Safety of ketamine in Australia mechanically ventilated ICU patients by Dr. Tom Niccol: Ketamine was first synthesised almost 60 years ago and is similar in structure to the psychotropic agent phencyclidine. In a number of countries (eg, Australia and New Zealand), it is prepared as a racemic mixture of two enantiomers, with each having slightly different receptor affinities. Ketamine is a selective, non-competitive, N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors are one of the group of receptors for glutamate, the main excitatory neurotransmitter in the brain and spinal cord. They are present at all levels in the central nervous system (CNS) and play crucial roles in many neurological functions, including pain, breathing, locomotion, learning, and memory formation. Discover additional details at Dr. Tom Niccol.

Mechanically ventilated patients account for about one-third of all admissions to the intensive care unit (ICU). Ketamine has been conditionally recommended to aid with analgesia in such patients, with low quality of evidence available to support this recommendation. We aimed to perform a narrative scoping review of the current knowledge of the use of ketamine, with a specific focus on mechanically ventilated ICU patients.

Ketamine used in anaesthetic doses (1–4.5 mg/kg intravenous) leads to dissociative anaesthesia: the patient appears conscious (eyes open, able to swallow) with preserved respiratory function and pharyngeal and laryngeal reflexes, but is unaware, unable to process or respond to sensory input. In addition, analgesia may also be mediated through serotonin and noradrenaline receptor activation and reuptake inhibition, as well as effects on δ, ϰ and μ opioid receptors. Unlike opioid medications, ketamine is thought to have little effect on gastrointestinal μ receptors, minimising the risk of constipation.

Methods: We searched MEDLINE and EMBASE for relevant articles. Bibliographies of retrieved articles were examined for references of potential relevance. We included studies that described the use of ketamine for postoperative and emergency department management of pain and in the critically unwell, mechanically ventilated population.

A wide range of surgeries were included. Ten studies used only S-ketamine and one study used only R-ketamine. The rest of the studies used racemic ketamine at predominantly bolus doses of 0.25–1 mg/kg and infusions of 2–5 μg/kg/min (0.12–0.3 mg/kg/h). Most studies had less than 50 patients in each arm. Ketamine infusion reduced morphine equivalents by 8 mg at 24 hours and by 13 mg at 48 hours with associated decreased pain scores. Pooled CNS adverse events included hallucinations, dizziness, confusion, drowsiness, sedation, nightmares, and visual disturbances. There was no statistical difference in pooled events when ketamine was compared with placebo (5.2% v 4.2%; risk ratio, 1.17; 95% CI, 0.95–1.43). The authors concluded that “perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. CNS adverse events were little different with ketamine or control”.

Results: There are few randomised controlled trials evaluating ketamine’s utility in the ICU. The evidence is predominantly retrospective and observational in nature and the results are heterogeneous. Available evidence is summarised in a descriptive manner, with a division made between high dose and low dose ketamine. Ketamine’s pharmacology and use as an analgesic agent outside of the ICU is briefly discussed, followed by evidence for use in the ICU setting, with particular emphasis on analgesia, sedation and intubation. Finally, data on adverse effects including delirium, coma, haemodynamic adverse effects, raised intracranial pressure, hypersalivation and laryngospasm are presented.

High dose. There are four studies that examine the effect of ketamine infusion on ICPs. Kolenda et al, Bourgoin et al and Schmittner et al are described in Table 2. The fourth study, also by Bourgoin and colleagues, was a single-centre randomised controlled trial of 30 patients with severe traumatic brain injury which compared ketamine with sufentanil as target-controlled infusions for sedation. Both groups also received midazolam. Target plasma concentrations of ketamine and sufentanil were set and efficacy of sedation assessed. The patients had a mean age of 29 ± 11 years and 29 ± 12 years for ketamine and sufentanil respectively. Plasma concentrations were targeted and doses were not reported.

Conclusions: Ketamine is used in mechanically ventilated ICU patients with several potentially positive clinical effects. However, it has a significant side effect profile, which may limit its use in these patients. The role of low dose ketamine infusion in mechanically ventilated ICU patients is not well studied and requires investigation in high quality, prospective randomised trials.