sedation and pain relief - medIND

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INDIAN JOURNAL OF ANAESTHESIA, OCTOBER 2003 396

SEDATION AND PAIN RELIEF Dr. P. Kumar The stress response to critical illness can have many deleterious effects. Appropriate use of sedation and analgesia can attenuate the stress response, alleviate pain and anxiety, and improve compliance with care. Agitation responds best to anxiolytic drugs; pain is best relieved by analgesics. A combination of these drugs can act synergistically, because most analgesics provide some degree of sedation. In select cases, neuromuscular blocking agents are required, but they should not be used without concomitant sedation and analgesia. Use of agents needs to be tailored to the needs of individual patients; indications, anticipated length of need, and underlying organ system derangements are important considerations. Sedation Sedation is a general term that refers to the “calming of an ICU patient with the use of medications.” Due to a critical illness or injury, an ICU patient may experience unpleasant feelings, anxiety, agitation, fear or pain. In addition, some of the procedures and supportive care, such as mechanical ventilation, may make a patient feel uncomfortable. The ICU staff will attempt to comfort patients by speaking to them and by reassuring them. Often these efforts are not enough to comfort patients and sedation is required. There are many different medications used for sedation. The selection of a specific medication for a patient depends upon many factors that the doctor must consider. Once selected, the medication may be given to a patient orally, intravenously (IV) or intramuscularly (IM). Some medications are given only as needed and others are given continuously. This is a very common question. Many ICU patients receive sedation because they are agitated. Rarely, patients may have worsening agitation with certain medications used for sedation. This is called a paradoxical reaction to the medication in view of multiple organ dysfunction1. Stopping the medication or switching to a different medication usually helps. Sedation is used as long as the patient remains uncomfortable, agitated, anxious, fearful, 1. M.D, D.A., Sr. Prof. and Head, Dept. of Anaesthisiology M.P.Shah Medical College, Jamnagar- 361008 Correspond to : E-mail : [email protected]

or in pain. The ICU staff will regularly decrease the medication to see if the patient still needs it. Are there any potential complications associated with the use of sedation? Each specific medication used for sedation has its own set of side effects and complications. In general, the two most common complications of the sedative medications are depressed breathing and decreased blood pressure. The ICU staff will monitor a patient’s breathing and blood pressure during sedation. Many sedative medications cause temporary amnesia and the patient may not clearly remember the events during the period of sedation. If sedation is needed for a long period of time, the patient’s body may get use to it. The sedation will need to be decreased slowly in these patients to avoid withdrawal symptoms. Patients may have subsequent hallucinations, delusions, depression, post traumatic disorders and cognitive problems. The Joint Commission on Accreditation of Health Care Organizations (Chicago, Jan 1,2001)2 has defined four levels of sedation: minimal, moderate, deep and general anesthesia (Table 1). Sedated patients should be drowsy but arousable and able to follow commands. In certain patients, especially those who are asynchronous with controlled modes of mechanical ventilation (“fighting the ventilator”) or in whom decreased oxygen consumption is desired, a deeper level of sedation is required. In general, sedation should be accompanied by analgesia because analgesics Table - 1 : Levels of sedation. Minimal sedation (anxiolysis) Patient responds normally to verbal commands. Cognitive function may be impaired, but ventilatory and cardiovascular functions are unaffected. Moderate sedation or analgesia (conscious sedation) Patient responds purposefully to verbal commands with or without light tactile stimulation. Spontaneous ventilation is adequate, and cardiovascular function is maintained. Deep sedation or analgesia Patient is not easily aroused but responds purposefully to painful stimulation. Patient may not be able to maintain a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function usually is maintained. Anaesthesia Consists of general anesthesia and spinal or major regional anesthesia. It does not include local anesthesia. Patients are not arousable, even by painful stimulation. The patient often requires assistance in maintaining a patent airway and positive pressure ventilation. Cardiovascular function may be impaired.

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potentiate the effect of sedatives, resulting in lower sedative dose requirements Sedation needs vary over the course of a patient’s stay in an intensive care unit (ICU). In the acute phase, a profound stress response may require deeper sedation and higher doses of analgesics. When a plateau is reached, sedative and analgesic requirements may decrease, but delirium may emerge. In the recovery phase, sedation and analgesia are tapered and discontinued. In 1995, a Society of Critical Care Medicine (SCCM) task force3 recommended midazolam hydrochloride and propofol for short-term sedation, lorazepam for longerterm sedation, and haloperidol for delirium. Most ICUs do not follow these recommendations, and sedative and analgesic regimens vary widely. Lack of a standardized approach to sedation and analgesia can lead to polypharmacy, overmedication or undermedication, and increased cost.4 Several scales have been used to assess the adequacy of sedation in ICUs. The simple-to-use Ramsay scale (Table 2) is the most common graded scale; the desired score depends on the indication for sedation. With additive (multiple-category) scales, the level of sedation is ranked by the sum of scores in several categories. The increased numbers of categories with additive scales improve validity but make this type of scale too cumbersome for routine use. Observational sedation scales are useless in patients receiving neuromuscular blocking agents. Blood pressure and heart rate are objective indicators but may be affected by underlying illness and drugs. Crippen5 pioneered the use of continuous neurologic monitoring with processed electroencephalography, particularly during neuromuscular blockade. Bispectral processed electroencephalographic monitoring has been correlated with observational sedation scales and is especially useful in deeply sedated or paralyzed patients.6 Table - 2 : Modified Ramsay scale for rating sedation. Indication

Score

Anxious, agitated, restless

1

Awake, cooperative, oriented, tranquil

2

Semiasleep but responds to commands

3

Asleep but responds briskly to glabellar tap or loud auditory stimulus

4

Asleep with sluggish or decreased response to glabellar tap or loud auditory stimulus

5

No response can be elicited

6

Adapted from Ramsay MA, Savege TM, Simpson BR, et al. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2(920): 656-9.

Benzodiazepines The benzodiazepines, which have anxiolytic and amnestic properties and anticonvulsant effects, are commonly used for sedation in ICUs. They undergo hepatic metabolism, some to active metabolites that may accumulate in the presence of renal and hepatic insufficiency. The most reliable and effective route of administration is intravenous, because the absorption of oral and intramuscular doses may vary. Benzodiazepines may be given intravenously by either intermittent bolus dosing or continuous infusion. Disadvantages of intermittent boluses include the need for high nursing input and the risk of underdosage or overdosage. With continuous infusions, bolus doses are given to obtain the desired level of sedation, and infusion is used to maintain that level. The continuing need for infusion as well as the dose should be reassessed daily; the infusion rate is decreased when sedative requirements are stable over a 24 hour period.7 Daily interruption of infusions, when feasible, may decrease the duration of mechanical ventilation and the length of ICU stay.8 Tolerance occurs with prolonged administration, and withdrawal syndrome may accompany rapid discontinuation of the drug. Three benzodiazepines diazepam, lorazepam, and midazolam are available for parenteral use (Table 3). Onset and duration of action are determined by lipid solubility. Respiratory depression and hypotension are dose-dependent. Hypotension occurs primarily in hypovolemic patients and is potentiated by the concomitant use of opioids. Table - 3 : Comparison of parenteral benzodiazepines Drug

Onset (min)

Half-life (hr)

Equivalent dose (mgkg-1 IV)

Average bolusdose (mg IV)

Comments

Diazepam

3-5

20-66

0.3-0.5

2-20

Not recommended for continuous infusion

Lorazepam

10-20

10-20

0.05

1-4

Drug of choice in hepatic failure; may accumulate in renal failure

Midazolam

72 hours) requires frequent monitoring of triglyceride levels to avoid pancreatitis. This risk may be reduced by using the 2% rather than the 1% formulation10. Microbial contamination of the lipid emulsion is a significant risk, and the infusion setup must be changed every 12 hours.

Lorazepam Lorazepam, a highly lipophilic benzodiazepine, is a more potent amnestic than diazepam. Lorazepam is metabolized by the liver to inactive metabolites. The halflife of lorazepam is prolonged in the setting of renal failure. Nevertheless, lorazepam is the benzodiazepine of choice in liver failure. Lorazepam is the preferred benzodiazepine for long-term sedation (>48 hours).3 It is water-insoluble and is dissolved in a propylene glycol carrier. Propylene glycol toxicity is possible with high-dose infusions.

Haloperidol Haloperidol is a butyrophenone derivative with a half-life of 14 hours. It is used for the treatment of delirium (not associated with alcohol withdrawal) in ICUs. Although not approved by the US Food and Drug Administration for intravenous administration, it has been shown in many studies to be safe when administered by this route.

Benzodiazepine reversal Flumazenil is a competitive antagonist of benzodiazepine effects. It is administered intravenously at a dose of 0.2 mg and increased to a maximum of 1 mg, which may be repeated at 20-minute intervals to a maximum dose of 3 mghr-1. Its duration of antagonism is short. With longer-acting benzodiazepines, resedation may result. Caution is needed with long-term benzodiazepine use, because withdrawal seizures may occur. Other sedatives Barbiturates and ketamine hydrochloride are no longer commonly used for sedation in ICUs. Etomidate, a short-acting sedative used for rapid-sequence intubation, can produce adrenocortical suppression after a single dose, making it inappropriate for use in critically ill patients.9 Propofol Propofol has a rapid onset of action and short halflife. Propofol has amnestic effects, but not to the degree of benzodiazepines. It is metabolized at least partially by the liver to inactive metabolites and excreted by the kidneys; however, the presence of renal or hepatic dysfunction does not significantly affect clearance. Propofol can accumulate in peripheral tissues, prolonging sedative effects. Tolerance to the drug has been reported after more than 7 days of use but may occur sooner.

With propofol the time to extubation is shorter once the drug is discontinued, but the degree of hypotension and cost are higher than with midazolam.

Hypotension may occur in hypovolemic patients. QT-interval prolongation, torsades de pointes, and neuroleptic malignant syndrome are infrequent but lifethreatening adverse effects. The recommended dose for intermittent intravenous administration is 1 to 10 mg every 4 to 12 hours. Analgesia Patients in ICUs may experience pain related to underlying illness or injury, medical procedures, and therapies, causing anxiety and discomfort, interference with sleep, prevention of early mobilization, and augmentation of the stress response. In patients with multiple organ system derangements, treatment of pain may compromise other system functions (causing, for example, respiratory depression or hypotension), and agents must be chosen with this in mind. Opioid analgesics are the drugs of choice for pain relief in the critically ill. Opioid analgesics are metabolized primarily by the liver and excreted in the urine. Tolerance may develop with prolonged administration. Routes of administration vary, but narcotic analgesics are most commonly given intravenously, by either intermittent bolus or continuous infusion. The intravenous route is preferred in ICU patients because absorption may vary with other routes. In alert patients, continuous patientcontrolled analgesia can be accomplished by intravenous or epidural administration. Patient-controlled analgesia allows adjustment of narcotic medication within preset


limits, decreases nursing burden, and reduces patient anxiety over inadequate or untimely delivery of analgesics. The intrathecal or epidural route can be used for administration of narcotics or local anesthetics. This mode is most effective in postoperative patients; it should be avoided in critically ill patients who are immunocompromised or who have coagulopathy, because epidural hematoma or abscess may result. Anesthetics can cause early respiratory depression, and narcotics can cause late respiratory depression. The use of intermittent intravenous boluses requires constant vigilance and a constant level of analgesia is difficult to achieve. It is important that continuous infusion be preceded by bolus dosing to achieve the desired level of analgesia; a constant level can then be maintained with continuous infusion. Monitoring of analgesia in the critically ill is difficult. Reliable, objective measures of pain are unavailable, and underlying disease or medications may alter blood pressure and heart rate, which are commonly used indicators in noncommunicative patients. The visual analogue scale is a useful tool for assessing pain in patients who are awake and communicative, which is often not the case in ICUs. Side effects The major dose limiting side effect of opioid analgesics is respiratory depression. Some narcotics, especially morphine and meperidine hydrochloride, may cause histamine release, resulting in pruritus, hypotension, and smooth muscle contraction. Opioids blunt the cough reflex and the sensation of dyspnea, an effect that can be advantageous, especially in mechanically ventilated patients. All narcotics, particularly the phenyl piperidines, can cause muscle rigidity, which may interfere with respiration. Hypotension generally occurs only in hypovolemic patients or in patients receiving very large intravenous doses. Narcotics reduce gastrointestinal motility and may cause nausea, vomiting, or ileus. Smooth muscle contraction may result in contraction of the bladder sphincter and urinary retention. Systemic side effects are minimized with epidural or intrathecal administration. Common side effects associated with these delivery modes include pruritus, nausea and vomiting, respiratory depression, and urinary retention (which occurs in up to 80% of patients). Morphine and meperidine Morphine is the narcotic analgesic of choice in ICUs. It has a rather slow onset owing to its lipid solubility. A

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potent metabolite, morphine-6-glucuronide, can accumulate in the setting of renal failure and cause prolonged sedation. The active metabolite of meperidine, normeperidine, can accumulate and cause tremor, pupillary dilatation, and seizures. Doses should be reduced in patients with renal insufficiency. Phenyl piperidines The phenyl piperidines, which are mu-receptor agonists, include fentanyl alfentanil hydrochloride, remifentanil and sufentanil citrate. Phenyl piperidines are more potent than morphine and have a faster onset of action. Fentanyl is the opioid analgesic of choice in patients with hemodynamic instability.3 Despite the drug’s short halflife, redistribution into peripheral tissues occurs and can cause prolonged effects. Fentanyl has an active metabolite that may accumulate in renal failure. Alfentanil has no active metabolite, making it the drug of choice in renal failure. All phenyl piperidines are considerably more expensive than morphine. Butorphanol (Butrum) can provide an effective sedation as well as a pain relief when used intravenously in patients with prolong stay. Narcotic reversal Naloxone hydrochloride (Narcan), an opioid-receptor antagonist, reverses most of the effects of narcotics. Intravenous doses of 0.4 to 2.0 mg are used. Smaller doses can reverse respiratory depression without affecting analgesia. Depending on the half-life of the analgesic used, naloxone may require additional dosing. Non narcotic agents Nonsteroidal anti-inflammatory drugs (NSAIDs) are mild analgesics that inhibit prostaglandin synthesis. Prostaglandins appear to be involved in the smooth muscle contraction seen in renal and biliary colic, conditions in which these agents are particularly effective. In addition to having anti-inflammatory activity, NSAIDs are antipyretic and inhibit platelet aggregation; they do not cause the sedation, respiratory depression, and hypotension that are common with opioid analgesics. Major side effects are platelet dysfunction, renal dysfunction, and gastrointestinal ulceration or irritation. NSAIDs are limited by the lack of intravenous formulations; however, ketorolac tromethamine may be administered intramuscularly or intravenously. In some patients, regionally injected local anesthetic blocks can reduce or eliminate the need for narcotic analgesics, control postoperative pain, attenuate the neurohumoral response to stress, and provide analgesia and anesthesia for invasive procedures.

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Neuromuscular blockade Appropriate sedation and analgesia methods are usually adequate to control agitation in patients in an ICU. However, neuromuscular blockade is necessary in certain situations11: •

Severe acute respiratory distress syndrome requiring inverse-ratio ventilation or permissive hypercapnia

•

Severe respiratory failure requiring improved chest wall compliance

•

Facilitation of independent lung ventilation

•

“Inappropriate” reflex hyperventilation (central nervous system disease)

•

Excessive shivering

•

Need for immobility (for magnetic resonance imaging, computed tomographic scanning, tracheostomy)

•

Tetanus or neuroleptic malignant syndrome

Neuromuscular blocking agents should be added only when sedation and analgesia have failed; they should never be used without concurrent sedation and analgesia. Neuromuscular blocking agents may be used to reduce oxygen consumption;12 control intracranial pressure; or facilitate endotracheal intubation, unconventional modes of mechanical ventilation, or procedures that require complete immobility. Vecuronium bromide, atracurium besylate and cisatracurium besylate are commonly used intermediateacting neuromuscular blocking agents. Vecuronium is effective in 3 to 5 minutes and has a duration of action of about 35 minutes. It has few cardiovascular side effects, except when combined with high-dose fentanyl or sufentanil infusion. Vecuronium may accumulate in the setting of renal or hepatic failure. Atracurium and cisatracurium are degraded by Hoffman elimination and ester hydrolysis and therefore do not exhibit half-life prolongation in patients with renal or hepatic failure. Laudanosine, a metabolite, may accumulate in renal failure and cause seizures; however, case reports suggest that clinical doses are unlikely to result in important central effects in humans.13 Cisatracurium is more potent than atracurium and does not cause the hypotension seen with high doses of that drug. Onset and duration of action are similar to those of vecuronium. Pancuronium bromide (Pavulon), a long-acting medication, is by far the least expensive neuromuscular blocking agent used for continuous infusion in ICUs. It has a vagolytic effect on the sinus node and blocks the

reuptake of norepinephrine. Tachycardia and hypertension are the major side effects. Resistance to paralytic effect may occur with prolonged use. Pipecuronium bromide (Arduan) and doxacurium chloride (Nuromax) are more potent and long-acting than pancuronium but are considerably more expensive. Monitoring of neuromuscular blocking agents When neuromuscular blocking agents are used, the degree of paralysis should be monitored with a peripheral nerve stimulator. The two most common sites for twitch monitoring are the ulnar nerve (adductor pollicis) and facial nerve (orbicularis oculi) Four electrical impulses are delivered over 2 seconds, a sequence known as train of four. In the absence of neuromuscular blockade, muscle contraction occurs with each stimulus (four twitches). The usual goal is to obtain one of four twitches, which corresponds to about 90% blockade. If no twitches occur, the “tetanus mode” may be used. A 5-second stimulation generates a sustained twitch, after which the train of four sequence is repeated. If no twitches occur, the patient is overparalyzed and the neuromuscular blocking agent is discontinued until two of four twitches return. If one or two twitches occur on post-tetanic train of four, the agent is held or decreased until one or two twitches return on simple train of four. References 1. Bion JE and Oh TE. Sedation in intensive care in Intensive care manual, 4 Ed. Oh T Editor. Oxford; Butter worthHeinemann. 1998; 673-678. 2. Adopted from Joint committee on Accreditation of health care org. Standards and intents of sedation and analgesia. Comprehensive Accreditation manual for hospitals: The official handbook. Chicago: The Joint commission, Jan1’ 2001. Update. 3. Shapiro BA, Warren J, Egol AB, et al. Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Society of Critical Care Medicine. Crit Care Med 1995; 23(9): 1596-600. 4. Dasta JF, Fuhrman TM, McCandles C. Patterns of prescribing and administering drugs for agitation and pain in patients in a surgical intensive care unit. Crit Care Med 1994; 22(6): 974-80. 5. Crippen DW. Using bedside EEGs to monitor sedation during neuromuscular blockade: a new way to gauge therapeutic effectiveness. J Crit Illness 1997; 12(8): 519-24. 6. Riker RR, Simmons LE, Prato BS, et al. Assessing sedation levels in mechanically ventilated ICU patients with the bispectral index and the sedation-agitation scale. (Abstr) Crit Care Med 1998; 26(1): A94.


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7. Blanchard AR, Love AA, Southwood RL, et al. Standardized, cost-effective sedation guidelines in a tertiary medical intensive care unit (MICU). (Abstr) Crit Care Med 1999; 27 (12 Suppl): A131. 8. Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342(20): 1471-7. 9. Moore RA, Allen MC, Wood PJ, et al. Perioperative endocrine effects of etomidate. Anaesthesia 1985; 40(2): 124-30. 10. McLeod G, Dick J, Wallis C, et al. Propofol 2% in critically ill patients: effect on lipids. Crit Care Med 1997; 25(12): 1976-81.

11. Blanchard AR. Sedation and analgesia in intensive care. Medications attenuate stress response in critical illness. Post Graduate Med. 2002; 111(2): 59-74. 12. Crone RK, Farnitol J. The effects of Pancuronium bromide on infants with hyaline membrane disease. J Paediatr. 1980; 97; 991. 13. Gwinnutt CL, Eddleston JM, Edwards D, et al. Concentrations of atracurium and laudanosine in cerebrospinal fluid and plasma in three intensive care patients. Br J Anaesth 1990; 65(6): 829-32.

ISANEWS ISA-AnnualConference-2005 The Indian Society of Anaesthesiologists, invites bids from state/city branches of ISA, interested to host the Annual Conference - 2005 in the proper format available with the Secretary. The bid should reach ISA office before 27th November 2003 and the decision will be reached during Annual Conference on 28th, December 2003 at Bhuvaneshwar. Secretary ISA (National)

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