Sedation/DeliriumKetamine for analgosedation in critically ill patients☆,☆☆,★
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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2020, Wilderness and Environmental MedicineCitation Excerpt :Previous studies reported that 0 to 76% of patients experience an emergence reaction with ketamine. The definition of these reactions varies between studies, but unpleasant emergence reactions seem to be uncommon.3,22,24,25 Hallucinations were frequently encountered in our study, and physicians mostly reported patients’ experiences of neuropsychiatric side effects to be positive.
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2020, Annals of Emergency MedicineCitation Excerpt :There is currently no evidence for or against subdissociative-dose ketamine for agitation in older adults. However, studies of subdissociative ketamine for pain in older adults found that it was effective but limited by adverse effects.67,68 More research is needed into the effects of low-dose ketamine in older adults before this medication can be recommended for routine use in the ED for agitation.
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Conflicts of interest: no conflicts of interest for any of the authors.
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Funding: No funding was obtained.
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Acknowledgments and credits: none.