Sunday, September 13, 2015

Sympathy for Ketamine: Is It Really a Sympathomimetic?

Probably not.

Ketamine, as we all know, is a popular yet polarizing drug in emergency medicine. For some, it's the drug of choice for any and every indication in the ED. For others, it's avoided at all costs since it causes brains, hearts and eyes to explode. With regards to exploding hearts, providers are often concerned that the drug should never be used in patients with cardiovascular disease because of the FACT that ketamine is a sympathomimetic. However, this FACT, often regarded as common knowledge and therefore not referenced (for instance, in the ACEP guideline for ketamine use in the ED) is not factual. In fact, it is based on data from the 60's and 70's that has been quoted for decades.

The practice of using review articles to cite review articles is generally regarded as poor form. For instance, a nice review paper of ketamine discussing many aspects of the drug states the following: 

"With the stimulation of noradrenergic neurons and the inhibition of catecholamine uptake, ketamine provokes a hyperadrenergic state (release of norepinephrine, dopamine, and serotonin). Inhibition of norepinephrine uptake is stereo specific: R(−) isomer only inhibits its neuronal uptake, while S(+) isomer also inhibits extra-neuronal uptake. There is a prolonged synaptic action, leading to an increased transfer of norepinephrine in the circulation."

The reference cited here is not a piece of literature supporting this argument, but rather, another review. Searching through this review, the referenced paper for the discussion of ketamine's "sympathetic activating actions" is another review, but this time, in German. Wunderbar!

So let's go back, back to the beginning.

As far as I can tell, the first investigation into the cardiovascular effects of ketamine occurred shortly after it's discovery. In 1969, Traber et al. described the involvement of the sympathetic nervous system in the pressor response to ketamine. (Traber DL, et al. Involvement of the sympathetic nervous system in the pressor response to ketamine. Anesth Analg. 1969;48(2):248-252). The investigators administered ketamine at 5 mg/kg, 10 mg/kg or 20 mg/kg doses to 12 mechanically ventilated dogs under epidural anesthesia. They followed the effects on MAP as a marker of sympathetic activation. From baseline, the 'low dose' 5 mg/kg dose did not produce any change in MAP from baseline. When the higher 10 and 20 mg/kg doses were administered, however, MAPs fell to a statistically significant margin. Furthermore, no changes in HR were observed. The authors concluded that the epidural anesthesia suppressed the ketamine pressor response, which is evidence that the response is mediated by the sympathetic nervous system. However, in models without spinal epidural anesthesia, there is evidence demonstrating similar findings (Bidwai AV, et al. The effects of ketamine on cardiovascular dynamics during halothane and enflurane anesthesia. Anesth Analg. 1975;54(5):588-592; Savege TM, et al. A comparison of some cardiorespiratory effects of althesin and ketamine when used for induction of anaesthesia in patients with cardiac disease. Br J Anaesth 1976 Nov;48(11):1071-81; Waxman K, et al. Cardiovascular effects of anesthetic induction with ketamine. Anesth Analg. 1980 May;59(5):355-8; Dewhirst E, et al. Cardiac arrest following ketamine administration for rapid sequence intubation. J Intensive Care Med. 2013 Nov-Dec; 28(6):375-9). While not formally addressed in the study, the KETASED study did not show (among other things) any difference in vasopressor use between etomidate and ketamine groups. If it was a sympathomimetic, one would expect to find some difference, but again, KETASED did not have a population large enough to detect such a finding, nor was it designed to do so.

While the cardiovascular effects reported in the historical literature suggest a cardiovascular neutral or depressant effect at above normal therapeutic dosing, reviews and texts may also state that ketamine increases norepinephrine transport into the peripheral circulation by inhibiting uptake and reuptake thereby increasing the concentration in the neuronal synapse. This argument is supported similarly by historical data (Baraka A, et al. Catecholamine levels after ketamine anesthesia in man. Anesth Analg. 1973; 52(2):198-200; Miletich DJ, et al. The effect of ketamine on catecholamine in the isolate perfused rat heart. Anesthesiology, 1973; 39(3):271-277). The human and animal models tested did not demonstrate clinical response to the increase in plasma norepinephrine or epinephrine. Furthermore, the current attitude toward plasma NE levels suggest they are (effectively) meaningless. (Goldstein DS, et al. Sources and Significance of Plasma Levels of Catechols and Their Metabolites in Humans. JPET June 2003; 305(3): 800-811).

Ultimately, the concern of sympathomimetic effects in a patient with cardiovascular disease would be that a drug, such as ketamine, would lead to an increase in myocardial oxygen demand and possibly lead to ischemia/necrosis. A 1979 paper examined this question in a dog model. Six dogs were anesthetized and mechanically ventilated and subsequently given doses of 5 mg/kg or 10 mg/kg of ketamine followed by a continuous infusion in 4 of the dogs. After the 5 mg/kg bolus, there was no change in HR or cardiac output but a decrease in MAP. For the 10 mg/kg bolus, CO and SV both increased by approximately 90%. While the investigators observed a 58% increase in myocardial oxygen consumption, there was an equal and associated increase in myocardial oxygen delivery and increased coronary blood flow. (Smith G, et al. The effects of ketamine on the canine coronary circulation. Anesthesia 1979;34:555-61). The leading theory argues that ketamine acts on voltage-gated calcium channels in a manner similar to calcium channel blockers (Baum, VC, et al. Ketamine inhibits transsarcolemmal calcium entry in guinea pig myocardium: direct evidence by single cell voltage clamp. Anesth Analg 1991; 73:804-807).

The evidence available makes it difficult to draw conclusions. While the evidence suggests ketamine is a sympathomimetic, the evidence arguing against it is of equally poor quality. Should ketamine be contraindicated in patients with cardiovascular disease? Perhaps. Is it often given to patients with an unknown history of such disease? Absolutely.