid therapy, and o�en we do not reevaluate and reexamine our common prac�ces in fluid management. Periopera�ve fluid therapy should maintain circula�ng volume, ensure end organ perfusion and oxygen delivery to the �ssues. (2) There is general agreement about these basic goals, but the means by which these goals can be achieved is ma�er of con�nuous debate among professionals (quan�ty, composi�on and �ming of iv fluids) (2). Current evidence sugges�ng that fluid balance have direct impact on outcome.

Tradi�onal approach to iv fluid therapy Tradi�onal approach to fluid administra�on is based on predic�ng and calcula�ng fluid therapy, and administering fixed doses of iv fluids based on calcula�ons per kilogram or per hour, or per dura�on and severity of surgical interven�on. Preopera�ve fluid losses were calculated by following 4/2/1 ml/kg/h maintenance rule, mul�plied by hours of preopera�ve fas�ng. This approach do not take into considera�on real preopera�ve fluid status, just es�ma�on, nor periopera�ve varia�ons in myocardial func�on and vascular tone (3). Calcula�ons of ongoing maintenance requirements, an�cipated surgical fluid losses, adjustment for unan�cipated fluid losses are derived by similar formulas. Whole concept is based on clinical predic�on and evalua�on of fluid losses, which can be grossly inaccurate. So, administering fluid therapy this way can lead to fluid overload (4).

Liberal vs restric�ve periopera�ve fluid therapy Avoiding periopera�ve hypervolemia and hypovolemia is s�ll challenging. Trials comparing restric�ve vs liberal (or standard, or tradi�onal) did not get answer on proposed ques�on, mainly because of different defini�ons of "liberal, "stan172

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dard" or "restric�ve" regimen of fluid administra�on, restric�ve regimen in one study could be liberal in another. So because of the diversity of such trials it is not easy to extrapolate meaningful clinical conclusion. (5)

In search of "adequate" periopera�ve fluid therapy Securing an adequate intravascular volume is ul�mate goal of hemodynamic management. Intravenous fluids are drugs as any others, and as such must have op�mally dosing. Hypovolaemia and hipervolemia also, can cause at the end impaired �ssue oxygena�on.e. Individualized "goal-directed therapy" is fluid �tra�on according to a certain hemodynamic goal in order to reduce organ–specific complica�ons and improve periopera�ve outcomes. In search of adequate periopara�ve fluid terapy, monitoring should be augmented by measurement of dynamic flow-based parameters (transoesophageal Doppler or pulse contour analysis, PPV, SVV) and op�mizing cardiac preload and cardiac output. Fluid therapy should be individualized based on those informa�ons obtained, we shouldt use this monitoring to assess actual hemodynamic status of a pa�ent (6−8).

Guidance from the literature Guidelines on intravenous fluid therapy for surgical pa�ents represents recogni�on of importance of such treatment, in clinical prac�ce they are most welcome by clinicians. We can refer to Bri�sh consensus guidelines on intravenous Fluid Therapy for adult Surgical Pa�ents (GIFTA SOUP).They are comprised of 28 recommenda�ons produced by six specialist socie�es, and cover preopera�ve, intraopera�ve and postopera�ve fluid management, preopera�ve mechanical bowel prepara�on, nutri�on and fluid therapy in acute kidney injury. (9) The aim of recent NICE (Na�onal Ins�tute for health and Care Excellence) guidelines is to help


prescribers understand the: physiological principles that underpin fluid prescribing pathophysiological changes that affect fluid balance in disease states, indica�ons for IV fluid therapy, reasons for the choice of the various fluids available, and principles of assessing fluid balance. It is hoped that guidelines will lead to be�er fluid prescribing in hospitalised pa�ents, reduce morbidity and mortality, and lead to be�er pa�ent outcomes. (10)

Fluid management remains subop�mal Despite being a fundamental component of surgical and periopera�ve care, fluid management remains subop�mal in clinical prac�ce and there is lot of space for educa�on and improvement.

References 1. Doherty M, Buggyl DJ. Intraopera�ve fluids: how much is too much? BJA 2012; 1: 11. 2. Bamboat ZM, Borideianou L. Perioperative fluid management. Clin Colon Rectal Surg 2009; 22(1): 28–33

3. Ganter T, Hofer C, Pi�et J. Postopera�ve intravascular therapy. In Miller R, ed. Miller’s Anesthesia, vol. 88, 7th Edn. Philadelphia: Churchill Livingstone, 2009; 2783–7 4. Strunden MS, Heckel K, Goetz AE, Reuter DA. Periopera�ve fluid and volume management: physiological basis, tolls and strategies. Ann Intensive Care 2011; 1: 2. 5. Bundgaard- Nielsen M, Secher NH, Kehlet H. Liberal’ vs. 'restric�ve' periopera�ve fluid therapy – acri�cal assessment of the evidence. Acta Anaesthesiol Scand 2009; 53: 843–51. 6. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A ra�onal approach to periopera�ve fluid management. Anesthesiology 2008; 109: 723–40. 7. Brandstrup B. Fluid therapy for the surgical pa�ent. BestPract Res Clin Anaesthesiol 2006; 20: 265–83. 8. Nisanevich V, Felsenstein I, Almogy G, Weissman C, Einav S, Matot I. Effect of intraopera�ve fluid management on outcome a�er intraabdominal surgery. Anesthesiology 2005; 103: 25–32. 9. Powell-Tuck J, Gosling P, Lobo DN, Allison SP, Carlson GL, Gore M, et al. Bri�sh Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Pa�ents - GIFTASUP. 2008. Available from: h�p://www.ics.ac.uk/downloads/2008112340_ GIFTASUP%20FINAL_31-10-08.pdf 10. NICE guidelines (dec 2013) Intravenous fluid therapy in adults in hospital available from : h�p://guidance.nice. org.uk/CG174.

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COLLOID VERSUS CRYSTALLOID Gurinder M Vasdev

Department of Anesthesiology, Mayo Clinic, Rochester MN USA

1. Introduc�on In 1995 US Hospital Guidelines suggested that the use of Colloids was preferen�al in the resuscita�on of major trauma vic�ms in to blood as a first line treatment. This was a result of medical industry search for non-blood related products to improve mortality, reduce blood born infec�ons, cross match related immune reac�ons religious preferences and cost. Much of the preliminary data was derived from military trauma vic�ms where transporta�on of large volumes of crystalloid was an issue. However, subsequent analysis has shown great controversy on exactly when and how to use colloids.

bumin is so effec�ve is that it distributes mainly to the extracellular compartment (>60%). In healthy people it has a half live of about 13-19 days with a turnover of approximately 15g per day. In ac�ve bleeding it is lost and cell saver devices cannot effec�vely retrieve albumin. 20-25% human albumin solu�ons are used when low volumes are required and cau�on in a pa�ent electrolyte balance is entertained. If 20-30% of blood volume is to be replaced, other blood cons�tuents (coagula�on factors, electrolytes, platelets and erythrocytes) needed to be administered. Hypervolemia may occur with albumin infusion as intracellular dehydra�on may occur with rapid rise of extracellular onco�c pressure.

2. Background Fluid, either crystalloid or colloid, is the first line in resuscita�on for hypovolemia. Choices and ra�onal for therapy is summarized below:

Albumin or Plasma Protein Frac�on Albumin (Human) 5% is a sterile, liquid prepara�on of albumin derived from large pools of human plasma. All units of human plasma used in the manufacture of Albumin (Human) 5% are provided by FDA approved blood establishments only. Commonly manufactured using the Cohn-Oncley cold ethanol frac�ona�on process followed by ultra- and di filtra�on, and then ends up with pasteuriza�on (60F for 10-11 hours). The manufacturing process provides a significant reduc�on in viral infec�on. Albumin is responsible for 70-80% of the colloid pressure of normal plasma, so it replenishes intravascular volume quickly and effec�vely. In addi�on it is a carrier of hormones, enzymes, drugs and toxins. It is osmo�cally equivalent to an equal volume of normal human plasma. Once infused, the degree and dura�on of volume expansion depends upon the ini�al blood volume. Hemodilu�on can be minimized if pa�ent have a normal star�ng blood volume. The reason why al-

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Hydroxyethyl Starch (HES) HES is a deriva�ve of thin boiling waxy corn starch, which mainly consists of a glucose polymer (amylopec�n) predominately composed of α-1-4connected glucose units with several α-1-6-branches. Subs�tu�on of hydroxyethyl groups on the glucose units of the polymer reduces the normal degrada�on of amylopec�n by α-amylase in the body. The low molar subs�tu�on (0.4) is the main pharmacological determinant for the beneficial effects, on intravascular volume and hemodilu�on. This effect depends on the mean molecular weight (130,000 daltons; range 110,000 - 150,000 daltons), the molar subs�tu�on by hydroxyethyl groups (0.4; range 0.38 - 0.45) on glucose units of the starch, the pa�ern of hydroxyethyl subs�tu�on (C2/C6 ra�o) of approximately 9:1, and the concentra�on (6%), as well as the dosage and infusion rate. Various types of hydroxyethyl starch show different pharmacokine�c s as starch is a polydisperse solu�on ac�ng as a colloid. Its ac�on depends on the number of onco�cally ac�ve molecules and not on the plasma concentra�on. Larger molecules have increased hematological and renal dysfunc�on and this has led to the 2014 withdrawal of HES from the Mayo Clinic formulary.


Modified gela�n Gela�n s are proteins formed when the connec�ve �ssues of animals are boiled. They dissolving in hot water and forming a jelly when cooled. Gela�ns are large molecular weight protein formed from hydrolysis of collagen. Gela�n solu�ons were first used as colloids in man in 1915. The early solu�ons had a high molecular weight (about 100,000). This had the advantage of a significant onco�c effect but the disadvantages of a high viscosity and a tendency to gel and solidify if stored at low temperatures. Reducing the molecular weight reduced the tendency to gel but smaller molecular weight molecules could not exert a significant onco�c effect. Several modified gela�n products are now available; – Succinated gela�ns (e.g. Gelofusine, Plasmagel, Plasmion) − Urea-crosslinked gela�ns (e.g .Polygeline) − Oxypolygela�ns (e.g. Gelifundol) The gela�n is produced by the ac�on of alkali and then boiling water (thermal degrada�on) on collagen from ca�le bones. Polygeline is supplied as a 3.5% solu�on of degraded gela�n polypep�des cross linked in a balanced salt solu�on (Na+ 145, K+ 5.1, Ca++ 6.25 & Cl- 145 mmol/l). It is sterile, pyrogen free, contains no preserva�ves and has a recommended shelf-life of 3 years when stored at temperatures less than 80F. As a small molecule it is quickly excreted by the kidney with a half-life of about 2 hours. Only about 30% remains in the body at 24 hours assuming normal renal func�on. The main advantages of gela�ns are that they lower the volume required for resuscita�on, excreted by the kidney, long shelf life and lower costs. They do not interfere with cross matching and have minimal infec�on risk. However, they are prone to anaphylactoid reac�on

Dextran Dextrans are highly branched polysaccharide compounds which produce an onco�c effect. They are produced by using the bacterial enzyme dextran sucrase from the bacterium Leuconostoc mesenteroides (B512 strain) in a sucrose medium. The commercially available dextrans include; Dextran 40 (MW 40,000) and Dextran 70 (MW 70,000). The main reason why they are not widely used is the high incidence of severe anaphylac�c reac�ons even more than the gela�ns or HES. The reac�ons are due to circula�ng dextran reac�ve an�bodies which cause a Type 1 Hypersensi�vity which may be acute or delayed. The mechanism of reac�on involves preferen�al produc�on of IgE, in response to certain polysaccharides. The

precise mechanism as to why some individuals are more prone to type-I hypersensi�vity is not clear. However, it has been shown that such individuals preferen�ally produce more of TH2 cells that secrete IL-4, IL-5 and IL-13 which in turn favor IgE class switch. IgE has very high affinity for its receptor (Fcε; CD23) on mast cells and basophils. The incidence and severity of reac�ons can be reduced by pretreatment with a hapten (Dextran 1). Dextran significantly interferes with cross matching and coagula�on. Because of its 8-hour dura�on of ac�on, a maximal dose of 20mls/kg is recommended. Dextran40 is used to improve microcirculatory rheology and is used in plas�c and vascular reconstruc�on surgery.

Crystalloid Crystalloid is available in hypertonic and isotonic solu�ons. Hypotonic solu�ons are used in certain therapeu�c manoeuvres and are not recommended for resuscita�on. Crystalloids consist of balanced saline, balanced salt solu�on of dextrose and any combina�on of the previous. Upon infusion, distribu�on occurs in line with the electrolyte content. Dextrose based solu�on equilibrate rapidly between intra- and extra-cellular fluid. Saline based solu�ons will follow the concentra�on of sodium ions within each compartment and distribute within 10 minutes depending on organ perfusion and renal clearance. Total body water (TBW) is a considera�on when dealing with edema in any one system. Hypertonic saline infusion were popularized as they improved perfusion without increasing TBW.

3. What is the best choice? Outcome studies In anesthesia we are faced with elec�ve non hemorrhagic shock, elec�ve hemorrhagic shock and emergency hemorrhagic shock. The first two scenarios start with a euvolemia or slightly dehydrated pa�ent and surgery ensues. The last scenario involves preopera�ve compromised pa�ent from their disease process, co-morbidi�es or trauma. There is a huge varia�on in individual prac�ce based on availability and percep�on. The use of colloid far exceeds the ra�onal for use in many hospitals and some of this may be linked with profit margins for colloid use. Analysis of randomized trails, where cost was not considered in clinical decision making, showed no difference in outcomes when albumin was compared with saline. Twenty-three trials reported data on mortality, including a total of 7754 pa�ents. The pooled rela�ve risk (RR) was 1.01 175


HES, 17 trials compared hydroxyethyl starch with crystalloids, including a total of 1172 randomized pa�ents. The pooled RR was 1.18 in favor of crystalloid. In June 2011 Anaesthesia and analgesia retracted 22 ar�cles by Dr. Boldt alleging fraud. Gela�n, 11 trials compared gela�n with crystalloid, 506 randomized pa�ents. The pooled RR was 0.91. no benefit. Dextran, 9 trials compared dextran with a crystalloid, 834 randomized pa�ents. The pooled RR was 1.24 in favor of crystalloid. So for a product to be used there should be clear and consistent improvement in outcome. However the studies have not detailed the so�er benefits from using intravascular expanders like wound healing, need for increased postopera�ve nursing, postopera�ve syncope and nausea and vomi�ng. There is a trend for low volume resuscita�on to improve bowel pulmonary func�on but the studies are not conclusive.

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Summary There is no significant improvement in outcome using colloids, but so�er end points need to be analyzed in more detail. HES is been removed from our formulary and gela�ns are rarely used. Most colloid resuscita�on occurs with albumin 5%. Dextran is used for its effects on rheology and not volume expansion.

References 1. Tullis JL. Albumin. Background and use. JAMA 1977; 237: 355–60. 2. Matejtschuk p et al. Produc�on of human albumin solu�on: a con�nually developing colloid Br J Anaesth 2000; 85(6): 887–95. 3. Jungheinrich C, Neff TA. Pharmacokine�cs of hydroxyethyl starch. Clin Pharmacokinet 2005; 44(7): 681–99. 4. Kien ND. Small-volume resuscita�on using hypertonic saline improves organ perfusion in burned rats. Anesth Analg 1996; 83(4): 782–8. 5. Finfer S et al. A Comparison of Albumin and Saline for Fluid Resuscita�on in the Intensive Care Unit. N Engl J Med 2004; 350: 2247–56. 6. Pablo P et al. Colloids versus crystalloids for fluid resuscita�on in cri�cally ill pa�ents. The Cochrane Library 2009, Issue 3 h�p://www.thecochranelibrary.com


HEMODYNAMIC ASSESSMENT BEFORE FLUID LOADING IN CRITICALLY ILL PATIENTS Gorazd Voga

Medical ICU, General Hospital Celje, Slovenia

Introduc�on Hemodynamic instability is the common reason for ICU admission and majority of cri�cally ill pa�ents require hemodynamic stabilisa�on. In order achieve rapid hemodynamic stability without overtreatment, which can have serious side effects, a balanced used of proper hemodynamic variables should be measured or es�mated for hemodynamic assessment and monitoring. The hemodynamic assessment is a "snapshot" of hemodynamic status by measuring various hemodynamic variables on admission and should be frequently repeated even in hemodynamic stable pa�ents. Hemodynamic monitoring, on the other hand, represents con�nuous measurement of relevant hemodynamic variables in order to detect the unexpected deteriora�on and/or to follow the effect of the treatment. The basic purpose of hemodynamic assessment/monitoring is to assess, if oxygen transport meets the actual demands and if not, which component is failing and why, in order to correct it properly and ensure normal organ func�on. In most pa�ents the first step in hemodynamic stabilisa�on is preload op�misa�on by fluid loading. Unfortunately, the common prac�ce is to start fluid loading according to unreliable hemodynamic variables such as arterial pressure. It must be pointed out that hypotension can be result of different causes and not only hypovolemia. Hypotensive pa�ents with adequate preload and excessive vasodila�on require vasopressors. On the other hand hypotensive pa�ents in cardiogenic shock and adequate preload require inotropic or mechanical support. Equally important as the start of fluid loading is the final goal of fluid loading which can be defined as adequate cardiac output and �ssue perfusion without excessive fluid accumula�on. Such hemodynamic stabilisa�on should be achieved as soon as possible in order to improve the prognosis of the pa�ents. In clinical prac�ce, however, goals of fluid loading are frequently not set and more frequently not achieved or exceeded.

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Hemodynamic assessment before fluid loading Correct treatment with fluids, vasopressors and inotropic agents should rely on proper assessment of arterial pressure, preload, flow and flow adequacy. This basic assessment should be performed in every cri�cally ill pa�ent. Since the first step in hemodynamic stabilisa�on is op�misa�on of preload by volume loading, the basic ques�on is which variables are required for safe use of fluids. It seems logical that assessment of preload and fluid responsiveness is mandatory. Assessment of preload can rely on pressures or volumes. Unfortunately, es�mates of filling pressures (central venous pressure and pulmonary artery occlusion pressure) are not accurate measures of preload and they cannot predict fluid responsiveness. Nevertheless, they should be measured as safety parameters: i.e. steep rise of filling pressures a�er volume loading indicates immediate stop of volume treatment. Therefore, for correct volume assessment, sta�c pressure and volume variables (intrathoracic blood volume, global end-diastolic volume, end-diastolic areas and volumes) must be measured, together with dynamic variables which can predict fluid responsiveness. However, the usual dynamic parameters of fluid responsiveness (stroke volume varia�on, pulse pressure varia�on, inspiratory changes of inferior vena cava diameter) are predic�ve for posi�ve response only in in approximately 50% of cri�cally ill pa�ents. Moreover, due to important limita�ons (adequate �dal volume, no spontaneous inspiratory effort, and no arrhythmias) they can be used in minority of cri�cally ill pa�ents. It should be remembered that in other pa�ents alterna�ve manoeuvres (expiratory occlusion test, passive leg raising or mini fluid challenge) can be used. The increase of stroke volume a�er volume challenge depends on the func�on of right and le� ventricle. It is therefore mandatory to assess the right ventricular func�on by es�ma�on its dimensions and contrac�lity (tricuspid annulus plane systolic displacement (TAPSE) or �ssue Doppler systolic velocity of tricuspid annulus). It is well known that in the pa�ents with dilated and poorly 177


contrac�le right ventricle, the dynamic variables can be false posi�ve. Since the increase of stroke volume depends on the contrac�lity of le� ventricle, its systolic func�on should be assessed by eyeballing or by parameters of contrac�lity (ejec�on frac�on, frac�onal area change, mitral annulus plane systolic displacement (MAPSE). Finally, there is no need to increase oxygen delivery if it is adequate and determina�on of at least one marker of flow adequacy (lactate level, mixed venous oxygen satura�on, central venous oxygen satura�on) is mandatory before we start fluid loading. When fluid challenge is performed, it is strongly recommended to follow the changes of stroke volume increase during fluid administra�on in order to stop fluid loading and prevent fluid accumula�on, when the stroke volume reaches its plateau. In order to detect the changes of stroke volume rapidly one of the methods that enable beat to beat measurements is mandatory (echocardiography, some of the methods with arterial pressure contour analysis).

Conclusion The decision for volume loading should rely not only on determina�on of preload and fluid responsiveness, but also on assessment of the cardiac func�on and flow adequacy. Hemodynamic assessment requires therefore integra�ve approach with measurement of variables that enable reliable es�ma�on of preload, flow and flow adequacy. During the fluid loading immediate hemodynamic response should be monitored. Unfortunately, the monitoring of microcircula�on is not ready for rou�ne use, nevertheless, its improvement and normalisa�on remains the main goal of hemodynamic support stabilisa�on.

Recommended further reading Vincent JL, Rhodes A, Perel A, et al. Clinical review: Update on hemodynamic monitoring - a consensus of 16. Cri�cal Care 2011; 15: 229–37. Shah MR, Hasselblad V, Stevenson LW, et al. Impact of the pulmonary artery catheter in cri�cally ill pa�ents. JAMA 2005; 294: 1664–70.

178

Antonelli M, Levy M, Andrews PJD, et al. Hemodynamic monitoring in shock and implica�ons for management. Intensive Care Med 2007; 33: 575–90. Pearse R, Dawson D, Fawce� J et al. Early goal-directed therapy a�er major surgery reduces complica�ons and dura�on of hospital stay. A randomised, controlled trial. Cri�cal Care 2005; 9: R687–93. Reinhart K, Kuhn HJ, Hartog C, Bredle DL. Con�nuous central venous and pulmonary artery oxygen satura�on monitoring in the cri�cally ill. Intensive Care Med 2004; 30: 1572–8. Pinsky MR, Payen D. Func�onal hemodynamic monitoring. Crit Care 2005; 9: 566–72. Takala J, Ruokonen E, Tenhunen JJ, Parviainen I, Jakob SM. Early non-invasive cardiac output monitoring in hemodynamically unstable intensive care pa�ents: a mul�-center randomized controlled trial. Crit Care 2011; 15: R148. Cecconi M, Benne� D. Should we use early less invasive hemodynamic monitoring in unstable ICU pa�ents? Crit Care 2011; 15: 173. Harvey SE, Welch CA, Harrison DA, Rowan KM, Singer M. Post hoc insights from PACMan--the U.K. pulmonary artery catheter trial. Crit Care Med 2008; 36: 1714–21. Muller L, Bobbia X, Toumi M, Louart G, Molinari N,Ragonnet B, Quintard H, Leone M, Zoric L, Lefrant JY, and the AzuRea group. Respiratory varia�ons of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing pa�ents with acute circulatory failure: need for a cau�ous use. Crit Care 2012; 16:R188. Mahjoub Y, Pila C, Friggeri A, Zogheib E, Lobjoie E, Tinturier F, Galy C, Slama M, Dupont H. Assessing fluid responsiveness in cri�cally ill pa�ents: False-posi�ve pulse pressure varia�on is detected by Doppler echocardiographic evalua�on of the right ventricle. Crit Care Med 2009; 37: 2570–4. De Backer D, Heenen S, Piagnerelli M, Koch M, Vincent JL. Pulse pressure varia�ons to predict fluid responsiveness: influence of �dal volume. Intensive Care Med 2005, 31: 517–23. Feissel M, Michard F, Mangin I, Ruyer O, Faller JP, Teboul JL. Respiratory changes in aor�c blood velocity as an indicator of fluid responsiveness in ven�lated pa�ents with sep�c shock. Chest 2001, 119: 867–73. Barbier C, Loubieres Y, Schmit C, Hayon J, Ricome JL, Jardin F, Vieillard-Baron A. Respiratory changes in inferior vena cava diameter are helpful in predic�ng fluid responsiveness in ven�lated sep�c pa�ents. Intensive Care Med 2004, 30: 1740–6. Monnet X, Osman D, Ridel C, Lamia B, Richard C, Teboul JL. Predic�ng volume responsiveness by using the endexpiratory occlusion in mechanically ven�lated intensive care unit pa�ents. Crit Care Med 2009, 37: 951–6. Teboul JL, Monnet X. Predic�on of volume responsiveness in cri�cally ill pa�ents with spontaneous breathing ac�vity. Curr Opin Crit Care 2008, 14: 334–9.


DO WE NEED ADVANCED HEMODYNAMIC MONITORING IN PATIENTS UNDERGOING CRANIOTOMY? Jasmina Markovič Božič Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Centre, Ljubljana, Slovenia

Introduc�on Hemodynamic stability and maintenance of cerebral perfusion pressure (CPP) are important in neurosurgical pa�ents (1,2). Fluid management includes maintenance of intravascular volume, preserva�on of cerebral perfusion pressure and minimiza�on of cerebral oedema (1). In pa�ents undergoing craniotomy diure�cs, preopera�ve fas�ng, induc�on of general anaesthesia and intraopera�ve bleeding may lead to hypovolemia and poor cerebral perfusion. On the other hand fluid overload increases complica�ons and hospital stay a�er surgery (2−4). It is, therefore, important that op�mal fluid levels are achieved. In clinical prac�ce we can assess circula�ng blood volume with conven�onal hemodynamic parameters (blood pressure, heart rate, central venous pressure) or advanced techniques like stroke volume varia�on or trans-oesophageal echocardiography (3,4). The effect of anaesthe�cs, as well as use of β-adrenergic blocking drugs, limits the value of blood pressure and heart rate for volume status assessment, urine output is also of limited value because of the frequent use of mannitol and loop diure�cs (2). It was shown that FloTrac system is a method for the individual tailoring of preopera�ve volume expansion and goal directed fluid therapy in pa�ents undergoing craniotomy (4). Remifentanil is an ideal narco�c agent during neurosurgical procedures that allows perfect �tra�on of the analgesic effect to various noxious s�mula�on intensi�es, along with rapid recovery and early neurological evalua�on (5,6). Anaesthesia can be maintained with sevofluran or propofol that allow rapid and predictable excre�on and fast recovery. Reported clinical trials failed to show advantage of any technique to change our daily prac�ce (8). Remifentanil based anaesthesia has an increased incidence of hypotensive episodes, the drug must be �trated in elder, obese and hypovolemic pa�ents. With increased clinical experience, pa�ents are hemodynamic more stable (5,6). The aim of this study was to compare intraopera�ve hemodynamic stability, fluid replacement and vasoac�ve drug consump�on between standard monitored and advanced monitored groups [email protected]

during remifentanil based anaesthesia with propofol in pa�ents undergoing craniotomy for supratentorial space occupying lesion.

Materials and methods 22 pa�ents (age 18-75 years, ASA physical status I, II or III) scheduled for elec�ve craniotomy of a supratentorial space-occupying lesion under remifentanil based anaesthesia with propofol were enrolled in this study. Pa�ents were randomised in two groups: using standard monitoring (group S) or advanced monitoring with pulse contour cardiac output, FloTrac method (group V). The standard monitoring included pulse oximetry, con�nuous arterial pressure recording, electrocardiogram, ETCO2, diuresis. Advanced monitoring consisted of standard monitoring plus con�nuous cardiac output/cardiac index (CO/CI) and systemic vascular variability (SVV) monitoring. Fluid replacement with infusion of 0,9% NaCl 6ml/h/kg the first hour and then 2,5 ml/h/kg was used. Anaesthesia was induced with propofol 12 mg/kg, remifentanil 0.5-1 μg/kg and rocuronium 0, 6 mg/kg. Ven�la�on was adjusted to ETCO2 30-35 mm Hg. Anaesthesia was maintained by con�nuous infusion of propofol 0.05-0.1 mg/kg/ min, remifentanil was adjusted regarding to anaesthesia response (0.1-2 μg/kg/min). In the S group adverse hemodynamic events that did not respond to changes in anaesthe�c regimen could be managed with ephedrine sulphate, atropine, urapidil or metoprolol, as appropriate. Hypotension following blood losses was maintained with colloids or blood replacement. In the V group hypotension was managed as follows: if CI was less than 2 and SVV was more than 10, colloid (HES 130/0,40; Voluven 6%) was given, if CI was less than 2 and SVV was less than 10, ephedrine sulphate 5-10 mg was given. In both groups hypertension (MAP > 30% of basal value) was treated with eleva�on of remifentanil infusion, if hypertension persisted, urapidil or metoprolol could be used. 30 minutes before the end of the surgery (at the �me of dura closer) metamizol 2.5 g and pir179


Sta�s�cal analysis Sta�s�cal program SPSS for Windows was used. Differences among groups were compared with Student t-test and χ2 test. Results are expressed as means ± SD or numbers of pa�ents. P-value < 0, 05 was considered sta�s�cally significant.

Results Demographic data and the dura�on of the surgical procedure didn’t differ between the two groups (table 1). Total doses of anaesthe�c drugs, ephedrine sulphate and volume loading used during surgery are shown in the table 2. In the V group significantly more crystalloids and colloids were used (1690, 91 vs. 1281,82, p = 0,05; 363,64 vs. 90,91, p = 0,03). Pa�ents didn’t need urapidil, metoprolol or blood replacement.

140

Group S Group V

120 Mean arterial pressure (mm)

itramid 5-10 mg were administered. The �me of the opera�on was determined as �me from pin head-holder placement to its removal. The orotracheal tube was removed as soon as the pa�ents breathed spontaneously and opened their eyes on command. Emergence hypertension was treated with urapidil or metoprolol, if necessary. Con�nuous intravenous infusion of piritramid was started postopera�vely as pa�ent control analgesia (PCA). Recorded parameters: mean arterial pressure and heart rate were monitored con�nuously and in the V group also CO/CI and SVV, intraopera�ve consump�on of remifentanil, propofol, crystalloids, colloids, blood and ephedrine, urapidil or metoprolol.

100 80 60 40 20 0

1

2

3

Fig. 1. Mean arterial pressure during surgery

1 – Basal MAP, 2 – MAP a�er the induc�on, 3 – Average MAP during the surgery, 4 – MAP at the end of the surgery

Mean arterial pressure (MAP) recorded during the surgery was not significantly different (p > 0, 05) between the two groups (Figure 1).

Discussion It is well known that anaesthe�c technique for craniotomy has strong impact on postopera�ve outcome. The prac�ce includes different clinical scenarios: trauma�c brain injury (TBI), intracranial tumours, brain neurovascular surgery (2). Quality of postanesthesia recovery and the rate of postopera�ve complica�ons are affected by efficiency in physiological, pharmacological and clinical variables manipula�on (10). During neurosurgery brain injury is induced in many forms and affects normal brain structures (brain �ssue and vasculature manipula�on, global hemodynamic changes). Anaesthesiologist should provide neuroprotec�ve measures that will reduce poor neurological outcome like motor and sensory deficits and cogni�ve dysfunc�on. Neuroprotec�on may be achieved by non pharmacological and pharmacological strate-

Table 1. Demographic data and the dura�on of the surgical procedure S 11 43,09±14,57 87,00±14,85 11/0 5/5/1 168,54 ±67,44 9,88±4,29

N Age (years) Weight (kg) Gender(M/F) ASA status (I/II/III) Dura�on of procedure (min) Hospital staying (days)

V 11 51,36±17,00 89,81±14,60 11/0 1/8/2 178,18± 51,00 9,25±1,98

Values are means ± SD or numbers of pa�ents. No differences between the groups were found.

Table 2. Total doses of anaesthe�c drugs, ephedrine sulphate and volume loading during surgery Propofol (mg) Remifentanil (mg) Rocuronium(mg) Ephedrine sulphate(mg) Crystalloids (ml) Colloids(ml) Total loss of blood (ml)

S 1210,36±434,00 15,93± 6,62 47,27 ± 4,67 1,82±6,03 1281,82 ± 397,03 90,91± 202,26 168,18± 167,74

Values are means ± SD. * p = 0,05, ** p = 0,03

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4

V 1248,64±400,66 15,03±5,67 50,91± 8,31 5,45±9,34 1690,91± 531,89* 363,64± 323,33** 295,45± 264,06


Table 3. Current status of periopera�ve neuroprotec�ve strategies that can work Liberal normoglycaemia 7,8-10 mmol/l Mean arterial pressure close to preopera�ve baseline ≥ 80 mmHg 20% Induced hypertension (interven�onal neuroradiology, cerebral aneurysm clipping, CEA, vasospasm a�er SAH, intracranial pathology with mass effect, systemic hypertensive disease, TBI) ≥ 120 g/l Preopera�ve haemoglobin Intraopera�ve haemoglobin ≥ 90 g/l

gies (table 3). Reported clinical trials failed to show any benefit of pharmacological agents (11−13). Remifentanil has been used successfully for brain surgery because of predictable emergence from anaesthesia without prolonged respiratory depression. It provides good hemodynamic control during par�cularly noxious por�ons of craniotomy procedures and it does not have effect on intracranial pressure or carbon dioxide reac�vity provided that ven�la�on is controlled (6,12,14). It may provide op�mal surgical condi�ons, reduce ischemic �ssue damage and suppress surgical stress response and intraopera�ve increase of blood glucose. In pa�ents who underwent brain surgery remifentanil pa�ents had significantly lower hospital stay and in-hospital mortality comparing to fentanyl (14). Anaesthe�c strategy for elec�ve and emergency cases should include appropriate pa�ent posi�oning, management of systemic and cerebral hemodynamic, fluid and electrolyte balance, coagula�on and postopera�ve preven�on and treatment of pain and PONV. Appropriate management of systemic and cerebral hemodynamic variables is a cornerstone of neuroanaesthesia (manipula�on of cardiac output, arterial blood pressure, cardiac rhythm, cerebral blood flow). In our study there were no significant differences in hemodynamic stability between the two groups, but we found significant differences between groups in fluid replacement. Fluid management of the neurosurgical pa�ent has advanced from "run them dry" to "run them isovolaemic, isotonic and iso-onco�c, but the induc�on of poten�al complica�ons by current strategies are s�ll unknown (9). Conven�onal hemodynamic parameters are insensi�ve and some�mes misleading in the assessment of intravascular volume (3,4). Advanced techniques provide goal directed fluid therapy which is currently the gold standard in fluid strategy. Fluid therapy should be planned individually and follow target values (for example op�misa�on of stroke volume). We should follow the trends and not the absolute values (15,16). Stroke volume varia�on (SVV) measured with the FloTrac method was found to be sensi�ve predictor of fluid responsiveness in healthy pa�ents before brain surgery (4). It is non-invasive, easy to use and provides real �me monitoring. In conclusion we found remifentanil based anaesthesia appropriate for elec�ve craniotomy for supratentorial lesions providing good hemodynam-

ic control and intraopera�ve condi�ons. With advanced monitoring we used more fluids for maintenance of CPP without significant consequences like brain oedema or longer hospital staying.

References 1. Tommasino C. Fluid management. In Newfield P & Co�rell JE (eds.). Handbook of neuroanaesthesia. Fourth edi�on. New York: Lippinco�-Williams & Wilkins, 2007, pp. 379–95 2. Bilo�a F, Guerra C, Rosa G. Update on anaesthesia for craniotomy. Curr Opin Anesthesiol 2013; 26: 517–22. 3. Berkenstadt H, Margalit N, Hadani M et al. Stroke volume varia�on as a predictor of fluid responsiveness in pa�ents undergoing brain surgery. Anesth Analg 2001; 92: 984–9. 4. Evalua�on of stroke volume varia�on obtained by the FloTrac/Vigileo system to guide preopera�ve fluid therapy in pa�ents undergoing brain surgery. The Journal of Interna�onal Medical Research 2012; 40: 1175–81. 5. Fodale V et al. Remifentanil and the brain. Acta Anaesthesiol Scand 2008; 52: 319–26. 6. Warner DS, Hindman BJ, Todd MM, et al. Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in pa�ents undergoing supratentorial craniotomy. Anesth Analg 1996; 83: 348–53. 7. Hogue CW Jr, Bowdle TA, O'Leary C, et al. A mul�center evalua�on of total intravenous anesthesia with remifentanil and propofol for elec�ve inpa�ent surgery. Anesth Analg 1996; 83(2): 279–85. 8. Citerio G, Pesen� A, La�ni R, Masson S, Barlera S, Gaspari F, Franzosi MG; NeuroMorfeo Study Group. A mul�centre, randomised, open-label, controlled trial evalua�ng equivalence of inhala�onal and intravenous anaesthesia during elec�ve craniotomy. Eur J Anaesthesiol 2012; 29(8): 371–9. 9. Tommasino C, Picozzi V. Volume and electrolyte management. Best Pract Res Clin Anaesthesiol. 2007; 21(4): 497–516. 10. Beheiry H. Protec�ng the brain during neurosurgical procedures: strategies that can work. Curr Opin Anesthesiol 2013; 25: 548–55. 11. Mantz J, Degos V, Laigle C. Recent advances in pharmacological neuroprotec�on. Eur J Anaesthesiol 2010; 27: 6–10. 12. Schifilli� D, Grasso G, Con� A, Fodale V. Anaesthe�crelated neuroprotec�on: intravenous or inhala�onal agents? CNS Drugs. 2010 Nov;24(11):893–907. 13. Zuo Z. Are vola�le anesthe�cs neuroprotec�ve or neurotoxic? Med Gas Res 2012; 2: 10. 14. Uchida K, Yasunaga H et all. Impact of remifentanil use on early postopera�ve outcomes following brain tumor resec�on or rectal surgery. J Anesth 2012; 26: 711–20 15. Corcoran T, Rhodes JE, Clarke S, Myles PS, Ho KM. Periopera�ve fluid management strategies in major surgery: a stra�fied meta-analysis. Anesth Analg 2012; 114: 640–51. 16. Pearse RM, Ackland GL. Periopera�ve fluid therapy. BMJ 2012; 26:344.

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STRATEGY FOR REDUCING ANTIMICROBIAL RESISTANCE IN INTENSIVE CARE UNITS

Slavče Antanasković1, Slađana Vasiljević2, Ana Antanasković3

Department for Anesthesiology and Reanima�on, Health Center Vranje, Serbia Department for Anesthesiology and Intensive Care, Mother and Child Health Care Ins�tute "Dr Vukan Čupić", Belgrade, Serbia 1 2

Introduc�on

Intensive Care Unit (ICU) is a special department of a hospital that provides intensive treatment for cri�cally ill pa�ents who have a drama�c reduc�on in reserves of vital systems. Appropriate treatment requires monitoring of all vital func�ons of the body. ICU pa�ents may have systemic disorders of the whole organism (polytrauma, sepsis, intoxica�on, hemorrhagic shock) or one vital organ disease (heart, lung, kidney and liver failure). Human (medical mul�disciplinary professional team headed by an anesthesiologist - intensivist), technological, pharmacological and physical condi�ons are essen�al for the appropriate ICU func�on. The cost of treatment in the ICU annually rise by about 10%. The planning of the highly educated medical staff for the ICU contributes to costs ra�onaliza�on ("cost effec�ve"). Analysis of costs ("cost benefit") shows that some developed countries are different in 300% in annual spending in the ICU. The types of the infec�on in ICU is based on posi�ve control cultures. If a pa�ent on admission to the ICU has a posi�ve control culture of the pharynx and rectum and develop infec�on with these pathogens, it is the primary endogenous infec�ons (55%). Subsequent posi�ve culture lead to secondary endogenous infec�ons (30%). If there was not posi�ve control cultures, these are exogenous infec�on (15%). Control cultures of the pharynx and rectum should be taken every 3-4 days during the ICU stay. Factors predisposing to infec�on of ICU pa�ents are: – from pa�ent: acute and chronic diseases, intuba�on, mul�ple catheters, reduced immune response, malnutri�on, pain, an increase in the gastric juice pH, age, use of broad spectrum an�bio�cs – from environment: opportunis�c microorganisms, rapid changes of pa�ents, contamina�on of space, equipment and medical personnel. Causes of fever in the ICU are: – postopera�ve: malignant hyperthermia, wound infec�on, atelectasis, thromboembolism, abdominal abscesses 182

[email protected]

– procedure: hemodialysis, endoscopy, blood transfusion and iatrogenic – frequent infec�ons: pneumonia, catheter related bloodstream infec�on, urinary catheter related infec�on – rarer infec�ons: paranasal sinusi�s, acalculous cholecys��s, pseudomembranous enterocoli�s, endocardi�s, meningi�s – non-infec�ous causes: drugs, SIRS, intes�nal infarc�on, pancrea��s, thromboembolism, adrenal insufficiency. According to the EPIC II 1-day prospec�ve point-prevalence study (Extended Prevalence of Infec�on in Intensive Care) in 1,265 par�cipa�ng ICUs (75 countries worldwide), 51% of the 12,796 pa�ents were considered infected, although no subdivision was made for hospital-acquired infec�ons(1). Many factors promote infec�on among hospitalized pa�ents including decreased host immunity, the variety of medical procedures and invasive techniques and poor infec�on control that may facilitate transmission of drug-resistant bacteria among hospital popula�ons (2). The most common nosocomial infec�ons are urinary tract infec�on, pneumonia and intravascular device-related bloodstream infec�on and comprise approximately 80% of all nosocomial infec�ons (3,4). An�bio�c use is important factor in the development of HAI. The inappropriate use of an�biotics contributes to the increase in drug-resistant bacteria, that are the source of approximately 70% of nosocomial infec�ons(5). In addi�on, these nosocomial infec�ons are associated with higher rates of morbidity and mortality. Methicilin Resistant Staphylococcus Aureus (MRSA) is one of the most common bacteria involved in nosocomial infec�ons. According to a Interna�onal Nosocomial Infec�on Control Consor�um (INICC) report on data summary of 422 ICUs of 36 countries in La�n America, Asia, Africa, and Europe, for 2004-2009, the frequency of MRSA was 71.4% to 84.1%, the frequency of Klebsiella pneumoniae resistant to ce�azidime or ce�riaxone 68.9% to 76.3%, Acinetobacter baumannii to imipenem 55.3% to 66.3%, Escherichia coli to ce�azidime 49.7% to 67.5% and Pseudomonas aeruginosa to piperacillin 36.2% to 41.7% (6).


The urinary tract infecton (UTI) is the most commom nosocomial infec�on in the ICU and accounts approximately 35% of such infec�ons(4). Urinary catheter is associated with approximatelly 80% of all nosocomial urinary tract infec�ons and nearly 20% of pa�ents with urinary catheter developed a urinary tract infec�on(7). Indweling catheter, over �me, becomes colonized with microorganisms forming a biofilm on the surface of the catheter and drainage system. These bacteria are resistant to an�microbials and host defenses and only by removing the catheter could be eradicated. An�microbial resistance among urinary pathogens is an increasing problem. About a quarter of E. coli isolates and one third of P. aeruginosa isolates from CAUTI cases were fluoroquinolone-resistant. Resistance to third-genera�on cephalosporins and carbapenems was also substan�al(10). In order to improve the preven�on and control of CAUTI, recently was published Guideline for preven�on of catheter-associated urinary tract infec�ons 2009(7) The ven�lator-associated pneumonia (VAP) accounts for approximatelly 15% to 20% of all nosocomial infec�ons(4). The most common pathogens are Pseudomonas aeruginosa, MRSA, Acinetobacter, other Staphylococcus spp., and Enterobacter spp.(8,9). Many cases of VAP are caused by more than one pathogen(8). Strategies to prevent VAP in hospitals focus on controlling the main causes: aspira�on of secre�ons into the lungs, coloniza�on of bacteria in the aerodiges�ve tract and use of contaminated equipment. The primary goal is to extubate the pa�ent as early as possible. Alterna�ve measure is to use the noninvasive ven�la�on(10). De-escala�on therapy (discussed later) reduced the mortality rate and achieve a more judicious use of an�bio�cs(11,12).With the inten�on to highlight prac�cal recommenda�ons in a concise format, recently was published Strategies to Prevent Ven�lator-Associated Pneumonia in Acute Care Hospitals(13). Catheter-related bloodstream infec�ons (CRBSI) account for approximately 15% of all nosocomial infec�ons (14). Almost 90% of all intravascular device-related bloodstream infec�ons is the result of the use of central venous catheters. Central venous catheters inserted either in the internal jugular or the femoral vein had greater risk to be colonized than catheters inserted in the subclavian vein(15). According to the INICC findings, the most common pathogens are Enterobacteriaceae (31.9% to 53% resistant to piperaciline tazobactam, ce�azidime and ce�riaxone), Coagulasenega�ve-staphylococci, Staphylococcus aureus (85.4% resistant to methicilin), Acinetobacter sp.,

Pseudomonas sp. (38.3% to 48.1% resistant to piperaciline tazobactam, imipenem, ce�azidime and ciprofloxacine), Candida sp.; Enterococcus sp. (24.3% resistant to vancomycin)(16). Mul�ple studies have shown that most CRBSIs are preventable. One successful strategy is the implementa�on of an educa�onal programme and the adherence to best prac�ce behaviours known to prevent CRBSIs, including hand washing, using full barrier precau�ons during the inser�on of CVCs, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. The benefit from the ini�a�on of the comprehensive preven�on programme was a reduc�on in the rate of CRBSI of 66%(17).

An�microbial resistance An�microbial resistance (AMR) is a global concern for the reason that reduces the effec�veness of treatment, resul�ng in prolonged illness and increased risk of spreading resistant microorganisms, greater mortality and increased health-care costs. Resistant organisms and nosocomial infec�ons present major challenges, especially in ICU. The use of broad-spectrum agents, even when appropriate, is a significant factor in the development of resistance in bacteria and fungi. Bacteria may be intrinsically resistant to ≥1 class of an�microbial agents, or may acquire resistance by de novo muta�on or via the acquisi�on of resistance genes from other organisms (18). Intrinsic resistance are common for the low virulence organisms, but in vulnerable pa�ents these organisms may cause problems (Pseudomonas sp., Acinetobacter) (19). Acquired resistance genes may enable a bacterium to produce enzymes that destroy the an�bacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug’s target site, or to produce an alterna�ve metabolic pathway that bypasses the ac�on of the drug (18). Acquisi�on of resistance may occur through next mechanisms: transforma�on (naked DNA from killed bacteria is incorporated into the genome of another bacterium), transduc�on (the DNA within the virus, bacteriophages, is exchanged or transferred to the host), conjuga�on (by plasmids, self-replica�ng circles of DNA that exist within the bacteria but are separate from the chromosome) and transposons (smalls segments od DNA that can move from plasmids to plasmids) (18,19). Transforma�on is common for ICU pa�ents on an�bio�cs and the most important routes of transmission of gene�c informa�on in ICU is by plasmids (19).

183


Management strategies An�bio�c resistance is a mul�faceted problem requiring mul�factorial interven�ons to prevent its emergence and further spread. A wide range of non-pharmacological and pharmacological measures are employed in order to prevent the infec�ons due to an�bio�c resistant organisms or to reduce the resistance. The basic principles involve containment of resistant species (e.g., isola�on and coloniza�on surveillance), infec�on preven�on (e.g., appropriate use of an�bio�c prophylaxis, limited u�liza�on of invasive devices), infec�on eradica�on (e.g., appropriate diagnosis and treatment) and op�mizing an�bio�c u�liza�on (20).

Non-pharmacological strategies Non-pharmacological strategies include microbiologic surveillance, isola�on, hand hygiene, the use of barrier precau�ons (gloves and gowns) in the care of colonized and infected pa�ents, the use of dedicated instruments and equipment for these pa�ents, minimizing the number of nursing and medical staff involved in each pa�ents' care and decreasing hospital stays (19,21). Microflora surveillance has shown that the range and frequency of micro-organisms isolated varies between ins�tu�ons and even within an ICU over �me. The collec�on of regular microbiological data allows a picture of common pathogens and their an�bio�c sensi�vi�es. New admissions to ICU should be screened for target organisms (nasal swabs for MRSA surveillance cultures and stool or perianal swabs for VRE surveillance cultures) and wherever possible isolated to prevent the introduc�on of resistant strains(19,21). Recent study es�mated the culture-based ac�ve surveillance for MRSA and VRE and the expanded use of barrier precau�ons (Hand Hygiene before and a�er contact with pa�ents or Their Immediate Environment and use of Gloves and Gown), as compared with exis�ng prac�ce, on the incidence reduc�on of coloniza�on or infec�on with MRSA or VRE in adult intensive care units (ICUs) (21). Ac�ve surveillance for MRSA and VRE included nasal swabs for MRSA surveillance cultures and stool or perianal swabs for VRE surveillance cultures within 2 days a�er pa�ents’ admission to the ICU, weekly therea�er, and within 2 days before or a�er their discharge from the ICU. The interven�on was not effec�ve in reducing the transmission of MRSA or VRE, although the use of barrier precau�ons by providers was less than what was required. One of the reason for this was the other routes of MRSA and VRE transmission, such as by contaminated instruments or equipment or by colonized health care workers (22). 184

Moreover, previous studies have observed that a reduc�on in the incidence of MRSA infec�on may not be evident un�l a year or more a�er ini�a�on of an interven�on(23,24). The SHEA guidelines recommend contact (or cohort) isola�on for all pa�ents known to be colonized or infected with MRSA, including hand hygiene and the use of gloves and gowns before interac�ng with in fected/colonized pa�ents or entering their environments(25). Previous quasi-experimental studies demonstrated the reducing the incidence of MRSA and VRE coloniza�on among ICU pa�ents by daily bathing of pa�ents with chlorhexidine and improved environmental cleaning(26-28). Recent study, in three phases at 13 ICUs, demonstrated reduced acquisi�on of an�microbial-resistant bacteria, par�cularly MRSA by improved hand hygiene plus unit-wide chlorhexidine body-washing(29). A�er a 6 month baseline period (phase 1), they did an interrupted �me series study of universal chlorhexidine bodywashing combined with hand hygiene improvement for 6 months (phase 2), followed by a 12-15 month cluster randomised trial (phase 3). They also demonstrated that screening and isola�on of carriers do not reduce acquisi�on rates of mul�drug-resistant bacteria, whether or not screening is done with rapid tes�ng (PCR tes�ng for MRSA and VRE and chromogenic screening for highly resistant Enterobacteriaceae) or conven�onal testing (chromogenic screening for MRSA and VRE). Decreasing the length and/or frequency of hospital stays has been hypothesized to decrease the risk for nosocomial MRSA transmission, and results from a number of studies provide support for this concept. For example, a study evalua�ng acquisi�on of MRSA in the ICU found length of ICU stay to be a significant independent risk factor for MRSA acquisi�on(30). Another study similarly reported that both an ICU stay of more than 2 days as well as being a trauma pa�ent were significant independent risk factor for MRSA acquisi�on in ICU(31).

Pharmacological strategies Pharmacological strategies include op�miza�on of an�bio�c u�liza�on, de-escala�on therapy, decoloniza�on with mupirocin, selec�ve diges�ve decontamina�on (SDD) and selec�ve oropharyngeal decontamina�on (SOD).

The op�miza�on of an�bio�c u�liza�on The op�miza�on of an�bio�c u�liza�on represent the appropriate use of an�bio�cs and the limita�on of unnecessary an�bio�c admin-


istra�on. It involves appropriate diagnosis, appropriate culture and sensi�vity data, the most appropriate treatment by selec�ng appropriate an�bio�cs and doses (through the use of pharmacokine�c and pharmacodynamic principles)(20,32). Underdosing and prolonged dura�on of an�microbial therapy should be avoided. There are various an�bio�c u�liza�on strategies including an�bio�c u�liza�on guidelines, hospital formulary-based an�microbial restric�ons, programs for restric�on of target an�microbials and an�bio�c cycling or rota�on(20,32).

An�bio�c cycling (an�bio�c rota�on programme) An�bio�c cycling is the planned withdrawal of commonly used an�bio�cs for a scheduled period (e.g. 6 months) to reduce selec�on pressure and the emergence of resistance(19). Different suites of an�bio�cs are then used which are themselves changed a�er scheduled period. The design of a rota�on protocol must take into account the pa�ent popula�on, incidence of infec�on, local bacterial ecology, and local an�bio�c an�microbial-suscep�bility profiles(33). Other important factors that have yet to be determined include determining the superiority of site-specific versus organism-specific rota�on strategies, op�mal dura�on of rota�on periods, op�mal number of an�bio�cs u�lized in a rota�on protocol, types of an�bio�cs u�lized, and in what order(33). The quarterly empiric an�bio�c rota�onal schedule in a surgical and trauma ICU, for the empirical treatment of pneumonia and peritoni�s or sepsis of unknown origin, was prospec�vely studied(34). A reduc�on in infec�ous and overall mortality was demonstrated. Moreover, sta�s�cally significant decline in the incidence of resistant infec�ons, gram posi�ve (S. aureus, S. epidermidis, and S. enterococus) and gram nega�ve (Pseudomonas and Acinetobacter) was detected. However, there was no significant decrease in hospital stay dura�on and vancomycin resistance. Previous study evaluated the effect of the quarterly rota�on of an�bio�cs (piperacillin/tazobactam, fluoroquinolones, carbapenems and cefepime/ce�azidime) on the incidence of ven�lator-associated pneumonia (VAP) caused by an�bio�c-resistant Gram-nega�ve bacteria(35). This interven�on reduced the incidence of VAP caused by an�bio�c-resistant Gram-nega�ve bacteria in the ICU, such as Pseudomonas aeruginosa, but did not affect the ICU mortality and microbial flora isolated through clinical cultures.

Restric�ve an�bio�c strategies Restric�ve an�bio�c strategies represent limi�ng access to an�bio�cs through formulary restric�on or an�bio�c surveillance teams in order to decrease the inappropriate use of an�bio�cs, especially broad-spectrum agents, thus decrease an�bio�c selec�on pressure and improve resistance profiles. Previous studies demonstrated that reatment with systemic an�bio�cs that have an�anaerobic ac�vity promotes high-density coloniza�on of VRE in the gastrointes�nal tract, and the use of fluoroquinolone has been associated with increased rates of MRSA coloniza�on or infec�on(36,37). Thus, efforts to reduce the unnecessary use of these agents may complement other interven�ons in order to prevent the infec�ons due to an�bio�c resistant organisms. Recent systema�c review evaluated the Interven�ons for improving of an�bio�c prescribing prac�ces for hospital inpa�ents(38). Persuasive interven�ons advised physicians about how to prescribe or gave them feedback about how they prescribed. Restric�ve interven�ons put a limit on how they prescribed (to decrease excessive prescribing); for example, physicians had to have approval from an infec�on specialist in order to prescribe an an�bio�c. Restric�ve interven�ons were associated with reduc�on in Clostridium difficile infec�ons and coloniza�on or infec�on with aminoglycoside- or cephalosporin-resistant gram-nega�ve bacteria, MRSA and VRE.

De-escala�on therapy The strategy of de-escala�on therapy was developed in order to improve the management of VAP. It involves the use of a broad-spectrum an�bio�c targeted to likely pathogens (according to the infec�on history of the healthcare facility and of individual pa�ent units) and once the results of cultures are known, the an�bio�c regimen is altered (8,9,11,39). This strategy has reduced the mortality rate and achieve a more judicious use of an�bio�cs (11,12).

Decoloniza�on with mupirocin Another interven�on that reduce MRSA coloniza�on is intranasal mupirocin, coupled with other systemic and topical agents. However, it is short-�me effec�ve and associated with the development of mupirocin resistance(40).

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Selec�ve diges�ve and oropharyngeal decontamina�on Selec�ve diges�ve decontamina�on (SDD) and selec�ve oropharyngeal decontamina�on (SOD) represent prophylac�c applica�on of topical nonabsorbable an�microbials to the stomach or oropharynx of pa�ents with or without addi�onal systemic an�microbials(41). This technique mainly eradicates poten�ally pathogenic gram-nega�ve aerobic bacteria in the gastrointes�nal tract. However, despite the modest decreases in mortality and decreases in bloodstream infec�ons, the major concern with the widespread implementa�on of SDD and SOD is an�microbial resistance(42). These strategies may promote overgrowth of MDR gramposi�ve bacteria, such as MRSA. As such, they are preferably used in se�ng with a very low baseline prevalence of MRSA(43). Recent systema�c review analised 64 unique studies of SDD and SOD in ICUs for the effect of SDD and SOD on the rates of colonisa�on or infec�on with an�microbial-resistant pathogens(44). There was no difference in the prevalence of colonisa�on or infec�on with me�cillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, aminoglycoside or fluoroquinolone-resistant Gram nega�ve bacili. There was a reduc�on in polymyxin-resistant Gram-nega�ve bacilli and third-genera�on cephalosporin-resistant Gram-nega�ve bacilli in recipients of selec�ve decontamina�on. Longterm harm effect of SDD and SOD and the development of an�microbial-resistance in this pa�ents in ICU could not been detected by available data and future research are recommended. A previous review recommended that SDD should be considered when it is an�cipated that mechanical ven�la�on will be required for more than 48 h, the choice of treatment should depend on local pathogen an�microbial suscep�bility and be supported by good infec�on control and planned prospec�ve suscep�bility surveillance(45).

Educa�on Finally, educa�on is a cornerstone of any an�bio�c stewardship program. It include 1-on-1 instruc�on, staff conferences, lectures, mailings of instruc�onal materials, clinical pharmacy consulta�ons, drug u�liza�on evalua�ons, hospital– pharmacy commi�ee newsle�ers and dissemina�on of clinical guidelines(46).

Conclusion An�bio�c resistance is a mul�faceted problem requiring mul�factorial interven�ons to prevent its emergence and further spread. A mul�186

disciplinary program designed by local clinicians, including infec�ous disease experts, which takes into account local bacterial ecology and resistance pa�erns and incorporates various an�bio�c u�liza�on strategies, offers the best chance to limit the appearance and dissemina�on of an�microbial resistance.

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BAD BUGS NEED NEW DRUGS Srdjan Pesic

Department for Pharmacology, School of Medicine, Niš, Serbia

Infec�ons caused with mul�drug resistant bacteria became a big therapeu�c problem in every day prac�ce even in hospitals and in community. There are few bacteria that are trying to 'escape' the effect of an�bacterial drugs. These microorganisms were named ~ESCAPE bacteria~. Mul�drug resistant, ESCAPE, bacteria are: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species. There are numerous data from the Centers for Disease Control and Preven�on (CDC) that show big increase incidence of infec�on due to methicillin-resistant S. aureus (MRSA), vancomycin-resistant E. faecium (VRE), and fluoroquinolone-resistant P. aeruginosa (1). It is interes�ng to note that more people now die of MRSA infec�on in US than of HIV/AIDS and tuberculosis combined (2,3). Today we have in our community bacteria resistant to almost all an�bio�cs, so called mul�drug or panan�bio�c-resistant infec�ons. At the same �me several highly resistant gram-nega�ve pathogens as Acinetobacter species, mul�drug-resistant (MDR) P. aeruginosa, carbapenem-resistant Klebsiella species and Escherichia coli becomes a serious therapeu�c problem (4−6). Possibili�es for treatment of these infec�ons are so extremely limited that clinicians are tried to use older, previously forgo�en drugs, such as colis�n, that are associated with significant adverse effects and for which there is no data for appropriate dosing and dura�on of therapy. There are growing number of elderly pa�ents and pa�ents undergoing surgery, transplanta�on, and chemotherapy and drama�c increases in popula�on in neonatal intensive care units which become immunocompromised with greater risk for severe infec�ons. Because of that seems the need for new an�bio�cs will be bigger during the �me. In 2009 Infec�ous Diseases Society of America (IDSA) & European Centre for Disease Preven�on and Control (ECDC)/European Medicines Agency (EMA) prepared analysis and declared that only 15-16 an�bio�cs were in development at that �me. Only 8 of inves�gated an�bio�cs had ac�vity against key Gram-nega�ve bacteria which 188

[email protected]

usually cause the most life-threatening infec�ons and, NONE of them had no ac�vity against bacteria resistant to all currently available drugs (7). Two years later, in 2011, situa�on was not be�er, IDSA updated statement: ten compounds ac�ve against resistant Gram-nega�ve bacteria were in clinical development as intravenous (IV) therapy. It was s�ll the case that NONE had ac�vity against bacteria resistant to all currently available drugs. There are no clinical studies inves�ga�ng therapeu�c effect of drug for the most life-threatening Gram-nega�ve infec�ons (hospital-associated pneumonia). More than 20% of pa�ents infected with this kind of pathogens die. IDSA was suggested and initates so called 10x20 strategy. It was idea to force pharmaceu�cals industries to develop at least ten new systemic an�bio�cs un�l 2020. This ini�a�ve have to bring together the most important leaders: global poli�cal, scien�fic, industrial, economic, intellectual property, policy and medical leaders to enforce inves�ga�on and development of new drug (8). We need to find out novel systemic an�bacterial drugs through the discovery of new drug classes as well to explore possible new drugs from the exis�ng classes of an�bio�cs (includes oral formula�ons) products that treat serious/life-threatening infec�ons that are resistant to current an�bio�cs (the ―ESKAPE‖ pathogens, e.g., emerging gram-nega�ve bacteria, S. aureus). In 2012 and 2013, an�bio�c development con�nues to stagnate. Only two systemic an�bacterial agents have been approved for use in humans by the FDA from 2008 through the current year. Only 30 years earlier, from 1983-1987, sixteen an�bio�cs were approved. Problem becomes bigger and bigger, we have had no new classes of an�bio�cs to treat Gram-nega�ve bacteria for more than 40 years. For example, the fluoroquinolones were the last new class of an�bio�cs introducesd into to prac�ce to treat Gram-nega�ve bacteria. An�bio�c resistance unfour�natelly con�nues to spread, par�cularly among the Gram-nega�ve bacteria (9,10). Thousands of people are now dying every year from infec�ons that used to be curable in the past.


The Centers for Disease Control and Preven�on recently warned that drug-resistant bacteria kill at least 23,000 people annually only in America and cost the U.S. health-care system $20 billion a year. CDC noted that at least three nightmare superbugs have become so virulent that they pose an "urgent" risk to the health. At first place is C. difficile, a deadly diarrhea-causing infec�on; at the second, a bloodstream infec�on that kills half the people it infects; and at the third place, a drug-resistant form of gonorrhea an age-old sexually transmi�ed disease that’s evolved to become resistant to the last drug available against it, raising the prospect of a sexually transmi�ed global epidemic. Finally, the main ques�on can be: why pharmaceu�cal companies not just develop new an�bio�cs? Maybe the answer can be that it’s too expensive. An�bio�cs require billions of dollars to develop, but people usually take them for just a few days. Research and development is extremely expensive process. It seems that the new developed an�bio�c can lose more than 20 million dollars. Drug companies can make billions, however, developing medica�ons for chronic diseases such as diabetes and heart disease, which are taken by pa�ents for the rest of their lives. The development of new drugs for bad bugs must be guided from governments, pharmaceu�cal industries and communi�es together because the problem is so big and have to be solved adequately for the health of next genera�ons.

References 1. Na�onal Nosocomial Infec�ons Surveillance System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004; 32: 470–85. 2. Klevens RM, Edwards JR, Tenover FC, McDonald LC, Horan T, Gaynes R. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992–2003. Clin Infect Dis 2006; 42: 389–91. 3. Boucher HW, Corey GR. Epidemiology of methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008; 46 (Suppl 5): S344–9. 4. Falagas ME, Blizio�s IA. Pandrug-resistant gram-nega�ve bacteria: the dawn of the post-an�bio�c era? Int J An�microb Agents 2007; 29: 630–6. 5. Bradford PA, Bratu S, Urban C, et al. Emergence of carbapenemresistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 b-lactamases in New York City. Clin Infect Dis 2004; 39: 55–60. 6. Urban C, Bradford PA, Tuckman M, et al. Carbapenem-resistant Escherichia coli harboring Klebsiella pneumoniae carbapenemase b-lactamases associated with long-term care facili�es. Clin Infect Dis 2008; 46:e127–30. 7. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infec�ous Diseases Society of America. Clin Infect Dis 2009; 48: 1-12. 8. Infec�ous Diseases Society of America. The 10 × ‘20 ini�a�ve: pursuing a global commitment to develop 10 new an�bacterial drugs by 2020. Clin Infect Dis 2010; 50: 1081-3. 9. Magiorakos AP, Srinivasan A, Carey RB, et al. Mul�drugresistant, extensively drug-resistant and pandrug-resistant bacteria: an interna�onal expert proposal for interim standard defini�ons for acquired resistance. Clin Microbiol Infect 2012; 18: 268-81. 10. Talbot GH. β-Lactam an�microbials: what have you done for me lately? Ann N Y Acad Sci 2013; 1277: 76-83.

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SEVERE VIRAL PNEUMONIA THERAPY Nada Popović1,2, Marina Stojanović2, Danijela Stojimirović2 School of Medicine, University of Belgrade, Serbia Center for Anesthesiology and reanimatology, Clinical Center of Serbia, Belgrade, Serbia

1 2

Despite significant advancement in an�microbial therapy, the occurrence of viral pneumonia is s�ll very high. Pneumonia is considered to be the seventh cause of mortality in the United States (1). Viral pneumonias are rare in previously healthy persons. The most frequent cause is a complica�on of an infec�on caused by Varicella Zoster virus and its clinical presenta�on is not too complicated. Life threatening viral pneumonias are most o�en seen in immune compromised pa�ents. These are HIV (human immune deficiency virus) pa�ents, an� malignant therapy pa�ents, transplanted pa�ents on immunosuppresive therapy and certain age groups (prematurely born children and very old pa�ents). It has been published that 29% of CAP’s (community associated pneumonia) are caused by a virus, mostly rhinovirus and influenza virus and that in 50% of pa�ents it is a mixed type infec�on, both viral and bacterial, which makes illness much worse (2).

Pathophysiological mechanisms of viral pneumonias Factors that contribute to occurrence of severe viral infec�ons, and that includes pneumonia too, can be divided into respiratory and immune factors. Respiratory factors are primarily: respiratory muscle weakness, lowered respiratory mucosa protec�ve ability, reduced pulmonary compliance, lowered elas�ne and collagen contents in alveolar duc�. Immune factors are: reduced prolifera�on and total T cell number, disorder in Th1 and Th2 response balance, higher concentra�on of inflamma�on mediators as well as mi�gated B cell response to new an�gens and higher concentra�on of auto an�bodies. Also, there is less NK cell cytotoxicity, reduced NK cell response to IL-2, heightened levels of TNF, IL-1,IL-6 and IL-8 (3). Exact pathophysiological mechanism of pneumonia occurrence is not completely known. After contamina�on, most respiratory viruses have a tendency to develop in the epithelium of the upper respiratory tract. Secondary infec�on of pulmonary �ssue occurs through haematogenic spreading or due to respiratory secre�on 190

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spreading. The virus alone is responsible for the mechanism of �ssue damage. Some viruses are cytotoxic and directly damage pneumocytes and bronchial cells while others cause inflamma�on, meaning immune response itself represents the main pathogenic mechanism. Viral transmi�ng differs with different type of viruses. Commonly infec�ons occurs through Flugge drops spreading, through direct contact with infected objects, organ transplanta�on or through applica�on of contaminated blood products (for example Cytomegalo- CMV-infec�on), aspira�on of asymptoma�c viruses from saliva to lower respiratory tract (CMV, herpes simplex virus-HSV), through reac�va�on of latent infec�on (HSV,CMV).

The most common causes of viral pneumonia Influenza virus (type A and B) is the most common cause of viral pneumonia, especially in the older popula�on with chronic illnesses. It is responsible for 300 000 hospitaliza�ons per year and 36 000 deaths are related to it, especially in the popula�on over 65 year of age (4). Clinical symptoms are mostly manifested as fever, muscle pain, headache, gastrointes�nal disorders, and symptoms that help to differen�ate that infec�on from infec�on caused by other respiratory viruses. In 5% of pa�ents, infec�on is complicated by pneumonia. Only a third of pa�ents with pneumonia present the characteris�c radiographic picture of alveolar infiltra�on. The exact prevalence of dual viral-bacterial pneumonia is s�ll unknown. Some studies suggest that it is 10% and it is presented with more serious clinical presenta�on (5). RSV-respiratory syncy�al virus is the second most frequent cause of viral pneumonia. Data from the Center for Disease Control and Preven�on shows that RSV is responsible for roughly 10 000 deaths each year (6). In a study which consisted of 1200 pa�ents with CAP (community associated pneumonia), RSV (4,4% cases) was the third most frequent cause of pneumonia, right a�er S.


pneumoniae (6,2%) and Influenza A and B viruses (5,4%). In 2-7% of cases, RSV infec�on is complicated with pneumonia. Clinical manifesta�on of RSV pneumonia is hard to differen�ate from pneumonias caused by other viruses or bacterias. O�en dyspnea and cough are present but what is the most characteris�c for this infec�on is that it starts with nasal conges�on and rhynorrhea which later progresses into wheezing and difficult breathing. On lung radiography, most o�en one can see bilateral alveolar infiltra�on and changes in inters��al lining. Around 70% of pa�ents have normal white blood cell count, compared to 55% of pa�ents with atypical pneumonia and 40% of pa�ents with bacterial pneumonia. In 11-33% of pa�ents with RSV pneumonia bacterial superinfec�on can be found (5).

Human metapneumo virus (hMPV) is a newly discovered respiratory pathogen. It usually causes bronchioli�s and pneumonias. Clinical presenta�on and radiographic findings are not significantly different compared to other viral infec�ons. Parainfluenza virus (PIV) usually causes sore throat, bronchioli�s and pneumonias in children, rarely in adults. Clinical presenta�on is in the form of fever, rhynorrhea, cough, and throat ache and is considered to be nonspecific. Corona viruses are RNA viruses. Interna�onal a�en�on was brought to these viruses and intensified from the year 2002 when an epidemic of a severe form of acute respiratory syndrome started in China. It was caused by a new form of corona virus SARS (severe acute respiratory syndrome). This infec�on is characterized with mild temperature, malaise and nasal symptoms. Pneumonia can be seen in toddlers, immune compromised pa�ents and older popula�ons. What is characteris�c for these pneumonias is that there is no dis�nc�ve radiographic features- infiltra�on that leads to undetermined occurrence of these pneumonias. Rhinoviruses-the most common causes of colds in all age groups. It can also be a cause of pneumonia, usually in children and immune compromised pa�ents but not as o�en as with the previously men�oned viruses.

Diagnosis Viral pneumonia diagnosis is based on clinical presenta�on (cough, elevated body tempera-

ture, expectora�on, pleural pain) which is mostly confirmed by lung radiography, computerized tomography or nuclear magne�c resonance imaging and, eventually, with microbiology. Physical examina�on in order to detect cracks or bronchial breathing sounds is less specific compared to lung radiography. Total blood count with white blood cell count, along with blood and urine checks, as well as microbiological analysis of nose swab, sputum or bronchial aspirate in intubated pa�ents present the basic diagnos�c procedures. Virus cul�va�on is s�ll a golden standard for diagnosis in most clinical laboratory se�ngs, but demands fast transport of specimens (on ice) for direct inocula�on. Fast detec�on of viral an�gens for the influenza virus test can be used for faster diagnosing (within 15 minutes) or therapeu�c choice. The test is 50-70% sensi�ve and 100% specific (7−9). Advantages of this test are high specificity, ability to differen�ate influenza A and B infec�on, speed which leads to results, ability to make decision whether to use an�bio�c, establishing diagnoses for epidemiological purposes. Disadvantages are price, high occurrence of false nega�ve results, falsely posi�ve results due to adenovirus infec�on as well as the fact that sensi�vity of the procedure is not the key factor in making a decision over therapeu�c approach in pa�ents with typical flu symptoms in a flu epidemic (7,8,10). In most ins�tu�ons this fast tes�ng has been used as an ini�al diagnos�c method and viral cul�va�on is only done if these tests were ini�ally nega�ve. Direct fluorescent tes�ng for an�body detec�on is available for influenza virus and RSV and takes roughly 2 hours for comple�on. Sensi�vity of the test for influenza virus is 85-95% and enables detec�on of animal subtypes like H5N1 (11,12). For the RSV virus this test has very low sensi�vity (20-30%) and is not considered to be clinically relevant (13). RT-PCR technique is s�ll considered to be the most sensi�ve and the most specific method to diagnose different viral infec�ons but being too expensive its clinical applica�on is quite limited to large centers only. Ability to detect SARS through PCR technique is connected to high occurrence of falsely nega�ve results in early disease, or infec�on, stages (14,15). Viral infec�on in adults is mainly a reinfec�on, so IgG an�body tes�ng has no diagnos�c value. Also, it is not useful to determine IgM an�body level. Serology tes�ng enables retrospec�ve diagnosis in a situa�on where we have a four-fold increase of a specific an�body detected by complement fixa�on or ELISE tes�ng.

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Criteria to diagnose severe pneumonia Severe pneumonia diagnosis criteria have been defined since 1987 (16,17). It has been shown that pa�ents with 2 of 3 criteria (tachypnea, diastolic hypotension, blood urea nitrogen BUN elevated levels) have a 21 �mes higher mortality risk compared to pa�ents without those criteria. Later, it was shown that this model has limited prognos�c value in pa�ents with renal insufficiency and in older popula�on (18,19). Because of that, a new model has been created whose validity has been confirmed in numerous prospec�ve studies and it includes presence of 5 criteria (20). These are: • confusion (on mental test basis or �me, space and toward other people disorienta�on) • nitrogen level ( BUN-blood urea nitrogen) ≥17mmol/l(≥20mg/dl) • breathing frequency ≥30/min • hypotension (systolic pressure less than 90mmHg or diastolic pressure less than 60mmHg) • over 65 years of age These criteria create an easily remembered abbrevia�on: CURB-65 (C-confusion, U-urea, Rbreathing frequency, B-blood pressure, 65 years of age). It has been shown that thirty days mortality rates with presence of 0,1 or 2 risk factors are 0,7%, 2,1% and 9,2% respec�vely. Mortality rate was significantly higher if there were 3, 4 or 5 risk factors present and it is 14,5%, 40% and 57% respec�vely. Also, level of illness can be determined with applica�on of Pneumonia Severity Index (PSI) score (21). If CURB-65 score is higher than 2, intensive treatment is impera�ve meaning the pa�ent Needs hospitaliza�on. If the pa�ent is in sep�c shock that demands vasopressor applica�on or if the pa�ent has a respiratory insufficiency that demands intuba�on and ar�ficial ven�la�on, that pa�ent has to be hospitalized in the intensive care unit (ICU). Direct admi�ance to the intensive care unit is recommended for all CAP pa�ents with at least 3 minor criteria. Proposed criteria for pa�ents with pneumonia to be admi�ed to the intensive care unit are presence of 2 major (sep�c shock or ar�ficial ven�la�on due to conspicuous respiratory insufficiency) or 3 minor criteria. Minor criteria are: breathing frequency over 30/min, par�al oxygen arterial blood pressure/inspiratory oxygen frac�on (PaO2/ FiO2) >250; signs of mul�-lobular infiltra�on on lung radiography, confusion, urea level >20mg/ dl; leucopenia due to infec�on ( 18) This represents a valid assessment of neuropathic component of pain (Freynhagen R, et al. Curr Med Res Opin 2006; 22:1911-20). The visual analogue scale and numerical scale are the most commonly used scales in measuring the severity of neuropathic pain. Scale Amount of pain 0 No pain 1 – 3 A li�le pain (li�le impact on daily ac�vi�es) 4 – 6 Quite a lot of pain (significant impact on daily ac�vi�es) 7 – 10 Worst pain

(disabling; inability to perform daily ac�vi�es)

Therapeu�c approach to the treatment of NP include – diagnosis, – causal therapy if possible, – symptoma�c therapy if causal is not possible, – treatment of comorbidi�es, with the aim to reduce the intensity of pain and improve the quality of life.

Treatment of NP can be non-invasive and invasive – Non-invasive treatment: pharmacological and non-pharmacological treatment. – Invasive treatment: installa�on of spinal cord s�mulator, neurolysis, intrathecal pump. The goal of treatment: to reduce the intensity of pain, to eliminate insomnia, to improve the quality of sleep, to eliminate combined depression and anxiety, to improve social and emo�onal quality of life. Non-pharmacological therapy includes the use of TENS units, magne�c therapy, acupuncture, behavioural and occupa�onal therapy, relaxa�on management. Pharmacological therapy (18,19) Symptoma�c pharmacological therapy of NP of malignant ae�ology is based upon the use of four groups of drugs: an�depressants, an�convulsants, local anaesthe�cs and opioids. An�depressants (20−22) have shown efficiency, according to available studies, in the treatment of the NP in pa�ents with cancer. Here, tricyclic an�depressants and selec�ve serotonin and noradrenalin reuptake inhibitors SNRI are used. The most commonly used drugs of this group are TCA amitriptyline, nortriptyline and imipramine. There is evidence that the analgesic effect of TCA drugs is independent from their an�depressive effect, so they have equal analgesic effect in pa�ents with depression as well as in pa�ents without depression. They are good analep�cs, although they have significant side effects. The most commonly used SNRI are venlafaxine and duloxe�ne, which are not strong analgesics, but have significantly fewer side effects and contraindica�ons. Apart from their analgesic effect, an�depressants have pronounced an�-depressive effect and are good in sleep regula�on. An�epilep�cs (23−26) have shown significant efficacy in the treatment of the NP, according to randomized studies conducted so far, especially with respect to blockers (ligands) of α2-δ subunit of voltage-dependent Ca channels at the K.M level. Representa�ves of this group of drugs are gabapen�n and pregabalin and a number of randomized studies have confirmed their efficacy in the therapy of the NP, and that is why they are recommended as the first-line drugs in the treatment of the peripheral NP of cancerous ae�ology. The treatment with gabapen�n starts with a dose of 300 mg and is �trated to the maximum effec�ve dose of 1200 mg per day, divided into three doses. The treatment with pregabalin can 207


ANTIDEPRESSANTS Contraindica�on Drug name Side effects • seda�on, Amitriptyline • heart block, 25-150mg, • use of MAO • confusion, Nortriptyline • falls, inhibitors 25-150mg; • allergies • hindered Demonstrated accommoda�on, efficacy in controlled • dry mouth, studies; • reten�on of urine, Imipramine, • cons�pa�on, Ini�al dose of • orthosta�c hypotension, 75 mg, divided • tachycardia, into 3-4 doses, not conduc�on blocks, recommended • increased risk of sudden in doses exceeding cardiac death in doses 200mg exceeding 100 mg! Venlafaksine • Selec�vely inhibit Venlafaksine, Venlafaksine • hypertension starts with the reuptake of • with MAO 37.5 - 75 mg per day, • ECG changes serotonin, inhibitors • Less affinity with gradual dose • heart failure • hyponatremia for the noradrenergic �tra�on to • anxiety • coronary heart 150 - 225 mg neurotransmit• disorders of GIT disease per day; ter system, • prolonged QT Duloxe�ne maximum dose • safe in cardio vascular • electrolyte SNRI • Do not have of 375 mg per day. an�cholinergic pa�ents imbalance proper�es • nausea/vomi�ng • hypertension Duloxe�ne • increase in liver Duloxe�ne 60 - 120 mg • liver and kidney enzymes per day • drowsiness diseases • with MAO • dizziness inhibitors Annex Group Mechanism of ac�on • Non-selec�vely inhibit the reuptake of noradrenalin and serotonin in nerve endings, • Block Na channels, • s�mulate endogenous TCI an�nocicep�ve ac�vity, and • reduce central sensi�za�on.

Drug group An�epilep�cs

Mechanism of ac�on Drug name Dosage Block Na channels Carbamazepine 2 - 3 x 400mg Oxcarbazepine Contraindica�ons: AV block, concomitant use of MAO, alcohol.

An�epilep�cs

Ligands α2-δ subunits Gabapen�n voltage-dependent Pregabalin Ca channels

Cau�on: glaucoma, decreased liver and kidney func�on. Gabapen�n: start with 100 – 300 mg once to three �mes a day, increase by 100 to 300 mg, three �mes a day, every 3 - 7 days un�l the maximum dose of 3 x 1200 mg per day. "Extendedrelease" gabapen�n 1800 mg effec�ve if administered twice daily. Pregabalin: start with 25 – 75 mg once a day, increase by 75 mg on a daily basis a�er 3 to 7 days, then by 150 mg every 3 to 7 days un�l the maximum dose of 2 x 300 mg.

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begin immediately with the effec�ve therapeu�c dose of 150 mg per day, divided into two doses. If no sa�sfactory results are obtained, the dose can be increased to 300 mg per day. The maximum recommended dose is 600 mg per day. These drugs have shown a significant level of efficacy in the treatment of comorbidi�es, such as anxiety, depression, and insomnia. Local anaesthe�cs and capsaicin (27−29) are recommended as the first-line therapy exclusively in the treatment of localized peripheral cancer pain. The advantage of this therapy is that there is no significant reuptake of the drug and no undesired side effects. As far as the local anaesthe�cs are concerned, lidocaine patches with 5% lidocaine are used to cover appropriate areas. Up to 4 patches can be used per day, with their effect con�nuing up to 18 to 24 hours. Capsaicin acts on the vanilloid receptor and is available as a cream or gel with 0.075% and 8% of ac�ve ingredients. It reduces the NP in approximately 40% of pa�ents in 60 minutes and the effect is maintained up to three months. Opioids (26,30) A large number of studies have shown that the opioids are effec�ve in the therapy of the NP. Oxycodone and fentanyl patches, morphine, methadone, tramadol and levofranyl can be used. Our experience shows that the chronic NP cannot be arrested with a single drug and that the best results are achieved by a combina�on of an�convulsants, from the group of ligands of voltagedependent calcium channels, opioids and local anaesthe�cs. Cor�costeroids (31) They have analgesic effect in neuropathic pain which is the result of inflamma�on or nerve compression structure. In addi�on, they have a favourable effect on improving the overall quality of life. Based on the clinical experience, two therapeu�c protocols are applied: dexamethasone 100 mg, then 96 mg, divided into four doses per day, with compression of K.M or in the events of acute a�acks of pain, when the pain cannot be arrested quickly with opioids. Small doses of 2 - 4 mg of dexamethasone, once or twice a day, are administered to pa�ents in terminal stages, who are experiencing pain regardless of the op�mum dose of opioids. Long-term use of cor�costeroids in not recommended. Alpha-2 adrenergic agonist clondine (32) There have been studies that show that the intrathecal administra�on of clondine can be effec�ve in the treatment of the NP which was resistant to the opioids.

NMDA receptor antagonists (33) There are numerous studies that confirm the efficacy of ketamine in the treatment of the NP. This drug is effec�ve in sub-anaesthe�c doses, but serious side effects including hallucina�ons limit its use. It is administered subcutaneously and the recommended dose is 0.1mk/kg/h. Neurolep�cs There is evidence that an�psycho�c drugs have analgesic effect (olanzapine).They are used in specific pain condi�ons, when there is no effect of conven�onal therapy.

Conclusion Neuropathic pain of malignant origin is a specific issue that requires a specific therapeu�c approach. The cause of the failure or par�al success in the treatment of pain in pa�ents with cancer can be unrecognized component of neuropathic pain. First-line drugs in the treatment of neuropathic pain are coanelgesics from the group of an�depressants and an�epilep�cs. Apart from their analgesic component, they can improve the quality of sleep and have a posi�ve effect on anxiety and depression, which are significant comorbidi�es of chronic neuropathic pain.

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CHRONIC POSTOPERATIVE PAIN � PREVENTION IS THE BEST TREATMENT Ana Mimić

Ins�tute for Anesthesia, Urology Clinic, Clinical Centre of Serbia, Belgrade, Serbia

Introduc�on Chronic postopera�ve pain (CPOP) is a common but under-diagnosed and under-recognized complica�on of surgery that has significant consequences for both the individual pa�ent and for society as a whole. It has been defined as Pain that develops a�er surgical interven�on and lasts at least 2 months. Other causes for the pain have to be excluded, in par�cular pain from a condi�on preceding surgery (IASP) (1). This condi�on can be found in literature by various Synonyms: Chronic post-surgical pain, persistent post-opera�ve pain and persistent post-surgical pain. Crombie et colleagues in 1998., were first to describe the connec�on between previous trauma and surgery and development of chronic pain (2).

Incidence of CPOP The incidence of CPOP varies between studies and from opera�on to opera�on (3). Table 1 shows the approximate incidence of chronic pain a�er some common opera�ons, according to IASP data.

Mechanisms of CPOP The mechanisms of CPOP are complex and not completely understood. Kehlet et al. in 2006 outlined 3 possible mechanisms and pathophysiology for CPOP (4): • Con�nuing inflammatory response, • Neuropathic pain, • Predisposi�on to CPOP due to the pa�ent's gene�c makeup. Inflammatory pain is the heightened pain sensi�vity that occurs in response to �ssue injury and inflamma�on. It is caused by the release of inflammatory mediators and lead to reduc�on in threshold of nociceptors (peripheral sensi�za�on), and increase the excitability of central nervous system neurons (central sensi�za�on) (1). Changes in sensory system are reversible, and inflammatory pain will persist as long as there is a focus of ongoing inflamma�on. In most affected pa�ents, postsurgical chronic pain closely resembles neuropathic [email protected]

pain(5). The most prominent clinical finding is the combina�on of sensory loss with paradoxical hypersensi�vity. Peripheral nerve injury is an important factor in the e�ology of neuropathic pain, but there is no simple con�nuum from acute to chronic pain that correlates with the dura�on or intensity of peripheral injury (3,4) Table 1. Incidence of chronic postopera�ve pain Type of opera�on

Incidence of Es�mated incidence Chronic pain of Chronic Severe (%) pain (%) Amputa�on 30-85 5-10 5-65 10 Thoracotomy Mastectomy 11-57 5-10 Inguinal hernia 5-63 2-4 CABG 30-50 5-10 Cesarian sec�on 6-55 4

Risk factors and preven�on While studying CPOP one ques�on arises. Why some people develop CPOP, whereas others, who have had an iden�cal opera�on and anaesthesia do not? It is obvious that the nerve injury is not the only cause of this condi�on. Most of the studies on CPOP recognize other risk factors, which can broadly be divided into two groups: surgery related and pa�ent related risk factors. Age and gender Findings of several studies show that women have higher postopera�ve pain than men(6). Pa�ent's age is also a very important predictor of CPOP. Increasing age seems to reduce the risk of chronic pain. Smith and colleagues showed an incidence of chronic pain a�er mastectomy of 26% in those aged 70 years, 40% in those between 50 and 69 years of age, and 65% in those between 30 and 49 years of age (7). Psychosocial factors It is well recognized that psychological, social, and economic factors play a major part in the chronic pain of non-surgical origin. There are also many publica�ons on the influence of psychosocial factors, such as anxiety, depression, on acute 211


postopera�ve pain(8). Unfortunately, there have been fewer studies on that topic in CPOP, and their results are contradictory. Gene�c suscep�bility The role of gene�c factor in development of CPOP is obviously important. So far the connec�on between gene�c polymorphism and chronic pain has been studied in animal models (9). Acute postopera�ve pain Many studies have shown a correla�on between severity of acute postopera�ve pain and CPOP. Katz and colleagues in a paper specifically studying risk factors showed that early postopera�ve pain was the only factor that significantly predicted long-term pain (10). Postopera�ve pain is also a risk factor for pain a�er Hernia repair (11), surgery for breast cancer, total hip arthroplasty (12) and Caesarean sec�on. Surgical factors Although the size of the opera�on does not show a simple correla�on with CPOP, the type of opera�on and how it is performed influences the incidence of CPOP(3). Several studies have shown that open procedures carries greater risk for CPOP than laparoscopic ones (11).

Preven�on is the best treatment

"As chronic pain is notoriously difficult to treat, it would be desirable to find methods to prevent the development of persistent postsurgical pain." (IASP) Even though there is limited evidence for effec�ve preven�ve strategies at present, so far two of them have the obvious results: effec�ve management of postopera�ve pain, and reduc�on of the surgical risk. Provision of good analgesia in postopera�ve period has the most important preven�ve effect on chronic postopera�ve pain. The influence of pre-emp�ve and preven�ve analgesic strategies s�ll remains unclear, even though studies found that the central sensi�za�on could be prevent by early analgesia (4). Various anaesthe�c techniques such as epidural analgesia, peripheral nerve blockade, local and topical administra�on of local anesthe�c are very useful in preven�on of CPOP. Evidence of pharmacological pretreatment with NMDA-receptor antagonist ketamine, alpha-2-delta ligands gabapen�n and pregabalin, are not consistent, and s�ll debatable (13). The primary focus for reduc�on in surgical risk needs to be an increased awareness among surgeons of ways to avoid intra-opera�ve nerve injury - eg, by careful dissec�on, and use of minimally invasive surgical techniques. 212

Table 2. Strategies for CPOP preven�on Strategies in reducing CPOP Informa�on about CPOP should be part of the informed consent for the surgery Iden�fica�on of the pa�ents at risk Aggressive periopera�ve pain management, and use of preven�ve strategies Op�mizing surgical techniques-minimally invasive surgery Pa�ents should con�nue to use their analgesics at home Regular follow-up should include the pain intensity assessment

Conclusion Despite advances in the understanding of the processes that lead to persistent pain and the increase of iden�fica�on of pa�ents at risk of developing such pain, the management and preven�on of chronic postsurgical pain remains inadequate. There is clearly a need for educa�on of all medical professionals as well as the general public about this problem.

References 1. Merskey H, Bogduk H, eds. Classifi ca�on of chronic pain descrip�ons of chronic pain syndromes and defi ni�ons of pain terms. Sea�le: IASP Press,1994. IASP 2. Crombie IK, Davies HT, Macrae WA. Cut and thrust: antecedent surgery and trauma among pa�ents a�ending a chronic pain clinic. Pain 1998; 76: 167–71. 3. Macrae WA. Chronic pain a�er surgery. Br J Anaesth 2001; 87: 88-98. 4. Kehlet H, Jensen T, Woolf C. Persistent postsurgical pain: risk factors and preven�on. Lancet 2006; 367: 1618-25. 5. Jung BF, Ahrendt GM, Oaklander AL, Dworkin RH. Neuropathic pain following breast cancer surgery: proposed classifica�on and research update. Pain 2003; 104: 1–13. 6. Katz J, Poleshuck EL, Andrus CL, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain 2005; 119: 16–25. 7. Smith WCS, Bourne D, Squair J, Phillips DO, Chambers WA.A retrospec�ve cohort study of post mastectomy pain syndrome. Pain 1999; 83: 91–5. 8. Munafo MR, Stevenson J. Anxiety and surgical recovery. Reinterpre�ng the literature. J Psychosom Res 2001; 51: 589–96. 9. Diatchenko L, Slade GD, Nackley AG, et al. Gene�c basis for individual varia�ons in pain percep�on and the development of a chronic pain condi�on. Hum Mol Genet 2005; 14: 135–43. 10. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain a�er thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain 1996; 12: 50-5. 11. Aasvang E, Kehlet H. Chronic postopera�ve pain: the case of inguinal herniorrhaphy. Br J Anaesth 2005; 95: 69–76. 12. Nikolajsen L, Brandsborg B, Lucht U, Jensen TS, Kehlet H.Chronic pain following total hip arthroplasty: a na�onwide ques�onnaire study. ActaAnaesthesiol Scand 2006; 50: 495–500. 13. Clarke H. et al. The Preven�on of Chronic Postsurgical Pain Using Gabapen�n and Pregabalin: A Combined Systema�c Review and Meta-Analysis.Anesth Analg 2012; 115: 428-42.


HYPOTENSIVE ANAESTHESIA AND PLASMA LEVEL OF NO Biljana Shirgoska, Jane Netkovski

University Clinic for Ear, Nose and Throat Surgery, Skopje, Macedonia

Hypotensive anesthesia is defined as a general anesthesia technique with reduc�on in mean arterial blood pressure (MAP) to 50-60 mm Hg in normotensive subjects (20% reduc�on of baseline MAP). The aim of induced hypotension is to decrease intraopera�ve blood loss, decrease the need for blood transfusions and improve opera�ng condi�ons. Last methods of induced hypotension are based on the use of rapid and short-ac�ng vasodilators as primary agents (nitroprusside, nitroglycerine, urapidil), supplemented by vola�le anesthe�cs (isoflurane) or beta-blockers (esmolol) to improve effect, reduce dosage and prevent side effects (reflex tachycardia, tachyphylaxis and rebound hypertension). Although fenoldopam has been shown to be effec�ve, cost issues may limit is widespread applica�on for this technique. The pharmacologic profile of dexmedetomidine indicates that this drug has poten�al in controlled hypotension and clinical data are needed to define its role. Proper posi�oning of the pa�ent and controlled ven�la�on aid are the oldest method in reducing blood loss. New anesthe�c agents, their poten�al reduc�on of mean arterial blood pressure and their combina�on are the most common used technique for induc�on hypotensive levels of MAP. Hypotensive anesthesia is indicated in: – oromaxillofacial surgery (mandibular osteotomy, facial repair), – endoscopic sinus or middle ear microsurgery, – spinal surgery and other neurosurgery (aneurysm), – major orthopaedic surgery (hip or knee replacement, spinal), – prostatectomy, – cardiovascular surgery and – liver transplant surgery. The major risks of induced hypotension are: – a reduc�on in blood flow of vital organs (brain and myocardium) and – eleva�on of intracranial pressure in neurosurgical pa�ents. [email protected]

Thus, major contraindica�ons of induced hypotension are severe coronary artery disease, hypertension combined with arteriosclerosis of cerebral vessels and increased intracranial pressure in pa�ents with cerebral disease. Safety surgery needs safety level of controlled hypotension. Pa�ent’s safety depends on: a) Anesthesiologists clinical an�cipa�on of the risks factors; b) Present co morbidity, defined as ASA more than 1 status. c) The level of the familiarity of the anesthesiologist with the technique of hypotensive anesthesia; d) The preopera�ve condi�on of cardiovascular system; Adult people aged 18 to 60 could proceed decrease of mean arterial blood pressure during general anesthesia without complica�ons. Pediatric pa�ents without co morbidity could precede 20% mean arterial pressure decrease of the referent values, preopera�ve values of the mean arterial pressure without complica�ons aldough pediatric pa�ents have no compensatory mechanisms as the adults. (1,2) Hypertensive pa�ents have misbalance of arterial blood flow and basal vascular tone. That is the reason why they could not tolerate mean arterial pressure decrease more than 20% of the preopera�ve values of mean arterial blood pressure. Pa�ents with body mass index >30kg/m2 have serious problems with arterial blood pressure because of the reten�on of the fluids, insulin resistance that could lead to hypertension. Fat �ssue produces AGT (angiotenzinogen). There is possi�ve corela�on between BMI and AGT. Pa�ent that have posi�ve hystory of transi�ry ischemical incidentes dont have any toleran�on of the mean arterial pressure decrease. Complica�ons are rare in otherwise healthy pa�ents, but may be higher in elderly pa�ents and those with underlying organ dysfunc�on. Therefore, careful assessment and selec�on of pa�ents, together with considera�on of the poten�al complica�ons, appropriate choice of drugs and invasive monitoring are essen�al for the safe prac�ce of induced hypotension. 213


Nitric oxide (NO) has an important physiological role in regula�ng vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial cons�tu�ve nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO produc�on. (3) Circula�ng NO is mainly produced by ecNOS and has an important role in regula�ng blood flow, par�cularly coronary flow. Reduc�on in basal NO release may predispose to hypertension, thrombosis, vasospasm and atherosclerosis. In animal models, restora�on of NO ac�vity can induce regression of preexis�ng in�mal lesions. On the other hand, high circula�ng NO levels, which occur with excess iNOS expression under pathological condi�ons are generally toxic. There are data indica�ng that markedly elevated NO levels are associated with endotoxic shock and exaggerated inflamma�on reac�ons and may lead to acute hepa�c dysfunc�on, as well as contribute to the pathogenesis of glomerulonephri�s and predispose to asthma, cardiomyopathy and a number of other disorders. The measurement of NO itself is difficult because of its very short half-life, and the stable metabolites of NO (NOx), have been frequently used as a reliable plasma measurement of NO produc�on. The factors influencing an individual’s con�nuous basal NO produc�on are not clear. More specifically, the associa�on between basal circula�ng NO levels and genotypic or phenotypic in vivo varia�ons in ecNOS, the key regulator of the basal NO produc�on in vasculature is not understood. Determina�ons of in vivo human ecNOS enzyma�c ac�vity and its associa�on with plasma NO are difficult because vascular �ssue homogenates would be required. As ecNOS genomic DNA can be readily obtained and analyzed from peripheral nucleated blood cells, it is possible to assess the associa�on between plasma NO and ecNOS at the DNA level. The defini�on of a gene�c contribu�on to basal NO produc�on is important for studies of the poten�al roles of NO and ecNOS in atherogenesis and hypertension, in both of which there is clustering in families.

Determina�on of Plasma NOx levels

Since NO is unstable and quickly oxidized to nitrate and nitrite a�er produc�on, to es�mate plasma NO levels, circula�ng NOx levels were determined using a modified method described by Moshage et al. Nitrate was measured as nitrite a�er enzymatic conversion by nitrate reductase and nitrite was 214

measured a�er deproteiniza�on using the Griess color reac�on which was read at a wavelength of 540 nm. Values obtained by this procedure represent the sum of nitrite and nitrate derived from NO. (4) Griess reac�on In the Griess reac�on, first reported by Johann Peter Griess in 1879 as a method of analysis of nitrite (NO(2)(-)), nitrite reacts under acidic condi�ons with sulfanilic acid (HO(3)SC(6)H(4)NH(2)) to form a diazonium ca�on (HO(3)SC(6)H(4)-N[triple bond]N(+)) which subsequently couples to the aroma�c amine 1-naphthylamine (C(10)H(7)NH(2)) to produce a red-violet coloured (lambda(max) approximately 540 nm), water-soluble azo dye (HO(3)SC(6)H(4)-NN-C(10)H(6)NH(2)).

The iden�fica�on of nitrite in saliva has been the first analy�cal applica�on of this diazo�za�on reac�on in 1879. For a century, the Griess reac�on has been exclusively used to iden�fy analy�cally bacterial infec�on in the urogenital tract, i.e. to iden�fy nitrite produced by bacterial reduc�on of nitrate (NO(3)(-)), the major nitrogen oxide anion in human urine. Since the discovery of the l-arginine/nitric oxide (l-Arg/NO) pathway in 1987, however, the Griess reac�on is the most frequently used analy�cal approach to quan�tate the major metabolites of NO, i.e. nitrite and nitrate, in a variety of biological fluids, notably blood and urine. The Griess reac�on is specific for nitrite. Analysis of nitrate by this reac�on requires chemical or enzyma�c reduc�on of nitrate to nitrite prior to the diazo�za�on reac�on. The simplicity of the Griess reac�on and its easy and inexpensive analy�cal feasibility has attracted the a�en�on of scien�sts from wide a spectrum of disciplines dedicated to the complex and challenging L-Arg/NO pathway. Today every laboratory in this area uses its own Griess assay. The simplest Griess assay is performed in batch commonly as originally reported by Griess. Because of the recogni�on of numerous interferences in the analysis of nitrite and nitrate in biological fluids and of the desire to analyze these anions simultaneously, the Griess reac�on has been repeatedly modified and automated. In recent years, the Griess reac�on has been coupled to HPLC, i.e. is used for post-column deriva�za�on of chromatographically separated nitrite and nitrate. Such a HPLC-Griess system is even commercially available. (5)


Anesthesia influence on endogenous produc�on of NO Galley HF and al. inves�gated the effects of anaesthesia on dynamic nitric oxide produc�on, concentra�ons of tetrahydrobiopterin and the accumula�on of cyclic GMP (cGMP) in the rat central nervous system (CNS). Rats were assigned to anaesthesia with halothane, isoflurane, pentobarbital, diazepam, ketamine or xenon (n=6 per group). A�er 30 min, [14C]L-arginine (i.v.) was given and, a�er a further 60 min of anaesthesia, rats were killed and exposed immediately to focused microwave radia�on. A�er removal of the brain and spinal cord, nitric oxide produc�on from radiolabelled arginine (and hence nitric oxide synthase ac�vity during anaesthesia) was measured as [14C]L-citrulline by scin�lla�on coun�ng. cGMP was determined by enzyme immunoassay and tetrahydrobiopterin by fluorescence HPLC, in brain regions and the spinal cord. Nitric oxide synthase ac�vity was similar in all brain regions but was lower in the spinal cord. cGMP was similar in all areas of the CNS and was significantly decreased in rats anaesthe�zed with halothane. Isoflurane produced similar effects. In contrast, ketamine and xenon anaesthesia increased cGMP in the spinal cord, brainstem and hippocampus. Diazepam and pentobarbital had no effect. Tetrahydrobiopterin concentra�ons were similar in all areas of the CNS and were increased in the cortex and hippocampus a�er anaesthesia. (6) We inves�gated the level of nitric oxide in hypertensive pa�ents scheduled on general anaesthesia in 2005.

Our results showed that there is a sta�s�cally significant difference of NO plasma level between the two groups of pa�ents. The level of NO was higher in the first group (ven�lated with O2/N2O) compared to the second group (ven�lated with O2/air). The mean arterial pressure and systemic vascular resistance were significantly decreased in the first group, as well. Our results suggest that nitrous oxide (N2O) most probably plays the role of NO donor in hypertensive pa�ents during the maintenance of the general anaesthesia with N2O/O2 mixture. (7)

References 1. Tobias JD. Controlled hypotension in children: a cri�cal review of available agents. Paediatr Drugs 2002; 4(7): 439–53. 2. Shirgoska B, Netkovski J, Zafirova B. The influence of remifentanil and remifentanil-plus-sevoflurane-controlled hypotension on mean arterial pressure and heart rate in children. Prilozi 2012; 33(1): 171–85. 3. Wang XL at all. Gene�c contribu�on of the endothelial cons�tu�ve nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vasc Biol 1997; 17(11): 3147–53. 4. Moshage H, Kok B, Huizenga JR, Jansen PL. Nitrite and nitrate determina�ons in plasma: a cri�cal evalua�on. Clin Chem 1995; 41: 892–896. 5. Tsikas D. Analysis of nitrite and nitrate in biological fluids by assays based on the Griess reac�on: appraisal of the Griess reac�on in the L-arginine/nitric oxide area of research. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 851(1-2): 51–70. 6. Galley HF et al. Differen�al nitric oxide synthase ac�vity, cofactor availability and cGMP accumula�on in the central nervous system during anaesthesia. Br J Anaesth 2001; 86(3): 388–94. 7. Shirgoska B. et al. Level of nitric oxide in hypertensive pa�ents scheduled on general anaesthesia. Prilozi 2005; 26(1): 13–24.

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ANESTHESIA FOR ESOPHAGECTOMY Biljana Stošić1,3, Radmilo Janković1,3, Danijela Stanković2, Dragana Stanković Đorđević3, Nenad Savić3, Ines Veselinović3 School of Medicine University of Niš Health Center Nego�n 3 Center for anesthesia, Clinical Center of Niš 1 2

Introduc�on Medias�nal surgery is a major undertaking and challenging to both the anesthe�st and the surgeon. Esophageal surgery can involve manipula�on of the contents of two major body cavi�es, the thorax and the abdomen, with consequences for the cardiorespiratory and gastrointes�nal systems. The management of these pa�ents is o�en lengthy and mul�disciplinary, and the anesthe�st has a pivotal role in achieving a successful outcome fromany surgical interven�on (1). It is recorded the progressive increase in the incidence of esophagogastric cancer over the past decade. Only one-third of pa�ents presen�ng with esophageal cancer are suitable for surgical resec�on (2−4). Over 40% are inoperable at presenta�on and a further 25% are unfit for surgery (3). Esophagogastric cancer is one of the most challenging pathological condi�ons confron�ng a surgeon on account of the magnitude of the surgical resec�on and reconstruc�on. Nonopera�ve treatment of esophageal cancer involves neoadjuvant chemoradiotherapy. Pallia�ve treatment, such as sten�ng and laser therapy, is directed primarily at relieving dysphagia.

to postopera�ve complica�ons following esophageal surgery (7,8). Physiological and opera�ve severity scoring systems such as POSSUM (Physiological and Outcome Severity Score for enUmera�on of Mortality and Morbidity) are unreliable in predic�ng mortality and morbidity a�er esophagectomy (9). Preopera�ve pulmonary and hepa�c func�on has been reported as significantly more impaired in pa�ents presen�ng with squamous cell carcinoma (8). By contrast, those with adenocarcinoma had a higher incidence of obesity and cardiac dysfunc�on. Hyperfibrinogenemia, a common finding preopera�vely, posi�vely correlates with the stage of the esophageal disease (10). Cardiopulmonary Reserve Pa�ents with esophageal disease o�en have a higher incidence of cardiovascular and chronic respiratory disease. Cardiovascular and chronic respiratory disease should be op�mized during the preopera�ve staging period in consulta�on with specialist physicians if necessary. Pa�ent coopera�on is crucial. The majority of pa�ents undergoing upper gastrointes�nal surgery only require basic preopera�ve inves�ga�ons (Table 1).

Anesthesia for esophageal surgery

Table 1. Rou�ne preopera�ve inves�ga�ons for esophagogastric surgery

Preopera�ve prepara�on

Hematological

Although esophageal surgery is s�ll associated with significant mortality, improved surgical techniques, anesthesia, and intensive care are all a�ributable to the improved outcome, when compared with past decades (1). Me�culous preopera�ve evalua�on, risk stra�fica�on, pa�ent selec�on, and op�miza�on are a prerequisite to successful surgical outcome a�er esophageal surgery (5,6). Coexis�ng Disease Pa�ents presen�ng for esophageal surgery have a high incidence of coexis�ng disease (6). The incidence of organ dysfunc�on and coexis�ng medical condi�ons increases with old age. Increasing age has been iden�fied as one risk factor in rela�on 216

[email protected]

Hemoglobin Coagula�on screen Blood cross-match (4 units) Biochemical Urea and electrolytes Liver func�on tests Blood glucose Arterial blood gases on air Electrocardiogram Res�ng 12 lead ECG Radiology PA chest X ray Pulmonary func�on Pre- and postbronchodila�on tests Exercise test Supplementary

Stair climb (Pulse, BP, and SpO2) Fiberop�c bronchoscopy Echocardiography Lung diffusion capacity


Exercise Tolerance Cardiopulmonary reserve can ini�ally be assessed by taking a careful history regarding a pa�ent’s physical ac�vi�es. Although subjec�ve, exercise tolerance can provide a measure of cardiorespiratory reserve. In recent years, there has been a growing interest in exercise tes�ng as a means of assessing a pa�ent’s cardiopulmonary reserve (11). One means of quan�fying exercise tolerance is to invite the pa�ent to climb several flights of stairs (12,13). Pa�ents with musculoskeletal disorders, peripheral vascular disease, and obesitymay be unable to complete any form of dynamic exercise tes�ng. Pa�ents unable to climb two flights of stairs were found to have a higher incidence of coexis�ng cardiopulmonary disease, higher ASA grade, and more periopera�ve complica�ons (14). Anesthesia for oncological surgery involving a thoracotomy las�ng over eight hours dura�on has been iden�fied as a par�cular risk in exercise-limited pa�ents. Pa�ents with unlimited exercise tolerance have fewer serious complica�ons (11). Dynamic respiratory exercise tes�ng involving expired gas analysis may be, however, more discrimina�ng. Nagamatsu et al. found a correla�on with postopera�ve complica�ons following esophagectomy and maximum oxygen uptake during exercise (15). Arterial oxygen desatura�on during exercise appears to have some predic�ve value as regards to postopera�ve complica�ons in pa�ents undergoing a pneumonectomy. Exercise-induced hypotension is an ominous sign and may indicate ventricular impairment secondary to coronary artery disease (16). Arterial blood sases Hypercarbia alone, in the absence of impaired exercise tolerance, does not appear to be a good predictor of postopera�ve complica�ons following esophagectomy. Preopera�ve hypoxia at rest on air, sugges�ng a preexis�ng intrapulmonary shunt, correlates with hypoxemia following thoracotomy for nonpulmonary surgery and with a higher incidence of pulmonary morbidity and mortality following esophagectomy (17). Hypoxic pa�ents who were also symptoma�c at rest required more postopera�ve ven�latory support, the hypoxia persis�ng for up to four days postopera�vely (18). A significant preexis�ng intrapulmonary shunt may preclude any subsequent one-lung anesthesia (OLA). In one study, the PaO2/FiO2 ra�o clearly differen�ated survivors from nonsurvivors, as did the level of procalcitonin 24 hours a�er surgery (19). Pulmonary Func�on Tests Much of the published evidence rela�ng pulmonary func�on tes�ng to outcome a�er thora-

cotomy concerns lung reduc�on surgery. Esophageal surgery, during which a lung is temporarily collapsed to facilitate surgical access, is, however, associated with postopera�ve pulmonary compromise (20,21). Pulmonary func�on tests must be considered in conjunc�on with the arterial blood gases and the pa�ent’s exercise tolerance. Where a reversible component is observed, this must be op�mized, if necessary, in consulta�on with a respiratory physician. It is to be expected that significantly impaired pulmonary func�on tests will result in difficul�es in maintaining adequate oxygena�on during OLA and during the postopera�ve period. Nagawa et al. reported that FVC (forced vital capacity) was the most reliable predictor of postopera�ve pulmonary complica�ons a�er esophagectomy (15). An FEV1 (forced expired volume in one second)