Incidence of diaphragmatic paralysis following ... - Wiley Online Library

Anaesthesia, 2001, 56, pages 350±369 ................................................................................................................................................................................................................................................

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Management of comatose head-injured patients: are we getting any better? I. A. Wilkins,1 D. K Menon2 and B. F. Matta2 1 Department of Anaesthesia and 2 Neurosciences Critical Care Unit, Box 93, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK Summary

This re-survey of neurosurgical centres was conducted to determine whether the publication of management guidelines has resulted in changes in the intensive care management of severely headinjured patients (defined as Glasgow Coma Score , 9) in the UK and Ireland. Results were compared with data collected from a similar survey conducted 2 years earlier. Almost 75% of centres monitor intracranial pressure in the majority of patients and 80% now set a target cerebral perfusion pressure of . 70 mmHg. The use of prolonged hyperventilation (. 12 h) is declining and the target Paco2 is now most commonly . 4 kPa. More centres maintain core temperature , 36.5 8C. Although wide variations in the management of severely head-injured patients still exist, we found evidence of practice changing to comply with published guidelines. Keywords

Intensive care: neurosurgical. Guidelines: impact.

................................................................................................. Correspondence to: Dr B. F. Matta Accepted: 24 May 2000

In surveys carried out 2 years ago, we highlighted the wide variation in the intensive care management of severely head-injured patients [defined as Glasgow Coma Score (GCS) , 9] in neurosurgical centres throughout the UK and Ireland [1, 2]. Since these initial surveys, two expert bodies have produced guidelines for the management of severe head injury [3, 4]. We surveyed neurosurgical centres to examine whether the management of severely head-injured patients had changed following publication of these guidelines. Methods

The directors of 44 neurosurgical centres in the UK and Ireland were asked to complete a questionnaire identical to that used 2 years earlier. After 4 weeks, a copy of the questionnaire was sent to all non-responders with a covering letter urging them to reply. The data collected in this survey were compared with results obtained 2 years ago using a Chi-squared test. The significance level was set at 0.05 and statistical analysis was performed using statview 4.0 (Abacus Concepts Inc., Berkeley, CA, USA). 350

Results

All 44 centres replied, but four of these did not treat severely head-injured patients and so were not analysed further. Compared with 1996, a greater proportion of units had dedicated junior staff (87 vs. 66%; Chisquared 13, d.f. 1, p , 0.05) and identifiable high-dependency unit (HDU) facilities (68 vs. 43%; Chi-squared 17, d.f. 1, p , 0.05). Only 54% of units had a written protocol for the management of raised intracranial pressure. The changes in management that we observed between the two survey periods are listed in Tables 1±3. Discussion

Recent guidelines [3, 4] suggest monitoring intracranial pressure (ICP) in all patients with a GCS , 9 or an abnormal computed tomography scan. Mean arterial pressure (MAP) should be maintained . 90 mmHg and cerebral perfusion pressure (CPP) . 70 mmHg. Intracranial hypertension should be treated when ICP is q 2001 Blackwell Science Ltd

Anaesthesia, 2001, 56, pages 350±369 Forum ................................................................................................................................................................................................................................................

Table 1 Changes in monitoring and treatment for acute head

injury. Values shown are number (%)

ICP monitored in . 50% of patients Units with protocol for managing ICP Treatment of intracranial hypertension Barbiturates Mannitol Furosemide Hyperventilation . 12 h CSF drainage Propofol Steroids Hypothermia Etomidate

1996 n 44

1998 n 40

19 (54) 24 (69)

28 (70)* 22 (56)

24 35 28 31 24 22 5 7 4

26 39 29 23 23 26 4 12 3

(69) (100) (80) (89) (69) (63) (14) (20) (11)

(65) (98) (73) (57)* (57) (65) (10) (30) (8)

ICP, intracranial pressure; CSF, cerebrospinal fluid. *p , 0.05.

. 25 mmHg. The guidelines advise against severe or prolonged hyperventilation and found no evidence to support the use of steroids in head injury. The availability of these guidelines appears to have altered ICU care for severely head-injured patients. Organisational changes in admission practice, unit staffing and HDU bed availability may have accompanied changed practice since our last survey. More centres now measure ICP in the majority of patients and aim for a CPP . 70 mmHg. Because episodes of either CPP , 60 mmHg or ICP . 20 mmHg or both are associated with a worse outcome [5], this represents an important improvement in patient care. There is an increasing appreciation of the fact that prolonged and/or profound hypocapnia can result in cerebral ischaemia and a worse outcome [6]. Fewer centres use prolonged hyperventilaTable 2 Changes in targets for acute head injury. Values shown

are number (%)

Target Paco2 (kPa) . 4.51 4.01±4.5 3.51±4.0 , 3.5 Target core temperature (8C) . 36.51 35±36.5 33±34.99 Target CPP (mmHg) 80 70 60 50

1996 n 44

1998 n 40

1 (3) 12 (34) 19 (54) 2

4 (10) 28 (70)* 8 (20) 0

19 (54) 13 (37) 3 (9)

13 (32) 22 (55)* 1 (3)

1 14 9 6

2 26 5 3

(3) (47) (30) (20)

CPP, cerebral perfusion pressure. *p , 0.05.

q 2001 Blackwell Science Ltd

(6) (72) (14) (8)

Table 3 Changes in general intensive care of acute head injuries.

Values shown are number (%)

Prophylaxis against stress ulceration Drug used Sucralfate H2 antagonists Feed started at , 24 h 24±72 h . 72 h Routine use of parenteral nutrition Routine chest physiotherapy Sedative for physiotherapy None Propofol Midazolam Fentanyl Other

1996 n 44

1998 n 40

30 (86)

37 (95)

16 (46) 14 (43)

26 (70) 11 (30)

12 21 2 1 28

(34) (75) (7) (4) (80)

23 13 3 0 30

(59)* (33) (8)

14 6 2 7 2

(50) (21) (7) (25) (7)

4 17 8 2 1

(13)* (57) (27) (6) (3)

(79)

*p , 0.05.

tion (. 12 h); more units aim for a Paco2 . 4.0 kPa, and no units aim for a Paco2 , 3.5 kPa. Also, the modulatory effect of temperature on outcome from acute neural injury is now recognised [7] and more units aim for a lower core temperature. While there has been one recent paper [7] highlighting the probable benefit of hypothermia, most of the data supporting the observed changes in practice were available well before our original survey. These changes in practice are probably not the consequences of new research data. It would appear that the publication of guidelines by authoritative sources made such data available to clinicians, and perhaps more importantly, provided an expert view on how such evidence should change practice. The availability of the guidelines may also have provoked critical examination of current practice and provided a template on which changes in clinical care could be organised. In conclusion, we have shown a change in clinical practice in line with recently published guidelines in the treatment of severe head injury.

References 1 Jeevaratnam DR, Menon DK. Intensive care management of severely head injured patients in the United Kingdom. British Medical Journal 1996; 312: 944±7. 2 Matta BF, Menon DK. Severe head injury in the UK and Ireland: a survey of practice and the implications for management. Critical Care Medicine 1996; 24: 1743±8. 3 Chesnut RM. Guidelines for the management of severe head injury: what we know and what we think we know. Journal of Trauma 1997; 42: 519±22. 351

Forum Anaesthesia, 2001, 56, pages 350±369 ................................................................................................................................................................................................................................................

4 Maas AIR, Dearden M, Teasdale GM, et al. EBIC guidelines for management of severe head injury in adults. Acta Neurochirugica 1997; 139: 286±94. 5 Rosner MJ, Rosner SD, Johnson AH. Cerebral perfusion pressure: management protocol and clinical results. Journal of Neurosurgery 1995; 83: 949±62.

6 Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomised clinical trial. Journal of Neurosurgery 1991; 75: 731±9. 7 Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. New England Journal of Medicine 1997; 336: 540±6.

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Incidence of diaphragmatic paralysis following supraclavicular brachial plexus block and its effect on pulmonary function P. H. K. Mak,1 M. G. Irwin,2 C. G. C. Ooi3 and B. F. M. Chow4 1 Senior Medical Officer and Honorary Clinical Assistant Professor, 2 Associate Professor, Department of Anaesthesiology, and 3 Associate Professor, Department of Diagnostic Radiology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong 4 Consultant, Department of Anaesthesiology, The Duchess of Kent Children's Hospital, Sandy Bay, Hong Kong Summary

Thirty unpremedicated ASA physical status 1±3 patients aged between 18 and 69 years, scheduled for upper limb surgery, received a conventional supraclavicular brachial plexus block using a nerve stimulator and bupivacaine 0.375% 0.5 ml.kg21. Spirometric measurements of pulmonary function and ultrasonographic assessments of diaphragmatic function were made before the block and at 10min intervals after injection until full motor block of the brachial plexus had developed. Complete paralysis of the ipsilateral hemidiaphragm occurred in 50% of patients. Seventeen per cent of patients had reduced diaphragmatic movement and the rest (33%) had no change in diaphragmatic movement. Those with complete paralysis all showed significant decreases in pulmonary function, whereas those with reduced or normal movement had minimal change. All patients remained asymptomatic throughout, with normal oxygen saturation on room air. Keywords Anaesthetics, local: bupivacaine. Anaesthetic techniques, regional: brachial plexus. Ventilation: diaphragm. Complications. ................................................................................................. Correspondence to: P. H. K. Mak E-mail: [email protected] Accepted: 8 November 2000

Local anaesthetic blockade of the brachial plexus is a commonly performed procedure for upper limb surgery. In common with many regional anaesthetic techniques, it may confer certain advantages over general anaesthesia and is often used in the management of patients with cardiorespiratory disease. However, it is not without risk 352

and it has been demonstraed that interscalene brachial plexus blockade is associated with a 100% incidence of ipsilateral hemidiaphragmatic paralysis [1]. This is due to the proximity of the phrenic nerve to the brachial plexus in the neck and may be avoided by using the axillary approach. Unfortunately, anaesthesia for all types of



Table 1 Patient characteristics. Values are

mean (SD) [range].

Age; years Body weight; kg Sex ratio; M: F

upper extremity surgical procedures cannot be reliably achieved with an axillary block [2]. The supraclavicular approach anaesthetises the brachial plexus as the three trunks pass over the first rib lateral to the subclavian artery and usually provides a more complete block of the arm. It has been suggested that this approach is the most effective technique for blocking the brachial plexus [3]. Several small studies have shown that ipsilateral phrenic nerve paralysis can occur with supraclavicular block, presumably due to retrograde spread of local anaesthetic within the brachial plexus sheath, although applying proximal digital pressure to the site of injection is not effective in reducing spread [4, 5]. The symptoms of phrenic nerve paralysis range from none to relatively severe, usually depending on the presence of pre-existing pulmonary dysfunction. In this study, we investigated the incidence of phrenic nerve paralysis and compromise of respiratory function in patients with supraclavicular brachial plexus anaesthesia performed using the classical approach. Methods

The study was approved by the Local Research Ethics Committee. Following written, informed consent, 30 ASA physical status 1±3 patients requiring upper limb

Total diaphragmatic paralysis (n 15)

Partial diaphragmatic paralysis (n 5)

No diaphragmatic paralysis (n 10)

51 [22±69] 58.6 (12.3) 8:7

39 [18±60] 51.8 (8.3) 3:2

51 [35±67] 62.3 (8.9) 7:3

surgery were recruited. None had coexisting acute or chronic pulmonary dysfunction. Patients were monitored with continuous ECG, pulse oximetry and intermittent non-invasive blood pressure. Each received a supraclavicular brachial plexus block using the classical approach, with the needle insertion point being immediately behind the mid-point of the clavicle [6]. The needle direction was caudal, posterior and medial. An insulated short-bevel needle was used (Stimuplex A, 24G 25 mm, B Braun, Munich, Germany), along with a nerve stimulator (Stimuplex-DIG, B Braun). Following location of the plexus, and when nerve stimulation was possible at a current , 0.5 mA, plain bupivacaine 0.375% 0.5 ml.kg21 was injected slowly. In this investigation, spirometry was used to investigate pulmonary function. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) were measured both sitting and supine before and after the performance of the block with bedside electronic spirometry (Pocket Monitor, Micro Medical Limited, Rochester, UK). Diaphragmatic movement on deep inspiration was measured with a 3.5-MHz ultrasound probe placed over one of the lower intercostal spaces in the midaxillary line in order to visualise the dome of the diaphragm on the same side as the block. The optimal

Figure 1 Percentage changes in

pulmonary function indices in the supine position in the three groups of patients undergoing supraclavicular brachial plexus block (total, partial and no phrenic nerve paralysis). Error bars indicate SEM.


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Table 2 Changes in pulmonary function Total paralysis (n 15) Sitting FEV1

FVC

PEFR

Supine FEV1

FVC

PEFR

Partial paralysis (n 5)

Before block; l After block; l Change; % p Before block; l After block; l Change; % p Before block; l.min21 After block; l.min21 Change; % p

3.7 (0.3) 3.1 (0.4) 2 17.9 (4.6) 0.002 4.3 (0.4) 3.5 (0.4) 2 17.2 (3.8) 0.0004 482 (55) 400 (51) 2 17.8 (4.3) 0.001

3.8 (0.4) 3.6 (0.3) 2 8.2 (2.1) 0.02 4.5 (0.3) 4.1 (0.3) 2 9.3 (2.5) 0.02 524 (61) 536 (77) 1 2.3 (13.3) 0.88

3.7 (0.5) 3.5 (0.4) 2 4.3 (2.0) 0.06 4.2 (0.6) 4.3 (0.5) 1 1.9 (2.7) 0.7 526 (105) 462 (85) 2 11.1 (4.4) 0.03

Before block; l After block; l Change; % p Before block; l After block; l Change; % p Before block; l.min21 After block; l.min21 Change; % p

3.5 (0.3) 2.8 (0.3) 2 22.9 (4.9) 0.0004 4.2 (0.3) 3.3 (0.3) 2 21.4 (5.3) 0.001 474 (60) 372 (39) 2 23.6 (4.6) 0.0002

3.8 (0.4) 3.4 (0.3) 2 12.4 (5.8) 0.1 4.5 (0.5) 4.0 (0.3) 2 9.0 (9.3) 0.39 513 (61) 536 (68) 1 0.5 (16.7) 0.98

3.7 (0.4) 4.0 (0.4) 1 8.5 (9.5) 0.4 4.4 (0.5) 4.6 (0.6) 1 3.4 (3.0) 0.3 490 (102) 444 (68) 2 8.9 (6.6) 0.2

position was marked on the skin (as a reference point for postblock assessments) and measurements were performed in the supine position using an HP 1000 Sonos ultrasound machine (Hewlett Packard, Andover, MA, USA) to track and measure diaphragmatic excursion. Those patients with diaphragmatic movement reduced by more than 75% were taken to be suffering from `complete paralysis', a reduction of between 25% and 75% was termed `partial paralysis' and less than 25% as `no paralysis'. Patients were questioned to ascertain subjective symptoms of respiratory dysfunction. Data were collected before and 10 min after the block had been performed. If there was no diaphragmatic paralysis, a second set of data was collected 10 min later. The onset of the block was determined by loss of motor power in the upper limb and absence of cold sensation to ice. Sedatives were only given when all the measurements were finished and data had been collected. Preblock and postblock data were compared using a paired Student's t-test and a probability less than 5% was taken to be statistically significant. All probability values quoted are comparisons with the control value, i.e. at time zero, before the block was performed. A regression analysis was performed to look at the relationship between the patient's body 354

No paralysis (n 10)

indices in the sitting and supine positions in three groups of patients after supraclavicular brachial plexus block. Values are mean (SEM).

weight and the percentage change in diaphragmatic movement. Results

The results are considered with reference to the three groups determined by the diaphragmatic response to supraclavicular brachial plexus block: complete paralysis (n 15, 50%), partial paralysis (n 5, 17%) and no paralysis (n 10, 33%). Patient characteristics are given in Table 1. There were no significant differences between the three groups of patients with respect to age, weight or sex. All patients developed complete sensory and motor block of the upper limb and general anaesthesia was not required. Those with complete diaphragmatic paralysis had a significant decrease in pulmonary function in both sitting and supine positions (Fig. 1, Table 2). Those with partial paralysis also tended to have a decrease in pulmonary function but this was not consistently statistically significant. Pulmonary function was unchanged in patients with preserved diaphragmatic movement. Oxygen saturation while breathing room air remained unaffected and only one patient, who had complete diaphragmatic paralysis, complained of respiratory symptoms. He said that he could feel reduced movement of his chest wall on the side of the block during deep inspiration but was not uncomfortable q 2001 Blackwell Science Ltd


or dyspnoeic. Regression analysis between the patient's body weight and percentage change in diaphragmatic excursion indicated no relationship (r 0.127, p 0.5), despite heavier patients receiving larger volumes of local anaesthetic. Discussion

Kulenkampff first described supraclavicular brachial plexus anaesthesia in clinical practice in 1912 [7]. The phrenic nerve lies in front of the anterior scalene muscle and its investing fascia is the only structure that separates it from the brachial plexus. Local anaesthetics injected around the proximal, i.e. interscalene, part of the plexus can therefore easily affect the phrenic nerve [8]. The axillary approach to the brachial plexus is substantially more distal and should not affect the phrenic nerve. However, it is not consistently reliable for surgery at or above the elbow and may miss the radial aspect of the arm and musculocutaneous nerve [2]. As a result of the compact arrangement of the trunks of the brachial plexus at the level of the first rib, the supraclavicular approach is extremely effective, resulting in rapid and profound neural blockade. It is therefore a popular approach [3]. In this study, we used a nerve stimulator to determine the correct position of the brachial plexus trunks as accurately as possible and achieved satisfactory anaesthesia in all patients. Ultrasonography was chosen as the method to demonstrate diaphragmatic movement as it reliably shows paradoxical movement of the diaphragm in the event of paralysis [9]. It is an easy procedure to perform and can be quickly learnt, although a consultant radiologist performed all measurements in this study. It also avoids the radiation hazards of X-ray screening, since measurement of diaphragmatic movement requires continuous screening that may take a few seconds to perform and may require several attempts [10]. Using this technique, the overall incidence of phrenic nerve involvement was 67% and, although the number of patients studied was small, this is in accordance with other studies [4, 5]. We chose an arbitrary reduction in diaphragmatic movement of less than 25% as indicating no paralysis, over 75% reduction indicating complete paralysis and values in between (25±75%) indicating partial paralysis. Those subjects who demonstrated partial phrenic nerve block at 20 min may have progressed to complete paralysis if measurements had continued after this time. Apart from partial phrenic nerve blockade, another explanation for reduced diaphragmatic movement might have been contributory movement from the contralateral diaphragm and accessory respiratory muscles preserving some respiratory effort on the ipsilateral side q 2001 Blackwell Science Ltd

despite complete phrenic nerve paralysis. It would only be possible to determine this by carrying out an electromyographic study of the affected hemidiaphragm. When considering the incidence of a particular sideeffect, it is important to ascertain its importance. The most likely consequence of phrenic nerve palsy would be an effect on respiratory function and we therefore performed spirometric measurements and sought subjective respiratory symptoms. We found that FEV1, FVC and PEFR were affected by phrenic nerve involvement and that the changes were proportional to the extent of diaphragmatic paralysis. This was also observed in a study investigating pulmonary function following phrenic nerve paralysis after interscalene anaesthesia [11], and is interesting, given that another study using healthy volunteers found that paralysis of the phrenic nerve did not affect pulmonary function [4]. Only one of our patients experienced respiratory symptoms, there was no incidence of respiratory distress and, in all cases, Spo2 remained unchanged. Therefore, it appears that the respiratory effects shown are of little clinical significance to fit patients. However, there are a number of reports of respiratory distress in patients with pre-existing respiratory morbidity [12] or obesity [13]. Our findings offer a plausible explanation for this and suggest caution in choosing the supraclavicular approach for such individuals. The performance of a supraclavicular block may also be a concern when one considers the reported incidence of pneumothorax, which ranges from 0.5 to 6% [14]. Several modifications of the supraclavicular approach have been described that aim to improve safety in this respect [15] and to simplify the anatomical landmarks. For instance, the plumb-bob technique [16] enjoys a high success rate with minimal complications in the hands of some clinicians. Another technique worth consideration is the infraclavicular approach [17]. As the site of needle insertion site is further away from the neck, we postulate that the incidence of phrenic nerve paralysis should be lower than with the supraclavicular approach. The coracoid process is used as a landmark for needle insertion with this technique and, since it is well away from the pleura, the incidence of pneumothorax should be very low. The drawback is that local anaesthetic will be deposited around the cords near the second part of the subclavian artery, some distance from the main trunks of the plexus, and complete block may therefore be difficult to achieve with a single injection. More recently, the mid-humeral approach has gained popularity, as this allows separate blockade of the major nerves of the arm. Since the needle insertion site is even further away from the neck, pulmonary complications should be rare [18]. However, the time required to 355


perform the block is longer than with a single injection technique, as four different nerves have to be individually located and blocked. In conclusion, brachial plexus block via the supraclavicular approach is a useful and attractive anaesthetic technique for upper limb surgery. It is a single injection technique and the anatomical landmarks are simple to learn. It gives uniform and complete anaesthesia of the brachial plexus, unlike blocks performed at other sites. However, as this study has shown, the risk of unilateral hemidiaphragmatic paralysis is high and, in contrast with a previous report [4], the resulting effects on pulmonary function are statistically significant. Interestingly, these effects do not appear to be clinically significant in healthy patients, but our results suggest that caution should be exercised in patients with pre-existing pulmonary impairment. References 1 Urmey WF, Talts KH, Sharrock NE. One hundred percent incidence of hemidiaphragmatic paresis associated with interscalene brachial plexus anesthesia as diagnosed by ultrasonography. Anesthesia and Analgesia 1991; 72: 498±503. 2 Lanz E, Theiss D, Jankovic D. The extent of blockade following various techniques of brachial plexus block. Anesthesia and Analgesia 1983; 62: 55±8. 3 Dupre LJ. Blocking of the brachial plexus: which technique (s) should be chosen? Cahiers D'anesthesiologie 1995; 43: 587±600. 4 Neal JM, Moore JM, Kopacz DJ, Liu SS, Kramer DJ, Plorde JJ. Quantitative analysis of respiratory, motor, and sensory function after supraclavicular block. Anesthesia and Analgesia 1998; 86: 1239±44. 5 Knoblanche GE. The incidence and aetiology of phrenic nerve blockade associated with supraclavicular brachial plexus block. Anaesthesia and Intensive Care 1979; 7: 346±9. 6 Cousins MJ, Bridenbaugh PO. Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd edn. LippincottRaven, 1998: 353±5. 7 Kulenkampff D. Anaesthesia of the brachial plexus. Zentralblatt Fur Chirurgie 1913; 40: 849±52.

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8 Partridge BL, Katz J, Benirschke K. Functional anatomy of the brachial plexus sheath: implications for anesthesia. Anesthesiology 1987; 66: 743±7. 9 Cohen E, Mier A, Heywood P, Murphy K, Boultbee J, Guz A. Excursion-volume relation of the right hemidiaphragm measured by ultrasonography and respiratory airflow measurements. Thorax 1994; 49: 885±9. 10 Hickey R, Ramamurthy S. The diagnosis of phrenic nerve block on chest X-ray by a double-exposure technique. Anesthesiology 1989; 70: 704±7. 11 Urmey WF, McDonald M. Hemidiaphragmatic paresis during interscalene brachial plexus block: effects on pulmonary function and chest wall mechanics. Anesthesia and Analgesia 1992; 74: 352±7. 12 Hood J, Knoblanche G. Respiratory failure following brachial plexus block. Anaesthesia and Intensive Care 1979; 7: 285±6. 13 Rau RH, Chan YL, Chuang HI, et al. Dyspnea resulting from phrenic nerve paralysis after interscalene brachial plexus block in an obese maleÐa case report. Acta Anaesthesiologica Sinica 1997; 35: 113±18. 14 Cousins MJ, Bridenbaugh PO. Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd edn. LippincottRaven, 1998: 356±7. 15 Pham-Dang C, Gunst JP, Gouin F, et al. A novel supraclavicular approach to brachial plexus block. Anesthesia and Analgesia 1997; 85: 111±16. 16 Brown DL, Cahill DR, Bridenbaugh LD. Supraclavicular nerve block: anatomic analysis of a method to prevent pneumothorax. Anesthesia and Analgesia 1993; 76: 530±4. 17 Wilson JL, Brown DL, Wong GY, Ehman RL, Cahill DR. Infraclavicular brachial plexus block: parasagittal anatomy important to the coracoid technique. Anesthesia and Analgesia 1998; 87: 870±3. 18 Gaertner E, Kern O, Mahoudeau G, Freys G, Golfetto T, Calon B. Block of the brachial plexus branches by the humeral route. A prospective study in 503 ambulatory patients. Proposal of a nerve-blocking sequence. Acta Anaesthesiologica Scandinavica 1999; 43: 609±13.



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A comparison of the intubating and standard laryngeal mask airways for airway management by inexperienced personnel A. Choyce,1 M. S. Avidan,2 A. Shariff,1 M. Del Aguila,1 J. J. Radcliffe3 and T. Chan1 1 Specialist Registrar, 2 Lecturer and 3 Consultant, Department of Anaesthesia, King's College Hospital, Denmark Hill, London SE5 9RS, UK Summary

Twenty-four inexperienced participants were timed inserting the intubating laryngeal mask airway and the laryngeal mask airway in 75 anaesthetised subjects. Adequacy of ventilation was assessed on a three-point scale. The pressure at which a leak first developed around the device's cuff was also measured. There was no significant difference in insertion time or the likelihood of achieving adequate ventilation between devices. However, the intubating laryngeal mask airway was better at providing adequate ventilation without audible leak (58/75 (77%) vs. 42/75 (56%); p 0.009). The median (range [IQR]) pressure at which an audible leak developed was higher for the intubating laryngeal mask airway, 34.5 (14±40 [29±40]) cmH2O, than for the laryngeal mask airway, 27.5 (14±40 [22±33]) cmH2O (p , 0.001). The intubating laryngeal mask airway is worthy of further consideration as a tool for emergency airway management for inexperienced personnel. Keywords

training.

Equipment: laryngeal mask airway; intubating laryngeal mask airway. Resuscitation:

................................................................................................. Correspondence to: Dr A. Choyce E-mail: [email protected] Accepted: 8 November 2000

The laryngeal mask airway has gained widespread acceptance as a general-purpose airway for routine anaesthesia. Studies have shown that unskilled personnel insert the laryngeal mask airway more rapidly and reliably than a tracheal tube and that it provides better ventilation than a facemask [1±4]. For these reasons, the laryngeal mask airway has been assessed as an airway device for use during cardiopulmonary resuscitation [5±7]. Training in inserting the laryngeal mask airway in manikins has been compared with that in anaesthetised subjects; the two modalities were not significantly different in terms of skill performance and retention [8]. The intubating laryngeal mask airway is a modified form of laryngeal mask airway designed to facilitate single-handed insertion and act as a conduit for tracheal intubation [9]. In the hands of those inexperienced in q 2001 Blackwell Science Ltd

advanced airway management, the intubating laryngeal mask airway did not increase the chance of successful tracheal intubation compared with direct laryngoscopy [10]. The same study showed that in common with the laryngeal mask airway, ventilation with the intubating laryngeal mask airway was superior to ventilation with a facemask [10]. In a recent study, we found that participants who had undergone only basic training were able to insert the intubating laryngeal mask airway in cadavers faster and more successfully than the laryngeal mask airway [11]. It may be that the cadaver model is not a good one for resuscitation. We wanted to investigate further the two devices for use in the emergency setting but felt it inappropriate to do this in true resuscitation. For this reason, we designed the present study in anaesthetised patients. 357


Methods

The King's College Hospital Research and Ethics Committee approved the present study. Participants were surgeons of all grades without anaesthetic experience. Adult patients aged 16±70 years of ASA physical status 1±2 and due to undergo elective surgery using a laryngeal mask were recruited following written informed consent. Patients with body mass index . 35 kg.m22 or other risk factors for regurgitation of gastric contents were excluded. Investigators were anaesthetists with clinical experience of both the intubating and the standard laryngeal mask airways. Each participant received basic training in the use of the two laryngeal mask airways from one investigator (AC) according to guidelines from the manufacturer's manuals [12, 13]. Instruction was given employing the Airway Management Training Manikin (Laerdale). Participants were considered adequately trained when they had achieved two sequential successful insertions with each device. They were then entered into the study and their performance with both devices was assessed in up to five anaesthetised patients. In the anaesthetic room, the patient was placed in the supine position with the head supported by a single pillow. Following institution of monitoring and preoxygenation via a Bain breathing system, patients were given fentanyl 2 mg.kg21 and midazolam 50 mg.kg21 1 min before a sleep dose of propofol. After induction of anaesthesia, the lungs were ventilated with isoflurane in oxygen for a 5-min stabilisation period, after which the expired isoflurane concentration exceeded 1.5 MAC. In the presence of two investigators, a trained participant then attempted to insert either an intubating laryngeal mask airway or a laryngeal mask airway in random order, determined by the toss of a coin. The time taken from first handling the device to insertion and attaching a self-inflating bag was recorded. Ventilation was then attempted and graded by two investigators as either poor (large leak; minimal or no ventilation; end-expired partial pressure of carbon dioxide (PE 0 co2) plateau , 4 kPa); moderate (some leak but adequate ventilation) or good (no leak and adequate ventilation). Adequate ventilation was defined as visible chest expansion and PE 0 co2 plateau . 4 kPa. If a participant failed to achieve adequate (i.e. moderate or good) ventilation then the device was removed and the subject re-oxygenated with bag and facemask by an investigator. The participant then had one further attempt at insertion with that device. This process was repeated for the other device. A size four device was used for female patients and a size five for males. The cuff was inflated with a standard volume of air after insertion (20 ml for the size four and 30 ml for the size five). If at 358

any time the patient's arterial oxygen saturation decreased below 94%, the attempt at insertion was discontinued. If adequate ventilation was achieved, oropharyngeal leak pressure was then measured as follows. A water manometer was attached to the breathing system via a Luer lock connection to an Intersurgicale breathing filter. Employing a leak test similar to that described by Keller et al. [14], the adjustable pressure release valve was then closed and a fresh gas flow of 5 l.min21 set. The pressure at which an audible leak first developed around the cuff of the device, heard at the mouth, was recorded. When using the intubating laryngeal mask airway, participants were encouraged to manipulate the handle to prevent a leak as had been demonstrated during the manikin training. If at a maximum pressure of 40 cmH2O no audible leak was heard, the test was discontinued. At the end of the study, participants were asked to complete a questionnaire to assess their views on each device. Data were analysed on an AEC P300 personal computer using Analyse-Itw for Microsoft Excel from analyse-It Software Ltd (Leeds, UK). To detect a 5 (SD 9) s difference in insertion times between devices, with a power of 90% and a level of significance of 0.05, 69 subjects would need to be recruited. These figures are based on a previous study in which the devices were inserted into cadavers [11]. The Wilcoxon signedrank test was used to compare insertion times and leak pressures. Fisher's exact test was used to compare adequacy of ventilation and to evaluate participants' responses to the questionnaire. A value of p , 0.05 was regarded as denoting statistical significance. Results

Patients were 38 females and 37 males; mean (SD) age and weight were 44.9 (13.1) years and 76.2 (11.3) kg, respectively. Participants were 24 surgeons: 10 house officers, five senior house officers, seven registrars and two consultants. After training, each inserted the airway devices in 1±5 (median 3) anaesthetised patients. The intubating laryngeal mask airway was inserted first on 36 occasions. Two participants failed to achieve adequate ventilation in single patients, one using the intubating laryngeal mask airway and one using the standard laryngeal mask airway. Table 1 shows the time to insertion, adequacy of ventilation and pharyngeal leak pressure for the two devices. All 24 participants completed the questionnaire. Twelve participants said the intubating laryngeal mask airway was easier to use, eight said the standard laryngeal mask airway was easier and four said they were the same. All felt confident at using the intubating laryngeal mask q 2001 Blackwell Science Ltd


Table 1 Time to insertion, adequacy of ventilation and pharyngeal leak pressure for the intubating and standard laryngeal mask airways

inserted by unskilled personnel in 75 patients. Values are median (interquartile range [range]) or number (proportion).

Time to insertion; s Adequate ventilation Good ventilation Leak pressure; cmH2O

Intubating laryngeal mask airway

Standard laryngeal mask airway

p-value

23 (17±38 [9±120]) 72 (96%) 58 (77%) 34.5 (29±40 [14±40])

24 (18±32 [11±120]) 66 (88%) 42 (56%) 27.5 (22±33 [14±40])

0.27 0.13 0.009 , 0.001

airway in an emergency situation compared with 22 for the standard laryngeal mask airway. Fifteen would choose the intubating laryngeal mask airway over the standard laryngeal mask airway, whilst nine would choose the latter. None of these differences was statistically significant. Discussion

Airway placement was achieved successfully in 98.7% of subjects with both devices; this result is similar to a study using experienced anaesthetists [15]. Our study did not show a significant difference in insertion times between the two devices in the hands of novice intubators, in contrast to our previous investigation in cadavers [11]. Also, insertion times for both devices were faster in our cadaver study (median times 14±16 s) than in the present one. Fear of traumatizing the anaesthetised subject and the improved dentition compared with the edentulous cadavers may have contributed to the longer insertion times, particularly for the intubating laryngeal mask airway. These findings are different from a recently published report that found that insertion times with the intubating laryngeal mask airway were similar in cadavers and in anaesthetised subjects [16]. This might be attributable to the fact that in our study the participants were novice intubators, whereas in the study by Keller and Brimacombe, participants were anaesthetists [16]. We found that the intubating laryngeal mask airway provided more adequate ventilation without audible leak. Also, it was the preferred device for 62% (15/24) of participants, although this failed to reach significance. A potential risk with both the intubating and the standard laryngeal mask airways is an incomplete seal, which may cause air leakage orally or insufflation of air into the stomach. Weiler et al. demonstrated that the incidence of gastric insufflation is increased if there is no external air leakage resulting in transmission of high airway pressures entirely to the oesophagus [17]. Whether or not this would increase the reported incidence of aspiration of 1.5% around a laryngeal mask airway during resuscitation q 2001 Blackwell Science Ltd

[6] is not known. It may be that by constantly adjusting the handle of the intubating laryngeal mask airway to maintain a pharyngeal seal, the incidence of aspiration may be reduced further. This warrants further investigation. It is unlikely that a similar manipulation of a less rigid laryngeal mask airway is possible. We chose to use size four and five masks and to inflate the cuffs to a volume less than the recommended maximum volume and nearer to the likely minimum effective volume to allow adequate ventilation. Recent studies [14, 18] and the manufacturer [13] recommend submaximal inflation volumes to provide the most effective seal. For the purposes of a training programme, it is important to give straightforward, didactic guidelines in terms of size and inflation volumes to help ensure retention of these details. We conclude that the intubating laryngeal mask airway is worthy of further consideration as a tool for emergency airway management. References 1 Reinhart DJ, Simmons G. Comparison of placement of the laryngeal mask airway with endotracheal tube by paramedics and respiratory therapists. Annals of Emergency Medicine 1994; 24: 260±3. 2 Davies PRF, Tighe SQM, Greenslade GL, Evans GH. Laryngeal mask airway and tracheal tube insertion by unskilled personnel. Lancet 1990; 336: 977±9. 3 Pennant JH, Walker MB. Comparison of the endotracheal tube and laryngeal mask in airway management by paramedical personnel. Anesthesia and Analgesia 1992; 74: 531±4. 4 Alexander R, Hodgson P, Lomax D, Bullen C. A comparison of the laryngeal mask airway and Guedel airway, bag and facemask for manual ventilation following formal training. Anaesthesia 1993; 48: 231±4. 5 Martin PD, Cyna AM, Hunter WA, Henry J, Ramayya GP. Training nursing staff in airway management for resuscitation. A clinical comparison of the facemask and laryngeal mask. Anaesthesia 1993; 48: 33±7. 6 Baskett PJF (Coordinator). The use of the laryngeal mask airway by nurses during cardiopulmonary resuscitation. Results of a multicentre trial. Anaesthesia 1994; 49: 3±7. 359


7 Kokkinis K. The use of the laryngeal mask airway in CPR. Resuscitation 1994; 27: 9±12. 8 Roberts I, Allsop P, Dickinson M, Curry P, Eastwick-Field P, Eyre G. Airway management training using the laryngeal mask airway: a comparison of two different training programmes. Resuscitation 1997; 33: 211±14. 9 Brain AIJ, Verghese C, Addy EV, Kapila A. The intubating laryngeal mask airway. I. development of a new device for intubation of the trachea. British Journal of Anaesthesia 1997; 79: 699±703. 10 Avidan MS, Harvey A, Chitkara N, Ponte J. The intubating laryngeal mask airway compared with direct laryngoscopy. British Journal of Anaesthesia 1999; 83: 615±17. 11 Choyce A, Avidan MS, Patel C et al. Comparison of laryngeal mask and intubating laryngeal mask insertion by the naõÈve intubator. British Journal of Anaesthesia 2000; 84: 103±5. 12 Brimacome JR, Brain AIJ, Berry AM. The Laryngeal Mask Airway Instruction Manual. Intavent Research Limited, 1996.

13 Brain AIJ, Verghese C. The Intubating Laryngeal Mask Airway Instruction Manual. Intavent Research Limited, 1998. 14 Keller C, PuÈhringer F, Brimacombe JR. Influence of cuff volume on oropharyngeal leak pressure and fibreoptic position with the laryngeal mask airway. British Journal of Anaesthesia 1998; 81: 186±7. 15 Baskett PJF, Parr MJA, Nolan JP. The intubating laryngeal mask. Results of a multicentre trial with experience of 500 cases. Anaesthesia 1998; 53: 1174±9. 16 Keller C, Brimacombe J. The intubating laryngeal mask airway in fresh cadavers vs paralysed anesthetised patients. Canadian Journal of Anaesthesia 1999; 46: 1067±9. 17 Weiler N, Latorre F, Eberle B, Goedecke R, Heinrichs W. Respiratory mechanics, gastric insufflation pressure, and air leakage of the laryngeal mask airway. Anesthesia and Analgesia 1997; 84: 1025±8. 18 Asai T, Towell TK, Koga K, Morris S. Appropriate size and inflation of the laryngeal mask airway. British Journal of Anaesthesia 1998; 80: 470±4.

F O RU M

Effect of halothane on the cerebral circulation in young children: a hysteresis phenomenon O. Paut and B. Bissonnette Department of Anaesthesia, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. Summary

To determine the effect of halothane on the cerebral blood flow velocity (CBFV) with increasing then decreasing concentrations, 11 children scheduled for minor surgery were studied. Anaesthesia consisted of halothane, vecuronium, nitrous oxide in oxygen and a caudal block. End-tidal carbon dioxide, temperature, heart rate and systolic arterial pressure were maintained constant. CBFV increased significantly between 0.5 and 1.0 MAC (p ,0.001), and 0.5 and 1.5 MAC of halothane (p ,0.001), but was not different after increasing concentration from 1.0 to 1.5 MAC. During the decreasing phase, CBFV decreased significantly from 1.5 to 1.0 MAC of halothane (p ,0.001), whereas there was no difference in CBFV when decreasing halothane MAC from 1.0 to 0.5 MAC. In children, the decrease in CBFV during decreasing halothane concentration is not superimposable to the increase in CBFV seen when increasing halothane concentration, suggesting the presence of cerebrovascular hysteresis to halothane. Keywords

Doppler.

Anaesthetic, inhaled, halothane. Circulation: cerebral blood flow. Monitoring: transcranial

................................................................................................. Correspondence to: Dr O. Paut, Department of Paediatric Anaesthesia and Intensive Care Medicine, La Timone Children's Hospital, 13385 Marseille cedex 5, France. E-mail: [email protected] Accepted: 27 November 2000 360



Volatile anaesthetics affect the cerebral circulation by dilating the cerebral vasculature, increasing cerebral blood flow (CBF), and by depressing the metabolic rate for oxygen (CMRO2) [1]. Under steady-state conditions, the ratio CBF/CMRO2 varies proportionally with the minimum alveolar concentration (MAC) administered [2]. Among the volatile anaesthetics currently in use, halothane has been shown to exert a significant effect on this ratio [1]. Thus, halothane may be an appropriate anaesthetic to investigate small changes in the cerebral circulation in healthy children. Previous investigators have reported a dose-dependent relationship between cerebral blood flow velocity (CBFV) measured with transcranial Doppler (TCD) sonography and the concentration of halothane in adults [3]. However, while studies on the effect of various concentrations of halothane have been performed during increasing gas concentration, none has studied the effect of combined increase±decrease gas concentration on the cerebral vasculature. Hysteresis is a failure of either one or two related phenomena to keep pace with the other, or any situation in which the value of one depends upon the other having been increased or decreased [4]. When applying this definition to cerebral blood flow, it means that CBFV under stable physiological conditions depends not only on the halothane concentration but also on the manner by which the stability was reached, either by increasing or decreasing concentration. Such a hysteresis effect between cerebral blood flow and arterial propofol concentrations has been previously described in sheep [5]. This study was designed to determine if halothane produces a hysteresis response on the cerebral circulation in anaesthetised infants and children.

Methods

Anaesthesia management Following approval from the Institution Ethics Committee, 11 unpremedicated infants and children, ASA physical status 1 or 2, between 4 months and 3.5 years

of age, undergoing elective urological surgery were studied. All patients were full-term at the time of birth. Patients with a history of neurological or cerebrovascular disease, and/or an unsuccessful caudal block were not studied. Anaesthesia was induced with intravenous thiopental (5.0 mg.kg21) and muscular relaxation provided by vecuronium (0.1 mg.kg21). After tracheal intubation, the lungs were ventilated with intermittent positive pressure ventilation with peak inspiratory pressures of 20±25 mmHg while positive end expiratory pressure was avoided. Anaesthesia was maintained with nitrous oxide (70%) in oxygen, halothane and vecuronium. A caudal block (1 ml.kg21 of 0.25% bupivacaine with 1 : 200 000 epinephrine) was performed before surgical incision. Good efficacy of the block was checked at the beginning of the surgical procedure. Normocapnia and normothermia were maintained at all time. All patients were supine and horizontal throughout the study. Compound sodium lactate solution (5 ml.kg21) was administered over 15 min in those patients fasted for more than 4 h. Maintenance fluids were administered at a rate of 2 ml.kg21.h21. Study protocol Systolic arterial pressure, heart rate, oxygen saturation, end-tidal carbon dioxide (FE 0 co2), temperature, end-tidal halothane concentration and inspired nitrous oxide and oxygen fractions (analysed with a calibrated PuritanBennett Datex 254 airway gas monitor, Datex Instrumentation Corp., Helsinki, Finland) were recorded during each CBFV measurement. Systolic arterial pressure and heart rate were maintained within 10% of the recordings at 0.5 MAC to ensure haemodynamic steady-state intervals using small incremental doses of intravenous phenylephrine (10 mg in 250 ml for a concentration of 40 mg.ml21). The patients received halothane following tracheal intubation at an initial concentration of 0.5 MAC, followed by subsequent increases in the concentration of halothane to 1.0 and 1.5 MAC. A minimum of 15 min was allowed for

Table 1 Physiological data at different halothane MAC. Results are given as mean (SD)

Halothane MAC

FE 0 CO2 (mmHg)

Heart rate (beat.min21)

Systolic blood pressure (mmHg)

Temperature (8C)

0.5 1.0 1.5 1.0 0.5

36.0 36.7 36.4 36.3 36.6

123.5 123.4 124.2 122.8 124.1

93.2 92.9 92.0 93.0 92.6

36.2 36.3 36.3 36.4 36.4

MAC MAC MAC MAC MAC

(increasing) (increasing) (increasing) (decreasing) (decreasing)

(1.9) (1.8) (2.1) (1.7) (1.9)

(26.4) (23.2) (22.1) (25.1) (23.4)

(10.3) (9.3) (10.0) (9.6) (10.1)

(0.4) (0.4) (0.3) (0.3) (0.4)

The minimum alveolar concentration (MAC) of halothane was increased from 0.5 to 1.5 and subsequently decreased to 0.5 MAC by stepwise 0.5 decrements. FE 0 CO2 (mmHg): end-tidal carbon dioxide pressure in mm of mercury.


361


Table 2 Demographical and physiological data recorded for each patient throughout the study period. Results are given as mean (SD)

Patient no.

Age (months)

Weight (kg)

FE 0 CO2 (mmHg)

Heart rate (beat.min21)

Systolic blood pressure (mmHg)

Temperature (8C)

1 2 3 4 5 6 7 8 9 10 11 Mean (SD)

4 7 11 21 21 29 32 33 37 37 38 24.5 (12.6)

6.4 7.1 12.1 12.5 12.5 11.7 14 15 15.1 14.5 18 12.6 (3.4)

36.4 38.8 35.1 35.1 39.1 36.7 38.0 34.7 34.0 39.1 37.0

160.5 139.8 146.8 116.6 140.3 119.5 131.6 86.1 116.7 89.4 131.8

105.0 96.2 90.3 82.0 99.8 90.4 80.5 83.0 82.1 88.1 110.2

35.9 36.8 36.2 35.9 36.7 36.1 36.2 36.5 36.9 36.5 36.7

(0.8) (0.4) (0.7) (1.0) (0.5) (0.7) (0.4) (0.7) (0.9) (1.0) (0.5)

equilibration at each 0.5-MAC increment. The concentration was adjusted to achieve MAC values for each age group [6, 7]. After recordings were obtained at 1.5 MAC of halothane, the concentration of halothane administered was decreased to allow various MAC levels to be attained for a period of 15 min. This allowed for stable CBFV and end-tidal halothane concentration recordings.

(8.4) (3.1) (4.0) (5.8) (2.5) (4.0) (3.0) (3.0) (6.0) (2.8) (6.1)

(2.1) (1.7) (3.4) (2.6) (1.3) (2.1) (1.0) (1.7) (4.0) (1.6) (1.3)

(0.1) (0.3) (0.2) (0.1) (0.1) (0.2) (0.1) (0.2) (0.2) (0.1) (0.0)

Doppler instrumentation The Neuroguard monitor (Medasonics, Fremont, CA, USA) was used to determine CBFV. This monitor has the following characteristics: emitted ultrasonic frequency, 2 MHz; emitting area, 1.5 cm2; effective range, 3.0± 10.0 cm; emitted ultrasonic power, 1000 mW with an operating range of ,100 mW in children. The methods for TCD measurements and analysis have been previously described [8]. All CBFV measurements in the middle cerebral artery (MCA) were obtained in triplicate with a 1-min interval between recordings at each MAC value studied. Statistical analysis The mean and standard deviation (SD) for age, weight, systolic arterial pressure, heart rate, temperature, FE 0 co2 and CBFV were determined. Comparison of quantitative parameters at each MAC value were determined using repeated measures anova and the Student±Newman± Keuls test for multiple comparisons. Statistical significance at a value of p ,0.05 was accepted. Results

Figure 1 Cerebral blood flow velocity (CBFV) at 0.5, 1.0 and 1.5 MAC halothane during increasing and decreasing concentrations. The CBFV 0.5±1.5 indicates the CBFV during the increasing concentration phase and the CBFV 1.5±0.5 indicates the CBFV during the decreasing concentration phase. *p ,0.001 between CBFV 0.5±1.5 at 0.5 MAC and CBFV 1.5± 0.5 at 0.5 MAC; §p ,0.001 between CBFV 0.5±1.5 at 1.5 MAC and CBFV 0.5±1.5 at 0.5 MAC; ¥p ,0.001 between CBFV 0.5±1.5 at 0.5 MAC and CBFV 0.5±1.5 at 1.0 MAC; **p ,0.001 CBFV 1.5±0.5 at 1.0 MAC and CBFV 1.5±0.5 at 1.5 MAC 362

Eleven children aged 24.5 (12.6) months and weighing 12.6 (3.4) kg were studied. The FE 0 co2, heart rate, systolic arterial pressure and temperature did not change significantly at any time throughout the study (Table 1). Table 2 summarises the demographic and haemodynamic data recorded for each patient throughout the steady-state period of TCD measurements. None of the children showed cardiovascular changes during the surgical procedure and the caudal block was considered successful in all. The TCD recordings at the MCA were completed in all infants and children during increasing and decreasing MAC of halothane. There were no complications from the use of the TCD in this study. q 2001 Blackwell Science Ltd


Figure 2 CBFV during increasing and

decreasing MAC halothane in two children. Further decrease to 0.2 MAC halothane was needed for the CBFV to return to the initial 0.5 MAC value. *p ,0.001 between CBFV 0.5±1.5 at 0.5 MAC and CBFV 1.5±0.5 at 0.5 MAC; **p ,0.001 between CBFV 1.5±0.5 at 0.4 MAC and CBFV 1.5±0.5 at 0.5 MAC; ¥p ,0.001 between CBFV 0.5± 1.5 at 0.5 MAC and CBFV 0.5±1.5 at 1.0 MAC.

During the increasing concentration phase, CBFV increased significantly between 0.5 and 1.0 MAC (p ,0.001) and between 0.5 and 1.5 MAC (p ,0.001) whereas the CBFV was not different between 1.0 and 1.5 MAC. During the decreasing concentration phase, CBFV was significantly different between 1.5 MAC and 1.0 MAC (p ,0.001) but not between 1.0 MAC and 0.5 MAC of halothane (Fig. 1). The CBFV was significantly higher at 0.5 MAC during the decreasing concentration phase compared with CBFV obtained at 0.5 MAC during the increasing concentration period (p ,0.001). In two children, the protocol was continued in this manner: MAC halothane was further decreased from 0.5 to 0.2 MAC in order to test at what level of MAC of halothane CBFV returned to its initial value measured at 0.5 MAC of halothane during the increase phase of the study. Figure 2 shows the CBFV recorded in those two children during variation of halothane concentration. The CBFV was greater at 0.5 MAC during the decreasing phase compared with 0.5 MAC during the increasing phase (p ,0.001). Two other assessments of CBFV were performed at reduced MAC values (0.4 MAC and 0.2 MAC) of halothane and showed higher CBFV at 0.4 MAC halothane (p ,0.01) but not at 0.2 MAC halothane compared with the initial CBFV recorded at 0.5 MAC. q 2001 Blackwell Science Ltd

Discussion

The present study demonstrates that the effects on CBFV of stepwise increase in the concentration of halothane from 0.5 to 1.5 MAC were not paralleled when the halothane concentration was decreased from 1.5 MAC to 0.5 MAC, even while maintaining haemodynamic steadystate conditions. Hysteresis has been sparsely described in the literature. Using an animal model of the cerebral pharmacokinetics of centrally acting drugs, Ludbrook et al. [5] showed a marked difference between the time course of arterial propofol concentrations and cerebral effects such as depth of anaesthesia and CBF. More interestingly, while they showed a significant anticlockwise hysteresis in the relationship between CBF and arterial concentration, there was no significant hysteresis when studying the relationships between sagittal sinus and brain concentrations and CBF [5]. In another study, they showed that the differences between arterial and brain concentrations of pethidine and alfentanil can be best explained by differences in the brain distribution volume [9]. Whether the different delay between blood concentrations and cerebral effect (hysteresis) of these opioids has an impact on time course of CBF is not clear. The CBF increase shown in their study can be related to either a direct cerebral vasodilatory effect, a drug-induced stimulatory effect or an increase in the carbon dioxide tension 363


[9]. The hysteresis effect observed in the present study may be attributed in part to an alteration in the intrinsic mechanism regulating CBF. Data obtained during induction of anaesthesia with halothane showed a marked increase in CBF before a change in CMRO2 [10]. This may suggest that the initial cerebrovascular response to halothane is a direct effect of smooth muscle within the cerebrovasculature [11]. This hysteresis may be mediated through either myogenic or neurogenic mechanisms. Little is known concerning the hysteresis effects of other volatile anaesthetics on CBFV. In children, a previous investigation failed to show a hysteresis effect of isoflurane on CBFV [12]. There are no data regarding sevoflurane as yet. A comparative study of the effect on CBFV of halothane and more recent anaesthetics such sevoflurane will be relevant to confirm the results of the present study. Cerebral blood flow is autoregulated through an integrated action of metabolic, myogenic and neurogenic mechanisms [13]. We propose that both metabolic and myogenic mechanisms contributed minimally to the effect of halothane in the present study since the carbon dioxide tension, oxygen tension, blood pressure, heart rate and temperature were unchanged throughout the study. Therefore, the neurogenic mechanism may explain the observed hysteresis response. Morphological observations indicated that the neurogenic effects on CBFV are conducted through two types of nerve endings in the walls of cerebral arteries [14]. Cerebral vasodilation may be precipitated by inhibition of ongoing sympathetic vasoconstriction and/or stimulation of b-adrenergic receptors [14]. Halothane may also have a direct b receptor effect on the cerebral blood vessels due to its action as a b-agonist on smooth muscle [15]. However, this latter speculation warrants further investigations. The effects of halothane on cerebral haemodynamics have been already studied in children. A recent study evaluated the changes in CBFV during induction of anaesthesia with either halothane or sevoflurane [16]. Both volatile agents decreased to the same extent the blood pressure and increased CBFV during induction of anaesthesia [16]. In a recent study designed to determine the effects of stepwise increases of halothane on CBFV, we showed that maximal effects are obtained at 1.0 MAC and that further increases in halothane concentration from 1.0 to 1.5 MAC failed to produce further increases in CBFV [17]. The current study confirms these previous results, i.e. maximal changes in CBFV were obtained at 1.0 MAC of halothane, and that a further increase to 1.5 MAC was not associated with any further modification [17]. To maintain systemic blood pressure and cerebral perfusion pressure constant, intermittent intravenous phenylephrine was administered. As recently shown, 364

phenylephrine does not cross the blood±brain barrier and has no direct effect on intracranial haemodynamics [18]. The CBFV variations observed in the present study suggest that the effects of halothane on the cerebral vasculature are associated with changes in concentration rather than an intrinsic cerebral effect of the vasoconstrictors. Therefore, phenylephrine must have been useful in preventing variations in CBFV potentially caused by systemic hypotension. The TCD sonography was used to determine the effects of halothane on the CBFV. It is a simple, easy to use, reproducible method of measuring CBFV [19]. It has been suggested that measured changes in CBFV can accurately reflect changes in CBF [20]. Two methodological measurement errors may have occurred in the present study. Firstly, intrapatient variability associated with repeated measurements over time may have accounted for a type I error. To minimise this error, a TCD probe was fixed in position at the start of each study and was not moved throughout the study period. Second, interpatient variability can result from different probe positions. This depends on the angle of insonation (i.e. the angle at which the Doppler beam impacts on the artery). Previous studies have shown that the angle of insonation measured in the temporal window for the MCA ranges from 08 to 308 from the perpendicular [21]. This interpatient variability in the angle of insonation for different probe positions may lead to a maximum error of 13% [21]. The reproducibility of both within- and between-patient measurements in this study suggests that these errors are within acceptable experimental limits. In summary, the results of this study suggest that halothane anaesthesia has a significant effect on cerebral circulation at varying concentrations in young children. After administration of 1.5 MAC of halothane, CBFV remains significantly increased for as long as 30±45 min even though halothane concentration is decreased to the initial concentration. The residual increase in CBFV at 0.5 MAC can only be avoided by reducing further the inhaled concentration. The decrease in CBFV during decreasing halothane concentration back from 1.5 to 0.5 MAC is not superimposable to the increase in CBFV seen when increasing halothane concentration from 0.5 to 1.5 MAC. These findings suggest the presence of cerebrovascular hysteresis to halothane. A comparative study of halothane with other volatile anaesthetics will be appropriate to confirm our results. Acknowledgments

We are grateful to our colleagues from the Department of Surgery, Division of Urology and the Operating Room Nurses for their patience during this study. Special thanks to Dr V. Lazzell for data collection. q 2001 Blackwell Science Ltd


References 1 Kuroda Y, Murakami M, Tsuruta J, Murakawa T, Sakabe T. Preservation of the ratio of cerebral blood flow/metabolic rate for oxygen during prolonged anesthesia with isoflurane, sevoflurane, and halothane in humans. Anesthesiology 1996; 84: 555±61. 2 Smith A, Wollman H. Cerebral blood flow and metabolism: effects of anesthetic drugs and techniques. Anesthesiology 1972; 36: 378±400. 3 Lam A, Wollman H. Intraoperative use of transcranial doppler ultrasonography. Neurosurgical Clinics of North America 1996; 7: 709±22. 4 Stedman. Stedman's Medical Dictionary, 25th edn. Baltimore: Williams and Wilkins, 1990. 5 Ludbrook G, Upton R, Grant C, Gray E. Brain and blood concentrations of propofol after rapid intravenous injection in sheep, and their relationships to cerebral effects. Anaesthesia and Intensive Care 1996; 24: 445±52. 6 Lerman J, Robinson S, Willis M, Gregory G. Anesthetic requirements for halothane in young children 0±1 month and 1±6 months of age. Anesthesiology 1983; 59: 421±4. 7 Gregory GA, Eger EID, Munson ES. The relationship between age and halothane requirement in man. Anesthesiology 1969; 30: 488±91. 8 Leon J, Bissonnette B. Transcranial doppler ultrasonography: nitrous oxide and cerebral blood flow velocity in children. Canadian Journal of Anaesthesia 1991; 38: 974±9. 9 Upton R, Ludbrook G, Gray E, Grant C. The cerebral pharmacokinetics of meperidine and alfentanil in conscious sheep. Anesthesiology 1997; 86: 1317±25. 10 Albrecht R, Miletich D, Rosenberg R. Cerebral blood flow and metabolites changes from induction to onset of anaesthesia with halothane or pentobarbital. Anesthesiology 1977; 47: 252±6.

11 Drummond J, Shapiro H. Cerebral physiology. In: Miller R, ed. Anesthesia, 4th edn. New York: Churchill Livingstone, 1994: 689±729. 12 Bissonnette B, Leon J. Cerebrovascular stability during isoflurane anaesthesia in children. Canadian Journal of Anaesthesia 1992; 39: 128±34. 13 Harder D. A cellular mechanism for myogenic regulation of cat cerebral arteries. Annals of Biomedical Engineering 1985; 13: 335±9. 14 Lee T, Hume W, Su C, Bevan J. Neurogenic vasodilatation of cat cerebral arteries. Circulation Research 1978; 42: 535± 42. 15 Klide A, Aviado D. Mechanisms for the reduction in pulmonary vascular resistance by halothane. Journal of Pharmacology Experimental Therapy 1967; 158: 28±35. 16 Berkowitz RA, Hoffman WE, Cunningham F, McDonald T. Changes in cerebral blood flow velocity in children during sevoflurane and halothane anesthesia. Journal of Neurosurgical Anesthesiology 1996; 8: 194±8. 17 Paut O, Lazzell V, Bissonnette B. Low concentrations of halothane produce maximal cerebrovascular changes in young children. Anaesthesia 2000; 56: 528±33. 18 Strebel S, Kindler C, Bissonnette B, Tschaler G, Deanovic D. The impact of systemic vasoconstrictors on the cerebral circulation of anesthetized patients. Anesthesiology 1998; 89: 67±72. 19 Sudikoff S, Banasiak K. Techniques for measuring cerebral blood flow in children. Current Opinion in Pediatrics 1998; 10: 291±8. 20 Bishop C, Powell S, Rutt D, Browse N. Transcranial doppler measurement of middle cerebral artery blood flow velocity: a validation study. Stroke 1986; 17: 913±15. 21 Aaslid R. Cerebral hemodynamics. In: Aaslid R, ed. Transcranial Doppler Sonography. New York: Springer-Verlag, 1986: 60±5.

F O RU M

Patient-controlled analgesia and postoperative nausea and vomiting: efficacy of a continuous infusion of ondansetron L. A. White,1 M. Vanarase,2 K. Brockbank3 and R. F. Barrett4 1 Specialist Registrar in Anaesthesia, 2 Senior House Officer in Anaesthesia, 3 Sister in charge, Pain Relief Service and 4 Consultant Anaesthetist, Salisbury District Hospital, Salisbury, Wiltshire SP2 8BJ, UK Summary

A continuous infusion of ondansetron was compared with a placebo infusion in 80 patients undergoing major breast reconstructive surgery. All patients received a standard anaesthetic and a bolus dose of ondansetron after induction. They were then randomly allocated to receive an


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intravenous infusion of ondansetron or a placebo infusion for 24 h in a double-blind fashion. Postoperative analgesia was provided by patient-controlled subcutaneous diamorphine. In the ondansetron group, the severity of nausea, measured by a 10-point verbal rating scale, was reduced (p 0.01) and fewer patients stated at postoperative interview that nausea and vomiting was a problem (p 0.01). Keywords Analgesia: patient-controlled. Pain: postoperative. Anti-emetic drugs: ondansetron. Complications: nausea; vomiting. ................................................................................................. Correspondence to: Dr L. A. White Accepted: 29 November 2000

Patient-controlled analgesia (PCA) using subcutaneous diamorphine has been used for postoperative analgesia in our hospital for five years. Internal audit has shown it to be effective, safe and labour saving. However, audit has shown a very high rate of postoperative nausea and vomiting (PONV) in users of PCA. Seventy per cent of women using PCA after major breast reconstruction experience PONV, most commonly in the second 12 h after surgery. Some ward clinicians and nurses believe that postoperative patients experience more nausea and vomiting when using PCA than when using intermittent intramuscular opioids. This has been noted elsewhere [1, 2] although well-controlled clinical trials also exist which do not support this observation [3]. It may be that patients in a routine ward are likely to receive anti-emetics regularly in combination with an intramuscular opioid, whereas PCA users receive them occasionally or not at all [1, 4]. Several studies [2, 5±8] have examined addition of antiemetics to the PCA infusion although the evidence that this is effective is not conclusive [4]. This may be because adequate plasma levels of the anti-emetic are not achieved in a system in which the dose is related to use of PCA for pain. Ondansetron infusions are used for prophylaxis of nausea in patients undergoing chemotherapy [9] and bone marrow transplantation [10]. A more effective method of delivering anti-emetic prophylaxis to high-risk patients using PCA is required and this study was designed to address this problem. Methods

Approval for the study was obtained from the Local Research Ethics Committee. Patients undergoing breast surgery were chosen because of the high risk of PONV [11, 12]. Eighty patients aged 18±70 years undergoing major reconstructive or augmentation breast surgery gave written informed consent. Patients of ASA physical status 366

> 3, those with significant gastric reflux or hepatic/renal disease and those who had received anti-emetics in the pre-operative 24 h were not studied. The use of the PCA pump was explained to all patients. They were also told that they would receive either an anti-emetic or a placebo intravenous infusion via a pump, that anti-emetic prophylaxis would be given and that intramuscular antiemetics would be available if required. Patients were unpremedicated and starved of clear fluids for 3±4 h. Anaesthesia was induced with propofol 2±3 mg.kg21 and fentanyl 1 mg.kg21 and maintained using isoflurane in air and oxygen via a laryngeal mask airway with spontaneous ventilation. Ondansetron 0.1 mg.kg21 up to 8 mg was given intravenously to all patients immediately after induction. Intravenous fluids were given at the discretion of the anaesthetist. Intramuscular diamorphine 5 mg was given after surgery commenced and 100 mg diclofenac per rectum was given at the end of the procedure before emergence except when contraindicated. Intravenous diamorphine was given in 1-mg increments by staff in the recovery room as requested by the patient. A PCA device (Grazeby 3300) was attached to a subcutaneous cannula (Wallace 23G Y-can) inserted in the upper arm, overlying the deltoid muscle. The PCA device was programmed to deliver a 2.5-mg bolus dose (1 ml) of diamorphine with a 20-min lock-out. A second syringe driver (Grazeby 3300) containing 0.9% saline or 0.5 mg.ml21 ondansetron in 0.9% saline was connected via a one-way valve to the intravenous cannula and was set at 2 ml.h21. Randomisation was performed by pharmacy staff using computergenerated random numbers. To achieve double-blinding, the trial syringes were made up by the pharmacy staff and no other staff were aware of their contents. During the first 24 h, episodes of vomiting were recorded by the ward staff and nausea scores were recorded at least every 4 h using a 10-point verbal rating scale where 0 no nausea and 10 the worst q 2001 Blackwell Science Ltd


Table 1 Characteristics of patients receiving continuous intravenous infusions of ondansetron or placebo, details of their surgery and

the amount of diamorphine used per 24 h. Values are mean (SD), number (proportion) or median (interquartile range [range]).

Age; years Body mass index (BMI); kg.m22 Risk factors:* Previous PONV Motion sickness Migraine BMI . 28 kg.m22 None Surgical procedure: Latissimus dorsi flap Bilateral breast augmentation Total dose of diamorphine used in 24 h; mg

Ondansetron n 40

Placebo n 40

44.7 (10.7) 25.7 (6.2)

43.2 (10.0) 25.3 (4.5)

21 16 10 7 8

24 17 15 7 7

(53%) (40%) (25%) (18%) (20%)

22 (55%) 18 (45%) 20 (10.0±27.5 [2±60])

(60%) (43%) (38%) (18%) (18%)

24 (60%) 16 (40%) 20 (12.5±27.5 [7.5±77.5])

*some patients had more than one risk factor.

imaginable nausea. This 24-h period was divided into six 4-h periods and the worst nausea score recorded in each of these periods was added together to give a nausea severity score for each patient. Pain and sedation scores were also noted. Escape anti-emetics (cyclizine 50 mg or prochlorperazine 12.5 mg intramuscularly) were given at the request of the patient. After 24 h, the anti-emetic/ placebo infusion was discontinued but the patient was allowed to continue with PCA if she wished. The total dose of diamorphine per 24 h and the use of intramuscular anti-emetics were recorded. The patients were interviewed on the second or third postoperative day by one of two investigators. Risk factors for PONV were recorded. The patients' opinions of the PONV experienced were assessed by asking them `How would you describe the Table 2 Nausea severity scores, opinions of postoperative nausea

and vomiting (PONV), incidence of nausea and vomiting and requirement for anti-emetic drugs in patients receiving continuous intravenous infusions of ondansetron or placebo. Values are number (proportion).

Nausea severity score: 0±10 11±19 20±29 . 30 Patients' opinions: PONV did not occur Occurred but not a problem Was a problem Was a dreadful problem Nausea Vomiting Requirement for anti-emetic drugs


Ondansetron n 40

Placebo n 40

25 (63%) 13 (33%) 2 (5%) 0

20 7 9 4

(50%) (18%) (23%) (10%)

11 16 9 4 28 19 16

10 5 13 12 31 24 20

(25%) (12%) (33%) (30%) (78%) (60%) (50%)

(28%) (40%) (22%) (10%) (70%) (47.5%) (40%)

p

sickness that you had?' and offering the following choices: (i) it did not occur; (ii) it did occur but was not a problem; (iii) it was a problem; or (iv) it was a dreadful problem. Patients' opinions of PCA as a method of analgesia were also assessed using a four-point verbal rating scale and the reason that PCA was stopped was noted. Sample size was chosen following power analysis [13] taking values for a and b of 0.05 and 0.9, respectively, with a reduction in PONV from 70% to 35%. Statistical analysis was carried out using the statistical software packages MINITAB and StatXact [14, 15]. Age, body mass index, presence of other risk factors and amount of diamorphine used were compared using an unpaired t-test or, for skewed distributions, a Mann±Whitney U-test. The Chi-squared test with Yates correction or Fisher's exact test was used to compare nausea, vomiting, pain, sedation and satisfaction scores and the requirement for escape anti-emetics.

Table 3 Reasons given for stopping patient-controlled analgesia

(PCA) by patients receiving continuous intravenous infusions of ondansetron or placebo. Values are number (proportion). No significant difference exists between the groups.

0.013

0.015

0.62 0.37 0.5

Not required for analgesia Patient thought that PCA was causing nausea and vomiting Felt dizzy or light-headed Intravenous cannula not required/not wanted Nurse's choice; patient unaware of reason

Ondansetron n 40

Placebo n 40

27 (68%) 7 (18%)

19 (48%) 13 (33%)

4 (10%) 1 (2.5%)

1 (2.5%) 3 (7.5%)

1 (2.5%)

4 (10%)

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Results

The two groups were similar for age, body mass index, presence of risk factors, surgical procedure and amount of diamorphine used per 24 h (Table 1). All recruited patients completed the study. In one patient, the randomisation code was broken because of persisting PONV despite intramuscular cyclizine 50 mg and prochlorperazine 12.5 mg. She was receiving a placebo infusion and was given intravenous ondansetron 4 mg, which was effective. Nausea severity scores and the proportion of patients who said that PONV was a problem for them were lower in the ondansetron group (Table 2). Similar proportions of patients experienced nausea or vomiting or received intramuscular anti-emetics (Table 2). Pain and sedation scores were similar in the two groups. Satisfaction with PCA as a method of analgesia was very high and very few patients regretted using it. Reasons for stopping PCA are shown in Table 3. Discussion

Anti-emetic prophylaxis in postoperative patients who are using a PCA device remains a problem which requires further investigation [4]. In the second postoperative 12 h, a number of factors may cause PONV. These include prolonged starvation followed by drinking or eating, early mobilisation, opioids given for pain, the residual effects of anaesthetic agents and the reduction in the effect of anti-emetics given during anaesthesia. The success of PCA as a method of delivering analgesia during this period [16] may be under threat from the growing opinion amongst ward staff that PONV is exacerbated by PCA [1, 2, 4]. Efficacy of anti-emetics such as droperidol added to the PCA is controversial [2, 4] and nausea rates remain high using this method [5]. Efficacy of transdermal hyoscine has been demonstrated but high levels of PONV occur [1, 17]. Ondansetron is effective in preventing PONV in high-risk surgical patients [11, 18], and some authors describe it as the `gold standard' anti-emetic [11]. At the time that this study was devised, there was some evidence that a 4-mg dose was inadequate for prophylaxis of opioid-induced emesis, and therefore an 8-mg dose was chosen [19, 20]. The use of a continuous infusion of ondansetron after this bolus aims to provide anti-emetic prophylaxis during the first 24 h. Ondansetron was used because of its reputation for high efficacy and lack of sideeffects [11, 16]. Our data support the hypothesis that a continuous infusion of ondansetron is a useful component of prophylaxis against PONV in this group of high-risk patients. The nausea severity scores were lower in the ondansetron group and fewer patients said that PONV had been a problem. However, the overall incidence of 368

nausea and of vomiting were not significantly different between the groups. It is clear from our results that not all patients who experience PONV describe it as a problem when interviewed later. Twenty-one patients in the study assessed PONV as `did occur, but not a problem'. In some patients the PONV was mild, as shown by a low nausea severity score. For other patients, there was a single episode of moderate or severe nausea, often with vomiting, but this was brief, self-limiting and therefore `not a problem'. These patients also had a low severity score. Of the 43 patients who vomited in this study, 12 said that the PONV was `not a problem'. These patients had a single high nausea score with zero scores in the other 4-h periods, giving a low nausea severity score. Ten of these patients were in the ondansetron group. The view that PONV prophylaxis has failed in any patient who vomits during the study period is not necessarily valid. Patients may regard a short episode of severe nausea and vomiting as acceptable, whereas a long period of mild or moderate nausea may be more of a problem. Questioning the patient postoperatively, using a verbal rating scale, and gaining their opinion of the PONV that they experienced, is a simple task and may be a useful outcome measure in trials of PONV. The verbal rating scale used here was designed for the purposes of this study and, being a non-validated tool, could correctly be regarded as a soft outcome measure. However, other indicators may be difficult to measure or interpret. Severely nauseated patients cannot operate visual analogue scales properly and assessments made by nurses may vary between observers. The presence or absence of vomiting is not a simple endpoint. Some patients regard vomiting as relief after a long period of nausea, whereas others take great care to avoid vomiting. This study was carried out on a busy surgical ward and every effort was made to ensure that all episodes of PONV were recorded. However, nurses were not always aware of all episodes as patients did not always seek assistance. The postoperative interview showed that the use of anti-emetics was erratic and reflected the difficulties in achieving a uniform anti-emetic policy on a busy surgical ward. Some severely nauseated patients declined treatment as they wished to avoid an intramuscular injection and there was considerable variation in the advice given by nurses as to whether an anti-emetic was necessary. Some patients had not wanted to trouble the nurses by asking for treatment and a few had asked for treatment but had not received it. Prophylaxis against PONV remains a controversial area despite many studies [21, 22]. Some small studies may be misleading because of their lack of power. Meta-analyses may also be unreliable because of publication bias and non-uniform data collection [22±24]. There is a need for q 2001 Blackwell Science Ltd


large randomised multicentre trials with proper risk stratification of patients. However, such trials are difficult and costly, and many trials would be needed to investigate different surgical procedures, patient groups and antiemetic regimens. In the absence of large trials, relatively small studies that include questioning of patients as an outcome measure are simple and convenient, and may be used to guide current practice. We found that the use of an ondansetron infusion following a bolus dose at induction of anaesthesia is a useful component of prophylaxis against PONV. It would now be appropriate to study the effect of ondansetron infusions in combination with other anti-emetics, such as droperidol or cyclizine. Acknowledgments

We would like to thank Ms Jo Henbury and her staff in the Pharmacy Department, Sister Maria Turewicz and her staff in the recovery room and the sisters and staff of Laverstock Ward for their help in running this study. We also thank Glaxo Ltd for the supply of ondansetron. References 1 Semple P, Madej TH, Wheatley RG, Jackson IJ, Stevens J. Transdermal hyoscine with patient controlled analgesia. Anaesthesia 1992; 47: 399±401. 2 Tramer MR, Walder B. Efficacy and adverse effects of prophylactic anti-emetics during patient-controlled analgesia therapy: a quantitative systematic review. Anesthesia and Analgesia 1999; 88: 1354±61. 3 Robinson SL, Fell D. Nausea and vomiting with use of a patient-controlled analgesia system. Anaesthesia 1991; 46: 580±2. 4 Woodhouse A, Mather LE. Nausea and vomiting in the postoperative patient-controlled analgesia environment. Anaesthesia 1997; 52: 770±5. 5 Dresner M, Dean S, Lumb A, Bellamy M. High dose ondansetron regimen vs droperidol for morphine patient controlled analgesia. British Journal of Anaesthesia 1998; 81: 384±6. 6 Roberts CJ, Millar JM, Goat VA. The anti-emetic effectiveness of droperidol during morphine patient-controlled analgesia. Anaesthesia 1995; 50: 559±62. 7 Walder AD, Aitkenhead AR. Anti-emetic efficacy of metoclopramide when included in a patient-controlled analgesia infusion. Anaesthesia 1994; 49: 804±6. 8 Alexander R, Lovell AT, Seingry D, Jones RM. Comparison of ondansetron and droperidol in reducing post-operative nausea and vomiting associated with patient-controlled analgesia. Anaesthesia 1995; 50: 1086±8.


9 Viner CV, Selby PJ, Zulian GB, et al. Ondansetron ± a new and safe anti-emetic in patients receiving high dose melphelan. Cancer, Chemotherapy and Pharmacology 1990; 25: 449±53. 10 Bosi A, Guidi S, Messori A, et al. Ondansetron versus chlorpromazine for preventing emesis in bone marrow transplant recipients: a double blind randomised study. Journal of Chemotherapy 1993; 5: 191±6. 11 Sadhasivam S, Saxena A, Kathirvel S, Kannan TR, Trikha A, Mohan V. The safety and efficacy of prophylactic ondansetron in patients undergoing modified radical mastectomy. Anesthesia and Analgesia 1999; 89: 1340±5. 12 Oddby-Muhrbeck E, Jacobsson J, Andersson L, Askergren J. Post-operative nausea and vomiting: a comparison between intra-venous and inhalation anaesthesia in breast surgery. Acta Anaesthesiologica Scandanavica 1994; 38: 52±6. 13 Cambell MJ, Machin D. Medical Statistics: a Commonsense Approach. Chichester: Wiley, 1990. 14 Minitab Ltd. Minitab release 12. Coventry, UK: Minitab Ltd. 1999. 15 Cytel corporation. StatXact Version 3. Massachusetts, USA: Cytel corporation, 1991. 16 The Royal College of Surgeons of England and the College of Anaesthetists. Report of the Working Party on Pain after Surgery. London: HMSO, 1990. 17 Harris SN, Sevarino FB, Sinatra RS, Preble L, O'Connor TZ, Silverman DG. Nausea prophylaxis using transdermal scopolamine in the setting of patient-controlled analgesia. Obstetrics and Gynaecology 1991; 78: 673±7. 18 Helmy SA. Prophylactic anti-emetic efficacy of ondansetron in laparoscopic cholecystectomy under total intravenous anaesthesia. A randomised double blind comparison with droperidol, metoclopramide and placebo. Anaesthesia 1999; 54: 266±71. 19 Le Roy I, Mortelmans B, Vandeput D, Deloof T, Vandenbroucke G. Prophylactic anti-emetic therapy for PCA with morphine: a double blind placebo controlled comparison of two doses of ondansetron. Acta Anaesthesiologica Belgica 1995; 46: 105±6. 20 Davies PR, Warwick P, O'Connor M. Anti-emetic efficacy of ondansetron with patient controlled analgesia. Anaesthesia 1996; 51: 80±2. 21 White PF, Watcha MF. Post-operative nausea and vomiting: prophylaxis versus treatment. Anesthesia and Analgesia 1999; 89: 1337±9. 22 Fisher DM. The `big little problem' of post-operative nausea and vomiting: do we know the answer yet? Anesthesiology 1997; 87: 1271±3. 23 White PF, Watcha MF. Has the use of meta-analysis enhanced our understanding of therapies for post-operative nausea and vomiting? Anesthesia and Analgesia 1999; 88: 1200±2. 24 Chalmers TC. Problems induced by meta-analyses. Statistics in Medicine 1991; 10: 971±80.

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