EDITOR:

Ketamine is a phencyclidine anaesthetic agent with a stimulatory effect on the cardiovascular system and an analgesic action. In addition to N-methyl-D-aspartate (NMDA) receptor antagonism, ketamine has interactions also with opioid, monoaminergic, non-NMDA glutamate and both nicotinic and muscarinic cholinergic receptors [1]. The use of ketamine is often limited by its adverse effects: vivid dreaming, unpleasant hallucinations, nausea and vomiting. However, during the past few years, the use of low-dose ketamine has gained increasing interest in anaesthesiology. Low-dose ketamine has been considered a safe adjuvant analgesic to opioids, local anaesthetics or other analgesic agents [2]. Low doses of ketamine have also been given in combination with, for example, midazolam, to provide intraoperative sedation and amnesia and during propofol anaesthesia to attenuate propofol-induced hypoventilation and to provide earlier recovery of cognition [3].

In general, anaesthetic agents inhibit cholinergic efferent vagal activity in the heart, which, in turn, is manifested as reduced high-frequency (HF) heart rate (HR) variability [4]. Such an effect has also been observed after anaesthetic doses (2 mg kg−1) of ketamine [5]. Particularly in patients with diseases impairing the cardiac autonomic regulation (e.g. heart diseases, diabetes mellitus, autonomic neuropathy), highly parasympatholytic agents put an additional strain on the control of cardiac function. Therefore, we wanted to investigate the impact of subanaesthetic doses of ketamine on cardiac parasympathetic regulation.

After Ethics Committee approval and written informed consent, a total of 16 male volunteers (18-27 yr, 165-188 cm, 60-91 kg) were enrolled in this open, nonrandomized trial. Nine subjects were participants in a positron emission tomography imaging study that evaluated the effect of subanaesthetic ketamine on regional cerebral blood flow and oxygen consumption [6]. An additional seven subjects served as controls. The health of the volunteers was determined with clinical examinations including a 12-lead electrocardiogram (ECG). They refrained from using alcohol or any medication for 48 h and fasted overnight before the study.

The subjects were equipped with a portable digital Holter ECG recording device (Oxford Medilog FD-3; Oxford Medical Ltd., Woking, UK). During the ECG recordings, the subjects lay in a supine position and breathed spontaneously at approximately 12-13 breaths min−1 [6]. After baseline measurements, racemic ketamine was administered as an intravenous (i.v.) infusion targeting at three pseudo-steady state serum concentrations of 30, 100 and 300 ng mL−1, at 50 min intervals. The actual measured serum concentrations were 37 ± 8, 132 ± 19 and 411 ± 71 ng mL−1 (mean ± SD), respectively [6]. 1000-beat segments of ECG data at baseline and at the end of each concentration level were subjected to analysis of heart rate variability. Equal measurements were performed in the control group, but without medication.

From the Holter ECG recording, stationary time series of consecutive R-R intervals were generated and subjected to power spectral analysis with fast Fourier transformation (WinCPRS software package; Absolute Aliens Oy, Turku, Finland). After linear detrending of the signals, total power of R-R interval variability was generated and the HF power was then extracted from the total power by integration over the frequency band 0.15-0.40 Hz [4]. The HF power is considered to reflect the parasympathetic activity in the heart.

The differences in treatment (ketamine, control) effects on the mean R-R interval and HF power were evaluated with repeated measurements analysis of variance (RM ANOVA, SAS version 8.02; SAS Institute Inc., Cary, NC). In order to eliminate the impact of possible differences in baseline levels, RM ANOVA was performed on changes from baseline. To achieve normal data distribution the HF power was log-transformed prior to statistical analysis. The statistical model included fixed effects for treatment, concentration and treatment-by-concentration interaction. When a significant treatment or treatment-by-concentration interaction effect was detected, analyses were continued with pairwise comparisons using t-tests within the same model. Both unadjusted and Bonferroni's test adjusted P-values are presented. Two-sided P-values of <0.05 were considered statistically significant.

The main results are presented in Table 1. At baseline, the mean ± SD HR was 58 ± 9 beats min−1. At 30 ng mL−1, ketamine had no significant influence on HR or HF power. At 100 ng mL−1, the average HF power was decreased by 41% from baseline (ketamine vs. control, P = 0.013). At 300 ng mL−1, the HR increased to 67 ± 10 beats min−1 and the average HF power was decreased by 57% from baseline (ketamine vs. control, P = 0.050). The difference between groups in the baseline HF variability values was mostly due to one participant in the ketamine group, whose HF power was 6899 ms2.

Table 1: Mean R-R interval and high-frequency (HF) power of R-R interval variability in the ketamine group (n = 9) and control group (n = 7).

Our main finding is that even small, subanaesthetic doses of ketamine can reduce markedly the HF component of heart rate variability, implying a distinct parasympatholytic influence in the heart [4]. It should be noted, however, that this effect is quite moderate in comparison with total parasympathetic blockade, which almost abolishes the HF component [4].

There are several possible mechanisms by which ketamine can suppress cholinergic efferent vagal activity. Ketamine is known to exert a direct inhibitory effect on both nicotinic and muscarinic acetylcholine receptors [1] and it can also inhibit NMDA receptor-mediated acetylcholine release, and nicotinic excitation in cardiac parasympathetic neurons in the brainstem.

Ketamine also has a well-known sympathomimetic action, which presumably arises from direct stimulation of central nervous system structures. In plasma concentrations of approximately 200-300 ng mL−1, ketamine increases markedly the adrenaline and noradrenaline plasma levels. The sympathetic excitation is evidently the reason for the ketamine-induced hypertensive effect during 100 and 300 ng mL−1 concentrations [6]. Normally the blood pressure rise would trigger the arterial baroreceptor reflex, leading to increased parasympathetic activity in the heart. Our opposite findings of decreased vagal activity and increased HR (at 300 ng mL−1) seem to indicate impaired baroreflex regulation and lend support to a direct parasympatholytic effect of ketamine. This attenuation of baroreceptor reflex possibly originates from the interaction of ketamine with the NMDA receptor in the nucleus tractus solitarius [7].

Furthermore, the sympathetic activation may also partly explain the observed cardiac anticholinergic influence, since adrenaline and noradrenaline can inhibit acetylcholine release in the atria, and noradrenaline the function of the dorsal motor nucleus of the vagus nerve.

In conclusion, even subanaesthetic doses of ketamine can exert a measurable anticholinergic effect in the heart, which is, however, quite moderate in comparison with total parasympathetic blockade.

J. Penttilä

M. Mäenpää

T. Laitio

J. Långsjö

S. Hinkka

H. Scheinin

1Department of Psychiatry, Päijät-Häme Central Hospital, Lahti, Finland

2Department of Anaesthesiology and Intensive Care, Turku University Hospital, Turku, Finland

3Turku PET Centre, Turku University Hospital, Turku, Finland

4Department of Biostatistics, University of Turku, Turku, Finland

5Turku PET Centre, Turku University Hospital, Turku, Finland

5Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland