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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Analgesia and sedation in critically ill patients

, M.D., Ph.D. and , M.D., Ph.D.

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Introduction

Analgesia and sedation in the intensive care unit (ICU) are important therapeutic modalities that are often handled as afterthoughts rather than integral parts of the overall care of the patient. Interviews of patients after discharge from the ICU have shown pain and anxiety to be among the most distressing recollections. Physiologically, modulating pain with the use of analgesics such as opioids is important, as recent work suggests that pain may influence immune function and coagulation, and may increase sympathetic outflow resulting in increased heart rate and myocardial oxygen demand (1). Sedation is indicated for the treatment of anxiety and agitation for similar reasons. Appropriate sedation is not only compassionate, but is vital to patient care as agitation may contribute to ventilator dyssynchrony, altered day/night cycle, and adverse events such as self-extubation. A recent study by Boulain et al. reported in a prospective observational study of 426 ventilated patients that unplanned extubations occurred in more than 10% of patients. At the moment of unplanned extubation, 61% of the patients were agitated. In this study, one death was attributed to unplanned extubation (2).

Having determined that analgesia and sedation are important components to management of the critically ill patient, what evidence is available to determine the best treatment options? Unfortunately, there are limited data from which to base treatment (3). The scientific study of pharmacologic agents requires a precise definition of the population of interest. Unfortunately, each critically ill patient is unique in terms of her or his baseline organ function, disease process, age, and volume of distribution. Therefore, it may well be inappropriate to extrapolate work done in other patient populations to the critically ill. As with many issues in critical care, one must have a firm understanding of pharmacologic and pharmacokinetic principles of sedative and analgesic medications in non-critically ill patients, integrate the available evidence obtained from critically ill patients, and apply this knowledge to individual clinical scenarios.

The evidence reviewed in this chapter was obtained from a MEDLINE search with the terms “critical care, intensive care, intensive care unit, and critical illness” combined with “analgesia, analgesics, pain, sedation, sedatives, and hypnotics”, and “randomized control trial, meta-analysis, controlled clinical trial, clinical trial, random, double and single blind, crossover, prospective studies”. The citations were limited to human studies in the English language. Reference lists of identified studies and relevant review articles were also searched. Pediatric studies were excluded as this population has different physiology and pharmacodynamics compared to adults and is beyond the scope of this chapter. In addition, studies of “fast-track” cardiac surgery patients were also excluded as these patients, while perhaps critically ill, are often postoperative patients with defined, unisystem disease that make poor comparisons for the “typical” critically ill patient. Furthermore, studies in postcardiac surgery patients may well be influenced by the intraoperative anesthetic management, making the data difficult to interpret.

Analgesia

Opioids are the cornerstone of analgesia in the critically ill. Other techniques such as regional and inhalational anesthesia are options, but opioids are effective and offer a wide therapeutic index in most patients. A review of opioid use for analgesia in critically ill patients is available regarding specific drug profiles and dosing strategies (3, 5, 6).

Morphine sulfate is the most frequently used opioid in the ICU. It is efficacious and affordable, but is associated with histamine release. For these reasons, a recent expert task force has recommended morphine sulfate as the preferred analgesic agent for critically ill patients (7). Fentanyl, a synthetic opioid roughly 100 times the potency of morphine, which does not cause histamine release, was recommended for analgesia in critically ill patients with hemodynamic instability, those manifesting symptoms of histamine release or with morphine allergy (7). To our knowledge, there are no prospective, randomized, control trials comparing morphine and fentanyl in critically ill patients. Based on the lack of evidence to support one agent over another and the pharmacology of currently available opioids, these recommendations are reasonable. Other opioids such as sufentanil, hydromorphone and meperidine offer no advantage and are more expensive. Meperidine deserves special mention as a drug to be avoided as it has an active metabolite that may accumulate in patients with impaired renal function and that may produce central nervous system excitation. In addition, meperidine has an atropine-like effect which often produces tachycardia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for routine use in critically ill patients as they offer no analgesic benefit over opioids and may alter platelet function and promote gastrointestinal bleeding and renal insufficiency.

Sedation

Sedation should be initiated only after excluding physiologic alterations that may present as anxiety or agitation. Sedation may be accomplished by a variety of agents including benzodiazepines and propofol. Opioids have some sedative properties, but their ability to provide deep sedation and amnesia are minimal. Sedative agents should be chosen based on the individual patient and clinical scenario, including anticipated duration of sedation. Duration of sedation is important as various agents may have different economic and side-effect profiles depending on duration of administration. The reader is referred to recent reviews of sedative agents in the critically ill for mechanisms of action and dosing strategies (3, 5, 6, 8).

Benzodiazepines

Benzodiazepines cause a dose-related depression of the central nervous system resulting in sedation and respiratory depression. The first widely used benzodiazepine in the ICU, diazepam, is currently not recommended because of pain and thrombophlebitis associated with peripheral vein administration along with concerns of prolonged sedation related to its lipophilic nature, active metabolites and long duration of action compared to other benzodiazepines.

Midazolam is a short-acting benzodiazepine whose duration of clinical effect is due to redistribution. Because of its short duration of action, midazolam has been recommended as the agent of choice for short-term (< 24 hours) sedation (7). However, during long-term sedation, midazolam has been associated with prolonged clinical effects felt to be secondary to an active metabolite and its lipophilic nature making it less desirable for long-term sedation.

Lorazepam, an intermediate-acting benzodiazepine that has no active metabolites and is less lipophilic than diazepam and midazolam, thereby decreasing the likelihood of peripheral accumulation, has been recommended for prolonged sedation in critically ill patients (7). The hemodynamic responses and quality of sedation have been shown to be similar between midazolam and lorazepam. One study reported faster (not significant but the study was under-powered) return to baseline mental status with lorazepam in patients requiring long-term (mean > 3 days) sedation.

Propofol

Propofol is a parenteral anesthetic agent that possesses anxiolytic, sedative and amnestic properties at sub-anesthetic doses. Its duration of action is brief (10–15 minutes) due to redistribution and is recommended that it be administered by continuous infusion. Propofol is prepared in a lipid emulsion; bacterial contamination and elevated triglycerides and pancreatic enzymes are complications of chronic administration. Because of these concerns, as well as drug costs, propofol has been recommended only for short-term sedation (7). It should be noted that propofol sedation in critically ill children has been associated with acidosis and arrhythmias and its use in this population is discouraged.

Several studies have compared propofol with benzodiazepines in critically ill patients. The premise behind many of these studies was to determine if a drug with a higher initial cost to administer (propofol) might actually save money in caring for patients if it could lower overall costs (by decreasing time to extubation and ICU length of stay in intubated patients). Prospective, randomized studies to date have only compared propofol to midazolam. All but two of these reports have studied patients with > 24 hour sedation. As there are data to suggest prolonged effects of midazolam with long-term administration, the appropriate comparison may be propofol with lorazepam in this group of patients. Available data show more hypotension and lower heart rate with propofol compared to midazolam administration with the greatest changes occurring with initiation of therapy. Recovery of mental status and time to extubation has been reported as not different from, or favoring propofol when compared to, midazolam. One study showed that despite higher cost to administer, propofol sedation was associated with economic benefit in patients sedated < 24 hours because it shortened time to extubation and associated critical care costs. There was no difference in total ICU costs in those patients sedated > 24 hours.

Other sedating agents

Haloperidol is a butyrophenone neuroleptic drug that is the preferred treatment of delirium, defined here as the inappropriate response to external stimuli. Opioids and benzodiazepines may worsen delirium by further altering the patient's perception. Haloperidol has minimal side effects on the cardiopulmonary system, but may be associated with prolongation of the QT interval. It has minimal amnestic or analgesic actions.

Etomidate is an intravenous anesthetic agent with minimal cardiopulmonary depressant effects. It reversibly inhibits adrenal steroid synthesis, and prolonged use has been associated with worsened outcomes in critically ill patients (6). Its use for prolonged sedation is contraindicated.

Ketamine is an intravenous analgesic and anesthetic agent that has sympathomimetic properties and is associated with hallucinations and dysphoria. Its routine use in the critically ill is discouraged.

Barbiturates such as thiopental ere effective sedating agents, but they provide little amnestic or analgesic actions. Rapid induction of hepatic enzymes and tolerance as well as significant hemodynamic alterations including tachycardia and hypotension limit their use as sedating agents in the critically ill.

Summary

There are a paucity of data from which to provide evidence-based recommendations for optimal management of analgesia and sedation in the critically ill patient. There is no evidence that one opioid is better than another for management of pain. The choice of benzodiazepine for sedation should incorporate anticipated duration of sedation. Propofol may be associated with more rapid emergence from sedation after discontinuation compared to benzodiazepines, but appropriate studies have not been performed. While drug cost may be an important determinant of cost-effective management of analgesia and sedation in critically ill patients, consideration of pharmacokinetics and pharmacodynamics may be of greater importance in selecting the most cost-effective regimen. Knowledge of drug profile, the clinical scenario, and continuous clinical monitoring are essential to appropriate and cost-effective management of sedation and analgesia in the critically ill patient.

References

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Lewis K S. et al. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm. (1994);51:1539–1554. [PubMed: 8092155]
2.
Boulain T. et al. Unplanned extubations in the adult intensive care unit. Am J Respir Crit Care Med. (1998);157:1131–1137. [PubMed: 9563730]
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Burrows R C. et al. Sedation and analgesia in the ICU - what evidence-based medicine is there? South African Med J. (1997);87:982. [PubMed: 9323402]
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Murray M J, De Ruyter M L, Harrison B A. Opioids and benzodiazepines. Crit Care Clin. (1995);11:849–873. [PubMed: 8535982]
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Wagner B K J, O'Hara D A. Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet. (1997);33:426–453. [PubMed: 9435992]
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Barr J, Donner A. Optimal intravenous dosing strategies for sedatives and analgesics in the intensive care unit. Crit Care Clin. (1995);11:827–847. [PubMed: 8535981]
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Shapiro B A. et al. Practice parameters for systemic intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Crit Care Med. (1995);23:1596–1600. [PubMed: 7664563]
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Lund N, Papadakos P J. Barbiturates, neuroleptics, and propofol for sedation. Crit Care Clin. (1995);11:875–886. [PubMed: 8535983]
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Ledingham I M, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet. (1983);1:1270. [PubMed: 6134053]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6870

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