Elsevier

Journal of Critical Care

Volume 35, October 2016, Pages 145-149
Journal of Critical Care

Sedation/Delirium
Ketamine for analgosedation in critically ill patients,☆☆,

https://doi.org/10.1016/j.jcrc.2016.05.016Get rights and content

Abstract

Purpose

The purpose of this narrative review is to provide practical and useful guidance for clinicians considering the use of intravenous ketamine for its analgosedative properties in adult, critically ill patients.

Methods

MEDLINE was searched from inception until January 2016. Articles related to the pharmacological properties of ketamine were retrieved. Information pertaining to pharmacology, pharmacokinetics, dosing regimens, adverse effects, and outcomes was obtained from relevant studies.

Results

Although the primary mechanism for ketamine's pharmacological effects is N-methyl-d-aspartate blockade, there are several potential mechanisms of action. It has a very large volume of distribution due to its lipophilicity, which can lead to drug accumulation with sustained infusions. Ketamine has several advantages compared with conventional sedatives such as preserving pharyngeal and laryngeal protective reflexes, lowering airway resistance, increasing lung compliance, and being less likely to produce respiratory depression. It causes sympathetic stimulation, which is also unlike other sedatives and analgesics. There are psychotomimetic effects, which are a concern in terms of delirium. Dosing and monitoring recommendations are provided.

Conclusions

Ketamine has a unique pharmacological profile compared with more traditional agents such as opioids, which makes it an appealing alternative agent for analgosedation in the intensive care unit setting.

Introduction

Ketamine was synthesized in 1962 and was first tested in a clinical trial in 1964 [1]. Although ketamine was initially used in clinical practice as a dissociative anesthetic agent, it soon became used to provide analgesia for a wide variety of painful conditions. The large number of studies involving ketamine for pain control has led to several systematic reviews of its use in noncritically ill patients such as those with chronic pain after surgery, complex regional pain syndrome, phantom limb pain, and postoperative pain and as an adjuvant analgesic to opioids [2], [3], [4], [5], [6], [7]. Although opioids are the prototypical medications used for analgosedation, they have adverse effects that often limit their use in critically ill patients. This has led clinicians to seek alternative analgosedative therapies such as ketamine. Given the unique mechanism of action of ketamine with its analgesic and sedative properties in low doses and anesthetic properties in high doses, there are surprisingly few randomized studies evaluating its use in the intensive care unit (ICU) setting.

The lack of evidence pertaining to ketamine is illustrated by the paucity of discussion of ketamine for pain management in the most recent clinical practice guidelines concerning the management of pain, agitation, and delirium in adult patients in ICU settings. In the guidelines, ketamine is only briefly mentioned as a nonopioid option for nonneuropathic pain, citing the lack of comparative outcome studies with other agents [8]. To date, only 1 systematic review has evaluated the efficacy of sustained infusions of ketamine restricted to an ICU population [9]. As authors of this review, we found few trials comparing ketamine to nonketamine analgosedation regimens [9]. The definition of analgosedation in the systematic review was the preference for medications that relieve pain and discomfort before instituting therapy with sedative agents that do not have analgesic activity.

Despite the lack of high-level evidence supporting the use of ketamine for analgosedation in critically ill patients, it continues to be used in the ICU setting, raising questions about appropriate patient selection, dosing, and monitoring. In our previous systematic review, we identified the major trials pertaining to the sustained use of ketamine, but we were unable to provide a more in-depth discussion about the pharmacological and pharmacokinetic properties of ketamine [9]. This narrative review complements our previous article by providing this information as well as elaborating on the evidence. The final section provides recommendations for the dosing and monitoring of intravenous (IV) ketamine for analgosedation in the ICU setting with particular emphasis on its use for critically ill patients with severe pain. Much of the information in this article is presented in the form of tables instead of text to facilitate potential incorporation into local protocols or guidelines. Therefore, the purpose of this narrative review is to provide practical and useful guidance for clinicians considering the use of IV ketamine for its analgosedative properties in adult, critically ill patients.

We performed a detailed literature search as described in our previous systematic review, but briefly, MEDLINE was searched from inception until January 2016, and articles related to the pharmacological properties of ketamine were retrieved [9]. Information pertaining to pharmacology, pharmacokinetics, dosing regimens, adverse effects, and outcomes was obtained from relevant studies. Relevancy from an outcomes perspective was considered on the basis of ketamine use for analgosedation in critically ill patients. However, recently published reviews and clinical studies were used to compile the sections pertaining to pharmacology and adverse effects given the relative dearth of ketamine investigations performed in the ICU setting.

Section snippets

Pharmacokinetics and pharmacology

As with many other medications, there is substantial interpatient variability with regard to the volume of distribution and clearance parameters of ketamine (Table 1) [10], [11], [12]. Furthermore, the variability of these parameters is markedly increased in critically ill compared with noncritically ill subjects. Ketamine has a very large volume of distribution due to its lipophilicity. This raises concerns about accumulation of ketamine in lipophilic tissues with potential redistribution and

Potential adverse effects

The unique properties of ketamine, particularly with respect to its adverse effect profile, make it an appealing alternative compared with conventional analgesic options used for analgosedation. For example, ketamine does not appear to have the potential adverse effects of the nonsteroidal anti-inflammatory drugs (NSAIDS) on the gastrointestinal tract (bleeding) and kidneys (acute kidney injury). In contrast to opioids, ketamine does not have the negative effects of the opioids on the mu

Studies of ketamine in the ICU setting

There have been 6 randomized studies of at least 24 hours’ duration comparing ketamine to nonketamine alternatives (Supplementary Table 1) [30], [31], [32], [33], [34], [35]. With the exception of the 93 patients in the study by Guillou et al that demonstrated morphine-sparing effects of ketamine [31], there were no more than 30 evaluable patients in each of the remaining studies that focused on end points such as gastrointestinal function, or cerebrovascular or cardiovascular hemodynamic

Dosing and monitoring IV ketamine for analgosedation in critically ill patients

Table 2 provides recommendations for the dosing and monitoring of IV ketamine in critically ill patients with severe pain states unresponsive to conventional therapies, whereas Table 3 provides a list of the more common and problematic adverse effects of ketamine broken down by rate- and non–rate-related reactions. The dosing recommendations focus on patients with more severe pain states based on the assumption that more conventional pharmacological (eg, opioids, NSAIDS) and nonpharmacological

Summary

Ketamine is increasingly being used for analgosedation in critically ill patients because of its unique pharmacological profile compared with more traditional agents such as opioids that are used for analgosedation. Unfortunately, there is a lack of high-level evidence from studies performed in the ICU setting upon which to base decisions to use, dose, and monitor ketamine. This article summarizes the pharmacology and evidence for use of ketamine in the ICU. It also provides suggestions for

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    Conflicts of interest: no conflicts of interest for any of the authors.

    ☆☆

    Funding: No funding was obtained.

    Acknowledgments and credits: none.

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