Efficacy of ketamine in Australia ventilated intensive care unit admissions from 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. See extra info on Tom Niccol Australia.
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.
Another CNS effect of ketamine is NMDA receptor blockade of the dorsal horn cells of the spinal cord. These are thought to be important in the pain “wind up” phenomenon, leading to opioid desensitisation, and increased acute and chronic pain. Ketamine boluses of 0.15 mg/kg have been shown attenuate this process. Estimates of the rates of chronic pain in the year after ICU admission are 14–77%, 28 and it is unknown what role ketamine may have in reducing this critical illness complication.
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.
A prospective open label trial of 146 patients who had undifferentiated agitation in the pre-hospital environment compared a median dose of 5.2 mg/kg intramuscular ketamine versus 10 mg intramuscular haloperidol in the pre-hospital environment. Hypersalivation occurred in 21/56 ketamine patients (30%) versus none in the haloperidol group, leading to intubation for this reason in four patients. Laryngospasm occurred in 3/55 patients (5%) in the ketamine group and none in the haloperidol group. Another prospective observational study examined the effectiveness of a median dose of 4.9 mg/kg intramuscular ketamine in 49 patients with pre-hospital profound agitation. Hypersalivation occurred in nine patients (18%), of which four received atropine therapy. Pre-medication with glycopyrrolate or atropine has been shown to decrease this adverse effect. 7Umunna and colleagues showed there was no increased hypersalivation when ketamine was used as an infusion at 2.0 mg/kg/h for analgesia and sedation.
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.