|Year : 2017 | Volume
| Issue : 1 | Page : 1-2
The ketamine enigma
Pradeep Bhatia, Swati Chhabra
Department of Anaesthesiology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
|Date of Web Publication||27-Jun-2017|
Department of Anaesthesiology, All India Institute of Medical Sciences, Jodhpur, Rajasthan
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Bhatia P, Chhabra S. The ketamine enigma. Indian Anaesth Forum 2017;18:1-2
Ketamine, first introduced into clinical practice in the 1960s as a general anesthetic, is a noncompetitive antagonist at the glutamate N-methyl-d-aspartate receptor and binds to sites located in the cortex and limbic structures of the brain. This mechanism is believed to be responsible for most of its dissociative effects. It interacts with muscarinic, nicotinic, and cholinergic receptors and inhibits the neuronal uptake of norepinephrine, dopamine, and serotonin resulting in the sympathomimetic effects. At high doses, ketamine binds to mu and sigma opioid receptors, resulting in the loss of consciousness. Ketamine is redistributed from the central nervous system and undergoes hepatic transformation by the cytochrome P450 system into its active metabolite, norketamine. Norketamine has about one-third of the anesthetic potency of ketamine with a half-life of 2.5 h. Ketamine metabolites are mainly excreted in the urine.
Ketamine is an excellent analgesic, preserves airway reflexes, is a bronchodilator, and causes less respiratory depression compared to other anesthetic agents. It is widely used for anesthesia in children, in traumatic shock, for sedation in emergency room, monitored anesthesia care, intensive care unit, in acute, neuropathic, and palliative care cases. Ketamine is useful in reducing the allodynia and hyperalgesia of neuropathic pain. The use of ketamine is limited by the signs of delirium or psychosis in the recovery stage.
Ketamine is also a potential anticonvulsant and is particularly helpful in the resistant phases of status epilepticus. Ketamine has also been used in treatment-resistant patients with depression. Mood is elevated rapidly after single injections of ketamine, and this feature is particularly valuable for suicidal patients. However, ketamine is not an alternative to electroconvulsive therapy. The long-term benefits of ketamine are not known.
Ketamine administration during surgery is increasing as some recent studies show that ketamine could prevent delirium and reduce pain after surgery. However, these studies were often in small cohorts. One similar study is published in this issue. The authors selected 120 patients of the American Society of Anesthesiologists physical status I–II undergoing laparoscopic surgeries and randomly allocated them into four groups. Groups 1, 2, and 3 received intravenous ketamine in dose of 1, 0.75, and 0.5 mg/kg, respectively, and control Group 4 received isotonic saline 30 min before incision. The authors concluded that preemptive administration of ketamine decreases postoperative analgesic requirement with satisfactory hemodynamic stability and no side effects in 0.5 mg/kg dose. Another study published in this issue by Chauhan et al. compared two combinations of propofol, fentanyl, and dexmedetomidine with and without ketamine for maintenance of anesthesia during spine surgeries done under motor-evoked potential (MEP) monitoring and found that the addition of ketamine led to better hemodynamics in patients undergoing spine surgery without affecting the MEP significantly.
Postoperative pain and delirium are two serious postoperative complications and are linked as pain can cause delirium. Avidan et al. in their study  published in The Lancet sought to find the effect of ketamine on delirium and pain. The Prevention of Delirium and Complications Associated with Surgical Treatments study is a multicenter, international randomized trial that enrolled adults older than 60 years undergoing major cardiac and noncardiac surgery under general anesthesia. Of the total 1360 patients assessed, 672 were eligible and randomized to three different arms, with 222 in the placebo group (normal saline), 227 in the low-dose ketamine group (0.5 mg/kg), and 223 in the high-dose ketamine group (1.0 mg/kg). The drug was administered to the patients following the onset of general anesthesia but before any surgical incision. The authors found no difference in delirium incidence between the combined ketamine groups and the group that received the placebo. The research group noted that there were no significant differences among any of the three groups in terms of maximum pain scores or median opioid consumption over time. This study was four-fold larger than any studies that had come before it with respect to pain and was rigorous in its methodology.
The editorial  in the same issue of the Lancet comments that these studies reflect, in part, a poor understanding of the pathophysiological mechanisms of major perioperative morbidity and mortality, as well as choosing interventions based on small studies, such as the one on ketamine with consequently low positive predictive value. The clinical recommendations based on meta-analyses of mostly small clinical trials in which ketamine is considered as an adjunct in the perioperative period to reduce pain and opioid use have also been questioned.
The future role of ketamine in clinical practice holds promise on the one hand, due to optimism as a potentially new antidepressant drugs, but pessimism on the other hand due to recent negative study. Like the past, the future studies may also contain surprises.
| References|| |
Gadre VN, Dhokte NS. Postoperative analgesia in laparoscopic surgeries with small dose of preemptive ketamine: A comparative study of three small doses. Indian Anaesth Forum 2017;18:3-8. [Full text]
Chauhan P, Aggarwal D, Mahajan H, Dhanerwa R. A comparative study of two combinations of propofol, fentanyl, and dexmedetomidine with and without ketamine for maintenance of anesthesia during spine surgeries done under motor-evoked potential monitoring. Indian Anaesth Forum 2017;18:9-13. [Full text]
Avidan MS, Maybrier HR, Abdallah AB, Jacobsohn E, Vlisides PE, Pryor KO, et al.
Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: An international, multicentre, double-blind, randomised clinical trial. Lancet 2017. pii: S0140-673631467-8.
Eisenach JC. Ketamine fails to prevent postoperative delirium. Lancet 2017. pii: S0140-673631504-0.