Ketamine for Analgosedation in Critically Ill Patients

Brian L. Erstad PharmD, Asad E. Patanwala PharmD

PII: S0883-9441(16)30088-0
DOI: doi: 10.1016/j.jcrc.2016.05.016
Reference: YJCRC 52170

To appear in: Journal of Critical Care

Please cite this article as: Erstad Brian L., Patanwala Asad E., Ketamine for
Analgosedation in Critically Ill Patients, Journal of Critical Care (2016), doi:
10.1016/j.jcrc.2016.05.016

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
 ACCEPTED MANUSCRIPT
1

Title: Ketamine for Analgosedation in Critically Ill Patients

Running Title: Ketamine for Analgosedation

Authors:

T
Brian L. Erstad, PharmD, MCCMa

P
Asad E. Patanwala, PharmDa

RI
SC
a
Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, 1295

NU
N Martin Ave, PO Box 210202, Tucson, Arizona, USA

Conflicts of Interest: No conflicts of interest for any of the authors

MA
Funding: No funding was obtained

Acknowledgements and credits: None

ED

Words Count: 2152

PT

Corresponding Author and Reprint Requests (none will be requested):

Asad E. Patanwala, PharmD

CE

Address: 1295 N. Martin, PO Box 210202, Tucson, Arizona, 85721, US

AC

Fax: 520-626-7355

Phone: 520-626-5400

Email: patanwala@pharmacy.arizona.edu
 ACCEPTED MANUSCRIPT
2

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,

T
critically ill patients.

P
RI
Methods: MEDLINE was searched from inception until January 2016. Articles related to the

pharmacological properties of ketamine were retrieved. Information pertaining to pharmacology,

SC
pharmacokinetics, dosing regimens, adverse effects, and outcomes were obtained from relevant

NU
studies.

Results: Although the primary mechanism for ketamine’s pharmacological effects is N-methyl-
MA
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
ED

sustained infusions. Ketamine has several advantages compared to conventional sedatives such
PT

as preserving pharyngeal and laryngeal protective reflexes, lowers airway resistance, increases

lung compliance, and is less likely to produce respiratory depression. It causes sympathetic
CE

stimulation, which is also unlike other sedatives and analgesics. There are psychotomimetic
AC

effects, which is a concern in terms of delirium. Dosing and monitoring recommendations are

provided.

Conclusions: Ketamine has a unique pharmacological profile compared to more traditional

agents such as opioids, which makes it an appealing alternative agent for analgosedation in the

intensive care unit setting.

Key terms (MeSH): ketamine; critical care; critical illness; hypnotics and sedatives; analgesics;

pain
 ACCEPTED MANUSCRIPT
3

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

T
soon became used to provide analgesia for a wide variety of painful conditions. The large

P
number of studies involving ketamine for pain control have led to several systematic reviews of

RI
its use in non-critically ill patients such as those with chronic pain after surgery, complex

SC
regional pain syndrome, phantom limb pain, postoperative pain and as an adjuvant analgesic to

NU
opioids.2-7 While 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
MA
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
ED

doses, there are surprisingly few randomized studies evaluating its use in the (intensive care unit)
PT

ICU setting.

The lack of evidence pertaining to ketamine is illustrated by the paucity of discussion of

CE

ketamine for pain management in the most recent clinical practice guidelines concerning the
AC

management of pain, agitation, and delirium in adult patients in ICU settings. In the guidelines,

ketamine is only briefly mentioned as a non-opioid option for non-neuropathic pain citing the

lack of comparative outcome studies with other agents.8 To date, only one 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 non-ketamine analgosedation

regimens.9 The definition of analgosedation in the systematic review was the preference for

medications that relieve pain and discomfort prior to instituting therapy with sedative agents that

do not have analgesic activity.

 ACCEPTED MANUSCRIPT
4

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

T
identified the major trials pertaining to the sustained use of ketamine, but we were unable to

P
RI
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,

SC
as well as elaborating on the evidence. The final section provides recommendations for the

NU
dosing and monitoring of 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
MA
paper 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
ED

practical and useful guidance for clinicians considering the use of IV ketamine for its
PT

analgosedative properties in adult, critically ill patients.

We performed a detailed literature search as described in our previous systematic review,

CE

but briefly, MEDLINE was searched from inception until January 2016 and articles related to the
AC

pharmacological properties of ketamine were retrieved.9 Information pertaining to

pharmacology, pharmacokinetics, dosing regimens, adverse effects, and outcomes were 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.
 ACCEPTED MANUSCRIPT
5

Pharmacokinetics and Pharmacology

As with many other medications, there is substantial inter-patient variability with regard

to the volume of distribution and clearance parameters of ketamine (Table 1).10-12 Further, the

T
variability of these parameters is markedly increased in critically ill compared to non-critically ill

P
RI
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

SC
prolonged clinical effects with sustained dosing, particularly in patients with more severe forms

NU
of obesity. Less than 50% of ketamine in human plasma is bound to either albumin or alpha-1-

acid glycoprotein, so clinically important protein binding displacement interactions are

MA
unlikely.13 Ketamine is available in the US as a racemic mixture, whereas the S-enantiomer that

is a more potent analgesic than either the racemic mixture or the R-enantiomer is available as an
ED

injectable product in other countries. Ketamine is metabolized by the P450 system primarily to
PT

norketamine, an active metabolite with approximately one-third the potency of the parent

compound, but the specific microsomal enzymes, sites of metabolism, and potential drug-
CE

enzyme and drug-drug interactions have yet to be fully elucidated.

AC

Although the primary mechanism for ketamine’s pharmacological effects is N-methyl-D-

aspartate (NMDA) blockade, other potential mechanisms of action depending on factors such as

drug dose and concentration include opioid receptor blockade, gamma aminobutyric acid

inhibition, and central nervous system (CNS) and peripheral autonomic neurotransmitter

alterations (Figure 1).14, 15 While concentration-related analgesic and anesthetic actions have

been documented, the capability of therapeutic drug monitoring is unlikely to be available

outside of research settings.

 ACCEPTED MANUSCRIPT
6

Potential Adverse Effects

The unique properties of ketamine, particularly with respect to its adverse effect profile,

make it an appealing alternative compared to conventional analgesic options used for

T
analgosedation. For example, ketamine does not appear to have the potential adverse effects of

P
RI
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

SC
of the opioids on the mu receptors of the gastrointestinal tract associated with ileus.

NU
Furthermore, ketamine preserves pharyngeal and laryngeal protective reflexes, lowers airway

resistance, increases lung compliance, and is less likely to produce respiratory depression
MA
(assuming large doses are not rapidly administered). The beneficial actions of ketamine on

pulmonary mechanics have led to research on its use as an alternative to standard therapies for
ED

more severe forms of asthma such as mechanically ventilated patients with status asthmaticus.16
PT

By increasing pulmonary airway pressures, there is a theoretical concern that ketamine could

aggravate pulmonary hypertension, so it should be used cautiously in patients with this

CE

condition. In summary, in contrast to other analgesic agents such as opioids, ketamine is

AC

unlikely to produce serious adverse effects on gastrointestinal or pulmonary function in the

majority of critically ill patients, which makes it an appealing alternative to conventional

therapies.

With respect to the CNS, ketamine has both excitation and depression properties

compared to the more general CNS depressive properties of opioids. In the early years of its use

this led to concerns that ketamine might have proconvulsant as well as anticonvulsant activity

and there were case reports in subjects of what appeared to be epileptic seizures.17 However,

follow-up investigations that included subjects with documented histories of focal or generalized
 ACCEPTED MANUSCRIPT
7

seizures failed to confirm this seizure concern and noted that ketamine suppressed or eliminated

electroencephalogram (EEG) discharges in patients having seizures suggesting a predominant

anticonvulsant effect.18, 19 A variety of explanations were offered for seizure-like activity noted

T
in the early case reports including inadequate monitoring, inappropriate conclusions about EEG

P
RI
recordings and CNS excitation, concomitant trigger events, and misinterpretation of skeletal

muscle tonic-clonic activity sometimes seen with ketamine as seizures. More recently the focus

SC
has been on the use of ketamine for treatment of refractory status epilepticus,20 although it is still

NU
relegated as more of a last-line medication in published guidelines due to the lack of high-level

evidence supporting this purported indication.21 Taken as a whole, the available evidence
MA
suggests that ketamine need not be avoided in patients at risk for seizures (e.g. traumatic brain

injury), particularly when used for analgosedation for short periods in the ICU setting.
ED

Ketamine has well known psychotomimetic effects that have been well elucidated in
PT

settings such as the emergency department when used for procedural sedation. Up to 30% of

adults may have ‘emergence reactions’ that manifest as hallucinations and psychosis; occurring
CE

during recovery.22 There is no clear relationship between ketamine dose and psychotomimetic
AC

effects, although gradual dose titration was shown in one retrospective study to decrease

psychotomimetic adverse events in patients with cancer.23 Lower doses (< 1 mg/kg by slow

infusion) and plasma concentrations (< 100 ng/mL) have been associated with schizophrenia-like

and dissociative symptoms in healthy volunteers.24, 25 In the critically ill, this is concerning

because these properties may predispose patients to delirium, which is associated with poor

outcomes.26 For example, in a recent systematic review of critically ill patients with or without

delirium, patients with delirium were more likely to die (risk ratio 2.19, 95% CI 1.78 to 2.70,

p<0.001) and had longer durations of ICU and hospital lengths of stay (standard mean difference
 ACCEPTED MANUSCRIPT
8

1.38, 95% CI 0.99 to 1.77, p<0.001 and standard mean difference 0.97, 95% CI 0.61 to 1.33,

p<0.001, respectively).27 Anecdotally, benzodiazepines have been shown to blunt this reaction,

which themselves are often avoided in the critically ill because of their association with

T
delirium.22 In addition, benzodiazepines interact with ketamine via the P450 pathway, extending

P
RI
the duration of effect of ketamine. This could result in drug accumulation and prolonged

recovery. In general, it is best to avoid ketamine administration in patients with a history of

SC
psychosis or other conditions such as drug withdrawal (e.g. alcohol, amphetamines) that may

NU
cause or mimic psychotic reactions. When ketamine is employed for analgosedation, we suggest

gradual dose titration with careful monitoring for psychotomimetic effects.

MA
The effect of ketamine on the cardiovascular system is particularly noteworthy because it

differs greatly in this regard to other commonly used sedatives (e.g. propofol, midazolam).
ED

Ketamine is sympathomimetic and facilitates adrenergic transmission, which in animal and

PT

isolated heart muscle studies offsets its direct myocardial depressant actions. It also increases

the systemic catecholamine concentrations by inhibiting reuptake. This is expected to result in

CE

an increased heart rate and blood pressure, which is opposite of other sedatives. This can be
AC

advantageous in patients with hypotension who require analgosedation. Even though this effect

is seen in healthy adults, it is uncertain if this would occur in patients with prolonged critical

illness who are catecholamine depleted. For instance, in one study a subset of critically ill

patients had reduced blood pressure and cardiovascular performance with ketamine.28 Although

concerns have been raised about potential detrimental increases in intracranial pressure

associated with ketamine, a recent systematic review found no evidence of increased intracranial

pressure or associated adverse neurologic outcomes associated with ketamine administration in

critically ill patients.29 Although ketamine appears to be safe in titrated doses for analgosedation
 ACCEPTED MANUSCRIPT
9

in most critically ill patients with cardiovascular instability, it is best avoided in patients with a

history of ischemic cardiac disease, patients with cardiovascular conditions such as hypertensive

crisis or heart failure that may be aggravated by ischemic injury, and patients with structural

T
impediments to blood or cerebrospinal fluid flow such as hydrocephalus that may be aggravated

P
RI
by increases in pressure.

Studies of Ketamine in the ICU Setting

SC
There have been six randomized studies of at least 24 hours duration comparing ketamine

NU
to non-ketamine alternatives (Supplemental Digital Content - Table 2).30-35 With the exception of

the 93 patients in the study by Guillou et al. that demonstrated morphine-sparing effects of
MA
ketamine,31 there were no more than 30 evaluable patients in each of the remaining studies that

focused on endpoints such as gastrointestinal function, or cerebrovascular or cardiovascular

ED

hemodynamic indices. Taken as a whole with the caveat of the small sample sizes, the studies
PT

suggest no substantial adverse effects of ketamine on cerebrovascular indices even in patients

with severe head injuries. When small elevations (e.g. 1-2 mm Hg) in intracranial pressure were
CE

found, usually in association with large doses of ketamine, concomitant elevations in cerebral
AC

perfusion pressure typically occurred. The systemic hemodynamic changes associated with

ketamine administration are unlikely to be consequential in most patients, but have the potential

to be beneficial (e.g. reduced doses of vasopressors in patients with hypotension) or harmful (e.g.

aggravation of pre-existing heart failure or myocardial ischemia) depending on ketamine doses

and specific patient characteristics. Other data from non-randomized evaluations of ketamine in

critically ill patients are consistent with these conclusions, albeit with other potential adverse

effect considerations such as psychotomimetic disturbances.36-41 Of note, many of the important

advantages and disadvantages of ketamine administration use in the clinical setting, including its
 ACCEPTED MANUSCRIPT
10

ability to produce dissociative anesthesia (i.e. loss of sensation and contact with environment

while eyes remain open and protective laryngeal and ocular reflexes remain intact), had been

identified in the anesthesia literature by 1968.42

T
Dosing and Monitoring IV Ketamine for Analgosedation in Critically Ill Patients

P
RI
Table 3 provides recommendations for the dosing and monitoring of IV ketamine in

critically ill patients with severe pain states unresponsive to conventional therapies while Table 4

SC
provides a list of the more common and problematic adverse effects of ketamine broken down by

NU
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 (e.g. opioids,
MA
NSAIDS) and non-pharmacological options are preferred as first-line interventions for patients

with less severe pain. The justification for unresponsiveness to conventional regimens is based
ED

on clinician discretion, but is likely due to maximum doses of analgesics such as NSAIDS or
PT

clinically important adverse effects related to analgesics such as NSAIDS and opioids.

The dosing recommendations listed in Table 3 require some explanation. A wide variety
CE

of ketamine dosing regimens have been employed in published studies, particularly in older
AC

studies conducted at a time when mechanically ventilated patients received continuous sedation

often without interruption and often with doses capable of inducing anesthesia.43 Examples

include the studies of patients with traumatic brain injury where daily doses of ketamine were

sometimes in the hundreds of milligrams. The dosing recommendations provided in this paper

are of a more conservative nature in an attempt to avoid dose-related reactions such as

psychotomimetic episodes that could lead to complex differential diagnoses in critically ill

patients who are prone to delirium and other CNS disturbances. A prolonged infusion of

ketamine may lead to drug accumulation and a longer recovery process, similar to other
 ACCEPTED MANUSCRIPT
11

commonly used lipophilic analgesics and sedatives. Thus we recommend that the use of

sustained ketamine infusions should only be done while utilizing daily awakening trials. One

option is to use a one-time 4-hour infusion as described in Table 3. This has been used in a

T
variety of cancer and non-cancer pain states with pain relief sometimes lasting for several days.

P
RI
Bolus doses may be needed during acute agitation. We have listed a bolus dose range of 0.2 to

0.5 mg/kg, but recommend that clinicians should start on the lower end of the range because in

SC
one study in health volunteers, all patients became temporarily unconscious at the high end of the

NU
range.44 However, this may not be the case in patients in severe acute pain in the ICU. Also, a

loss of consciousness may be desirable in some situations in the critically ill. If sedation is
MA
required prior to a procedure than even higher doses such 1 mg/kg will likely be needed. Note

that some state nursing statutes preclude IV push injections of medications considered to be
ED

anesthetics such as ketamine. Some institutions have such restrictions based on dose used. Thus
PT

the decision to utilize bolus dosing of ketamine into analgosedation regimens needs to consider

the need for physician presence at the bedside and institution specific policies. Ketamine is
CE

compatible with morphine, fentanyl, or hydromorphone and investigators primarily in non-ICU

AC

settings have evaluated such combinations as continuous infusions or by patient-controlled

analgesia PCA.45, 46 We recommend avoiding fixed combinations because it reduces flexibility in

dosing. However, ketamine infusions can be Y-sited with these other opioids if required as part

of a multimodal regimen when IV access is limited in the critically ill.

Summary

Ketamine is increasingly being used for analgosedation in critically ill patients due to its

unique pharmacological profile compared to more traditional agents such as opioids that are used

for analgosedation. Unfortunately, there is a lack of high-level evidence from studies performed
 ACCEPTED MANUSCRIPT
12

in the ICU setting upon which to base decisions to utilize, dose and monitor ketamine. This

paper summarizes the pharmacology and evidence for use of ketamine in the ICU. It also

provides suggestions for dosing and monitoring IV ketamine when used for analgosedation in

T
critically ill patients.

P
RI
SC
NU
MA
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT
13

REFERENCES

[1] Dorandeu F: Happy 50th anniversary ketamine. CNS neuroscience & therapeutics
2013;19:369
[2] Alviar MJ, Hale T, Dungca M: Pharmacologic interventions for treating phantom limb pain.

T
The Cochrane database of systematic reviews 2011:CD006380
[3] Bell RF, Dahl JB, Moore RA, et al.: Perioperative ketamine for acute postoperative pain.

P
The Cochrane database of systematic reviews 2006:CD004603

RI
[4] Chaparro LE, Smith SA, Moore RA, et al.: Pharmacotherapy for the prevention of chronic
pain after surgery in adults. The Cochrane database of systematic reviews 2013;7:CD008307

SC
[5] Laskowski K, Stirling A, McKay WP, et al.: A systematic review of intravenous ketamine
for postoperative analgesia. Canadian journal of anaesthesia = Journal canadien d'anesthesie
2011;58:911-923
[6] O'Connell NE, Wand BM, McAuley J, et al.: Interventions for treating pain and disability in

NU
adults with complex regional pain syndrome. The Cochrane database of systematic reviews
2013;4:CD009416
[7] Subramaniam K, Subramaniam B, Steinbrook RA: Ketamine as adjuvant analgesic to
MA
opioids: a quantitative and qualitative systematic review. Anesthesia and analgesia 2004;99:482-
495, table of contents
[8] Barr J, Fraser GL, Puntillo K, et al.: Clinical practice guidelines for the management of pain,
agitation, and delirium in adult patients in the intensive care unit. Critical care medicine
ED

2013;41:263-306
[9] Patanwala AE, Martin JR, Erstad BL: Ketamine for Analgosedation in the Intensive Care
Unit: A Systematic Review. Journal of intensive care medicine 2015;
PT

[10] Clements JA, Nimmo WS: Pharmacokinetics and analgesic effect of ketamine in man.
British journal of anaesthesia 1981;53:27-30
[11] Clements JA, Nimmo WS, Grant IS: Bioavailability, pharmacokinetics, and analgesic
CE

activity of ketamine in humans. Journal of pharmaceutical sciences 1982;71:539-542

[12] Hijazi Y, Bodonian C, Bolon M, et al.: Pharmacokinetics and haemodynamics of ketamine
in intensive care patients with brain or spinal cord injury. British journal of anaesthesia
AC

2003;90:155-160
[13] Dayton PG, Stiller RL, Cook DR, et al.: The binding of ketamine to plasma proteins:
emphasis on human plasma. European journal of clinical pharmacology 1983;24:825-831
[14] Mion G, Villevieille T: Ketamine pharmacology: an update (pharmacodynamics and
molecular aspects, recent findings). CNS neuroscience & therapeutics 2013;19:370-380
[15] Sleigh J, Harvey M, Voss L, et al.: Ketamine – More mechanisms of action than just
NMDA blockade. Trends Anasth Crit Care 2014;4:76-81
[16] Heshmati F, Zeinali MB, Noroozinia H, et al.: Use of ketamine in severe status asthmaticus
in intensive care unit. Iranian journal of allergy, asthma, and immunology 2003;2:175-180
[17] Ferrer-Allado T, Brechner VL, Dymond A, et al.: Ketamine-induced electroconvulsive
phenomena in the human limbic and thalamic regions. Anesthesiology 1973;38:333-344
[18] Celesia GG, Chen RC, Bamforth BJ: Effects of ketamine in epilepsy. Neurology
1975;25:169-172
[19] Corssen G, Little SC, Tavakoli M: Ketamine and epilepsy. Anesthesia and analgesia
1974;53:319-335
 ACCEPTED MANUSCRIPT
14

[20] Fang Y, Wang X: Ketamine for the treatment of refractory status epilepticus. Seizure
2015;30:14-20
[21] Brophy GM, Bell R, Claassen J, et al.: Guidelines for the evaluation and management of
status epilepticus. Neurocritical care 2012;17:3-23
[22] Green SM, Li J: Ketamine in adults: what emergency physicians need to know about

T
patient selection and emergence reactions. Academic emergency medicine : official journal of
the Society for Academic Emergency Medicine 2000;7:278-281

P
[23] Okamoto Y, Tsuneto S, Tanimukai H, et al.: Can gradual dose titration of ketamine for

RI
management of neuropathic pain prevent psychotomimetic effects in patients with advanced
cancer? The American journal of hospice & palliative care 2013;30:450-454
[24] Morgan CJ, Mofeez A, Brandner B, et al.: Acute effects of ketamine on memory systems

SC
and psychotic symptoms in healthy volunteers. Neuropsychopharmacology : official publication
of the American College of Neuropsychopharmacology 2004;29:208-218
[25] Stefanovic A, Brandner B, Klaassen E, et al.: Acute and chronic effects of ketamine on

NU
semantic priming: modeling schizophrenia? Journal of clinical psychopharmacology
2009;29:124-133
[26] Mattila MA, Larni HM, Nummi SE, et al.: Effect of diazepam on emergence from ketamine
MA
anaesthesia. A double-blind study. Der Anaesthesist 1979;28:20-23
[27] Salluh JI, Wang H, Schneider EB, et al.: Outcome of delirium in critically ill patients:
systematic review and meta-analysis. Bmj 2015;350:h2538
[28] Lippmann M, Appel PL, Mok MS, et al.: Sequential cardiorespiratory patterns of anesthetic
ED

induction with ketamine in critically ill patients. Critical care medicine 1983;11:730-734
[29] Cohen L, Athaide V, Wickham ME, et al.: The effect of ketamine on intracranial and
cerebral perfusion pressure and health outcomes: a systematic review. Annals of emergency
PT

medicine 2015;65:43-51 e42

[30] Bourgoin A, Albanese J, Leone M, et al.: Effects of sufentanil or ketamine administered in
target-controlled infusion on the cerebral hemodynamics of severely brain-injured patients.
CE

Critical care medicine 2005;33:1109-1113

[31] Bourgoin A, Albanese J, Wereszczynski N, et al.: Safety of sedation with ketamine in
severe head injury patients: comparison with sufentanil. Critical care medicine 2003;31:711-717
AC

[32] Christ G, Mundigler G, Merhaut C, et al.: Adverse cardiovascular effects of ketamine

infusion in patients with catecholamine-dependent heart failure. Anaesthesia and intensive care
1997;25:255-259
[33] Guillou N, Tanguy M, Seguin P, et al.: The effects of small-dose ketamine on morphine
consumption in surgical intensive care unit patients after major abdominal surgery. Anesthesia
and analgesia 2003;97:843-847
[34] Kolenda H, Gremmelt A, Rading S, et al.: Ketamine for analgosedative therapy in intensive
care treatment of head-injured patients. Acta neurochirurgica 1996;138:1193-1199
[35] Schmittner MD, Vajkoczy SL, Horn P, et al.: Effects of fentanyl and S(+)-ketamine on
cerebral hemodynamics, gastrointestinal motility, and need of vasopressors in patients with
intracranial pathologies: a pilot study. Journal of neurosurgical anesthesiology 2007;19:257-262
[36] De Pinto M, Jelacic J, Edwards WT: Very-low-dose ketamine for the management of pain
and sedation in the ICU. Journal of opioid management 2008;4:54-56
[37] Kiefer RT, Rohr P, Ploppa A, et al.: Complete recovery from intractable complex regional
pain syndrome, CRPS-type I, following anesthetic ketamine and midazolam. Pain practice : the
official journal of World Institute of Pain 2007;7:147-150
 ACCEPTED MANUSCRIPT
15

[38] Park GR, Manara AR, Mendel L, et al.: Ketamine infusion. Its use as a sedative, inotrope
and bronchodilator in a critically ill patient. Anaesthesia 1987;42:980-983
[39] Tobias JD, Martin LD, Wetzel RC: Ketamine by continuous infusion for sedation in the
pediatric intensive care unit. Critical care medicine 1990;18:819-821
[40] Umunna BP, Tekwani K, Barounis D, et al.: Ketamine for continuous sedation of

T
mechanically ventilated patients. Journal of emergencies, trauma, and shock 2015;8:11-15
[41] White MC, Karsli C: Long-term use of an intravenous ketamine infusion in a child with

P
significant burns. Paediatric anaesthesia 2007;17:1102-1104

RI
[42] Corssen G, Miyasaka M, Domino EF: Changing concepts in pain control during surgery:
dissociative anesthesia with CI-581. A progress report. Anesthesia and analgesia 1968;47:746-
759

SC
[43] Miller AC, Jamin CT, Elamin EM: Continuous intravenous infusion of ketamine for
maintenance sedation. Minerva anestesiologica 2011;77:812-820
[44] Kochs E, Scharein E, Mollenberg O, et al.: Analgesic efficacy of low-dose ketamine.

NU
Somatosensory-evoked responses in relation to subjective pain ratings. Anesthesiology
1996;85:304-314
[45] Lee DK, Wang DP, Harsono R, et al.: Compatibility of fentanyl citrate, ketamine
MA
hydrochloride, and droperidol in 0.9% sodium chloride injection stored in polyvinyl chloride
bags. American journal of health-system pharmacy : AJHP : official journal of the American
Society of Health-System Pharmacists 2005;62:1190-1192
[46] Wang L, Johnston B, Kaushal A, et al.: Ketamine added to morphine or hydromorphone
ED

patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-
analysis of randomized trials. Canadian journal of anaesthesia = Journal canadien d'anesthesie
2015;
PT
CE
AC
 ACCEPTED MANUSCRIPT
16

Figure 1. Summary diagram of the neuropharmacological actions of ketamine, and the resultant

clinical effects. The rapid effects and actions are represented at the top left, and the more delayed

and prolonged effects and actions represented towards the bottom right. [NMDA = N-methyl-D

T
aspartate, HCN1 = hyperpolarisation-activated cyclic nucleotide channels, ACh = acetyl choline,

P
RI
nACh = nicotinic acetyl-choline receptors, AMPA = a-amino-3-hydroxy-5-methylisoxazole-4-

propionic acid, mGluR = metabotropic glutamate receptors, ERK1/2 = extracellular signal-

SC
regulated kinases, NOX = NADPH oxidase, BDNF = brain-derived neurotrophic factor, mTOR

NU
= mammalian target of rapamycin, Rgs4 = regulator of G protein signalling 4, L-type Ca2 = L-

type calcium channels, GFAP = glial fibrillary acidic protein]. Reproduced with permission from
MA
Sleigh J, Harvey M, Voss L, Denny B. Ketamine - More mechanisms of action than just NMDA

blockade. Trends Anaesth Crit Care 2014;4:76-81.

ED
PT
CE
AC
 ACCEPTED MANUSCRIPT
17

Table 1. Pharmacokinetics and Pharmacology of IV Ketamine.

 Linear pharmacokinetics but larger variability in critically ill patients

 Alpha half-life ≈ 5-17 minutes; beta half-life ≈ 180 minutes (healthy volunteers, surgery)

P T
to 300 minutes (critically ill patients); volume of distribution (beta phase) ≈ 5 L/kg in

RI
healthy volunteers undergoing surgery vs. 16 L/kg in critically ill patients

SC
o Clinical implications: immediate onset of action; peak effect of analgesia (and

elevation in blood pressure) < 5 minutes; duration of analgesia < 5 minutes if dose

NU
is < 0.125 mg/kg (10-20 minutes if higher)
MA
 Protein binding ≈ 47% (greater affinity for alpha-1- acid glycoprotein than albumin)

o Clinical implications: protein binding interactions unlikely

ED

 Clearance by cytochrome P450 mediated via N-demethylation and hydroxylation of

parent compound to norketamine (1/3 as potent as ketamine) and dehydronorketamine

PT

(analgesic effect unclear); ≈ 19 mL/min/kg in surgical patients vs. ≈ 36 mL/min/kg in

CE

critically ill patients

o Clinical implications: potential for accumulation of parent drug and/or active

AC

metabolites with prolonged administration in patients with severe hepatic or renal

dysfunction; potential for increased metabolism by P450 inducers (e.g. rifampin)

and decreased metabolism by P450 inhibitors (e.g. benzodiazepines)

 Blood concentrations for analgesia: 100-150 ng/mL (> 600 ng/mL for anesthesia)

 Pharmacological actions

o Opioid receptor blockade: delta, kappa, and mu receptor blockade but analgesia

not reversed by naloxone

 ACCEPTED MANUSCRIPT
18

o CNS anticholinergic: psychic and sedative effects

o GABA inhibition: involved in anesthesia but not analgesia

o NMDA-block: important for many pharmacological properties including anti-

T
nociceptive effect and psychosis

P
RI
o Hyperadrenergic state: increased release and decreased neuronal uptake of

norepinephrine, dopamine, and serotonin (potential for interactions with drugs

SC
affecting these mediators)

NU
CNS = central nervous system; GABA = gamma-aminobutyric acid; NMDA = N-methyl-D-
aspartate MA
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT
19

Table 2. Dosing and Monitoring IV Ketamine for Analgosedation in Critically Ill Patients.*
Use Precautions, Dosing Monitoring
Warnings,
Contraindications
Severe pain Contraindications: Intravenous Infusion Pain, sedation and delirium

T
unresponsive hypersensitivity, Dosing (concentration scores to assess for efficacy

P
to acute intermittent 1 mg/mL; stable in and adverse effects
conventional porphyria, acute normal saline or 5%

RI
therapies myocardial infarction dextrose): Of particular concern are:
(not an or decompensated Option 1:  Persistent unrelieved

SC
approved heart failure, acute  Ketamine 0.6 pain (e.g., score > 4 on
FDA psychosis mg/kg given as 0-10 numeric rating
indication; Precautions/warnings: a one-time 4 scale)

NU
ketamine is a uncontrolled high hour IV  Hemodynamic
schedule III blood pressure, infusion (~2.5 instability (e.g., SBP <
medication history of psychosis, MA ug/kg/min) 90 or > 160 mm Hg,
in the US) history of ischemic HR < 60 or > 120)
cardiovascular Option 2:  Respiratory depression
disease, history of  Ketamine 0.2- (rate < 12 or oxygen
psychotic or 0.5 mg/kg IV saturation < 92%)
ED

emergence reactions bolus given  Excessive sedation

to ketamine, history over at least 1 (particularly a concern
of ketamine abuse minute when ketamine is
PT

followed by combined with other

continuous sedatives)
infusion started  Psychotic or
CE

at 1 ug/kg/min psychotomimetic
(0.06 mg/kg/hr) episodes including
 If inadequate delusions, dysphoria,
AC

pain control, hallucinations,

bolus doses impaired or
may be disorganized thinking,
increased up to vivid dreams or
a maximum of nightmares
0.5 mg/kg and  Tonic/clonic
the infusion movements
may be  With prolonged
increased in 1 administration (e.g.,
mcg/kg/min weeks) allodynia and
increments hyperalgesia have been
every 15 min reported with abrupt
up to a discontinuation of
maximum dose ketamine
of 20 ug/kg/min
(1.2 mg/kg/hr) BIS monitoring is not useful
or until adverse
 ACCEPTED MANUSCRIPT
20

effects occur since ketamine administration

does not change and may even
increase the index

SBP = systolic blood pressure; HR = heart rate; BIS = bispectral index

T
* The dosing regimens were derived primarily from studies involving the use of ketamine for

P
postoperative pain control and the limited number of studies conducted in the ICU setting; note

RI
that much higher doses of ketamine were administered in some of the studies of critically ill
patients with neurotrauma who received ketamine for analgosedation with combined clinical and

SC
hemodynamic endpoints

NU
MA
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT
21

Table 3. Adverse Effects Related to IV Ketamine Administration.

Rate-Related Adverse Effects Other Adverse Effects

Larger intravenous doses infused over < 60 Emergence and psychotomimetic reactions

T
seconds increase the risk of respiratory Emesis (does not appear to be dose-related)

P
depression, high blood pressure and Sympathomimetic effects of most concern for

RI
tachycardia aggravation of pre-existing conditions such as

SC
hypertensive crisis and symptomatic coronary disease

NU
Hypotension, bradycardia and enhanced skeletal
MAmuscle tone (muscle movement or clonus), but

uncommon with low doses

Potential for increases in intracranial and intraocular

ED

pressure (usually not clinically important)

PT

Neurological and urinary toxicity concerns with more

prolonged dosing
CE

For use during pregnancy, animal data suggest low

AC

risk but data in humans in limited; case report data

suggests that abuse during the last trimester may be

responsible for growth retardation and hypo-reflexia

To avoid venous irritation, dilute to a maximum

concentration of 5 mg/mL with 5% dextrose or

normal saline
 ACCEPTED MANUSCRIPT
22

PT
RI
SC
NU
MA
ED
PT

Figure 1
CE
AC
 ACCEPTED MANUSCRIPT
23

Highlights

 Ketamine preserves preserving pharyngeal and laryngeal protective reflexes

 It is less likely to produce respiratory depression

P T
 It causes sympathetic stimulation, which can be advantageous in hypotensive patients

RI
 There are psychotomimetic effects, which is a concern in terms of delirium

SC
 A prolonged infusion of ketamine may lead to drug accumulation

NU
MA
ED
PT
CE
AC