Resurfacing of ketamine: The subanesthetic paradigm.

“Infinite diversity in infinite combinations… symbolizing the elements that create truth and beauty.” -Commander Spock.

Ketamine is probably the drug that will qualify for being used for maximally divergent anesthetic and nonanesthetic clinical effects in the widest variety of doses and with an innumerable combination with other drugs. Despite its broad clinical benefits, it was never really recognized as a favored drug in the anesthesiologist's armamentarium and bided its time being useful to fringe practitioners (read anesthesiologists providing services in nontertiary care setups!). The resurgence of ketamine as a mainstream drug, however, owes its extensive usefulness in low- or sub-anesthetic doses.

Ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist and acts by binding to the open ion channel of these receptors and preventing ion and current flow through them, the NMDARs are intricately and intimately associated with not only the occurrence of acute pain but also the development of opioid tolerance, opioid-induced hyperalgesia, and chronic pain by the mechanism of suppression of central sensitization.[1] The multiple sites of NMDARs in central, spinal, and peripheral nervous tissue beget equally multiple clinical effects. The main reason for the reluctance by the anesthesiologists to use the drug seems to be its potent psychomimetic effects including hallucinations and dysphoria, central sympathomimetic effects, variable increase in intraocular and intracranial pressure, inconsistent effect on seizure threshold, and a consistent increase in salivary and respiratory secretions. The powerful psychomimetic side effects are also the reason for its abuse potential. Most of these side effects, however, are commonly and pronouncedly seen with higher doses of ketamine, usually >0.5 mg/kg. The so-called anesthetic doses (dose at which dissociative anesthesia is induced in patients) are typically ≥1 mg/kg. The recent interest in ketamine primarily lies in its divergent uses but without its unpleasant side effects and utilizes low- or sub-anesthetic doses of the drug.

In recent times, scores of different nonanesthetic uses of low-dose ketamine have been explored. Some of these uses are now validated indications for ketamine. Subanesthetic doses of ketamine have been used successfully in the treatment of chronic regional pain syndrome and other chronic pain disorders.[2] The use of low-dose ketamine as adjuvant to other drugs is also widely practiced in patients with refractory cancer pain.[3] One of the most exciting developments is its use for the treatment for major and refractory depression.[4] There is also a renewed interest in its use in the treatment of acute pain in the emergency department.[5] Off-label and incidental use of ketamine in subanesthetic doses has been reported for many other indications including refractory status epilepticus,[6] acutely exacerbated and/or refractory asthma,[7] and vaso-occlusive crisis in sickle cell disease.[8] Anesthesiologists, of course, have been using it safely and consistently for procedural sedation, gastrointestinal endoscopy, bronchoscopy, and even postoperative analgesia. The possibility of its usefulness in low doses has opened up new avenues for its use in perioperative period as well.

Subanesthetic dose of ketamine has been found to be associated with many advantages when used during surgical procedures either under regional or general anesthesia.[9] The use of low-dose infusion of perioperative ketamine was seen to be associated with decreased opioid consumption in the intra- and post-operative period in patients undergoing orthopedic and spine surgery under general anesthesia in a few recent studies.[101112] Interestingly, low-dose ketamine infusion was also found to improve the cognitive dysfunction in elderly patients undergoing ophthalmic procedures under retrobulbar block with intravenous sedation utilizing midazolam and fentanyl.[13] The role of ketamine in decreasing the perioperative immune response is also a subject of recent research which has shown positive results although more studies are required to evaluate and evidence the issue with certainty.[1415]

In the previous edition of the journal, Gorlin et al., from Mayo Clinic, Arizona, Phoenix, have reviewed the usage of ketamine in subanesthetic doses for perioperative analgesia.[16] Despite many studies and reviews utilizing the drug in so-called “subanesthetic,” “subdissociative,” and “low-dose” ketamine, the actual dose and route of administration of ketamine for the said purpose remain undefined. Gorlin et al. have provided a practical guide to this in the review with suggested dosages for boluses and infusions in the perioperative period for various kinds of surgical procedures. In continuance with this previous review, Vadivelu et al., elaborate more on the overall role of ketamine in anesthesia and non-anesthesia practice in the present issue.[9]

It, thus, may be expected that with more recommendations and reasons to use low-dose ketamine and with our increasing use of ketamine, more such guidelines would be available inducing the mainstream anesthesiologists to use the drug utilizing its infinite diversity with infinite combination to its maximum advantage.

“…I like to believe that there are always possibilities.” -Commander Spock.