Elsevier

Medical Hypotheses

Volume 83, Issue 1, July 2014, Pages 103-107
Medical Hypotheses

The suppression of endogenous adrenalin in the prolongation of ketamine anesthesia

https://doi.org/10.1016/j.mehy.2014.03.033Get rights and content

Abstract

This study investigated whether or not the anesthetic effect of ketamine in rats is dependent on adrenal gland hormones. The study was performed on two main rat groups, intact and adrenalectomized. Rat were divided into subgroups and given appropriate doses of ketamine, metyrapone or metyrosine. Durations of anesthesia in the groups were then recorded. Endogenous catecholamine levels were measured in samples taken from peripheral blood. This experimental results showed that ketamine did not induce anesthesia in intact rats at doses of 15 or 30 mg/kg, and that at 60 mg/kg anesthesia was established for only 11 min. However, ketamine induced significant anesthesia even at a dose of 30 mg/kg in animals in which production of endogenous catecholamine (adrenalin, noradrenalin dopamine) was inhibited with metyrosine at a level of 45–47%. Ketamine at 60 mg/kg in animals in which endogenous catecholamine was inhibited at a level of 45–47% established anesthesia for 47.6 min. However, ketamine at 30 and 60 mg/kg induced longer anesthesia in adrenalectomized rats with higher noradrenalin and dopamine levels but suppressed adrenalin production. Adrenalin plays an important role in the control of duration of ketamine anesthesia, while noradrenalin, dopamine and corticosterone have no such function. If endogenous adrenalin is suppressed, ketamine can even provide sufficient anesthesia at a 2-fold lower dose. This makes it possible for ketamine to be used in lengthy surgical procedures.

Introduction

Ketamine is a phencyclidine-type material administered by the intravenous route [1]. Intravenous ketamine is used in the induction of general anesthesia and in brief surgical procedures. A high dose of ketamine induces general anesthesia, while a low dose has an analgesic effect [2], [3]. However, the use of ketamine in high doses causes serious side-effects, such as somniloquy, high blood pressure, severe confusion and extreme fear [4], [5], [6]. It has been suggested that the side-effects of ketamine stem from its sympathomimetic activity [7]. The use of ketamine in patients with coronary artery disease is questionable, because the sympathomimetic property of the drug increases the need for myocardial oxygen [8]. Ketamine has been reported to cause mydriasis and establish a bronchodilator effect by blocking muscarinic receptors [9]. Studies report that it causes bronchodilator effects through catecholamine discharge, stimulation of β2 adrenergic receptors and inhibition of vagal pathways in humans [6]. It has furthermore been reported that ketamine blocks nicotinic receptors in humans [10] and raises intracellular calcium levels by interacting with voltage dependent calcium channels [11]. These adverse effects of ketamine impose important restrictions on its use. Another disadvantage of ketamine is that its effect is short-lived. For that reason, ketamine is preferred in surgical procedures of short duration, or else the dose is repeated several times in longer procedures. Inducing sufficient anesthesia with smaller doses of ketamine can reduce the adverse effects of the drug and increase its value in longer surgical procedures. One previous study reported that the effect of thiopental sodium rose by several times in adrenalectomized rats compared to intact rats. In addition, it reported that cortisol (corticosterone in rats), an adrenal cortex hormone, plays no role in the extension of the duration of the effect of thiopental sodium. However, that study did not investigate whether there is a relation with adrenal medulla hormones (adrenalin (ADR), noradrenalin (NDR) and dopamine (DOP)) [12]. Synthesis of adrenal gland hormones is known to be suppressed with metyrosine [13]. Metyrosine is used in doses of 100–300 mg/kg in animals [14]. It compromises synthesis of catecholamines in the adrenal medulla by inhibiting tyrosine hydroxylase [15]. Metyrosine reduces catecholamine levels at a level of 35–80% [16]. However, while NDR and DOP are produced in the central nervous system (noradrenergic and dopaminergic) and adrenal medulla, ADR is only manufactured in the adrenalin medulla in mammals [17]. The synthesis of ADR in the body can therefore be halted with adrenalectomy, but synthesis of NDR and DOP cannot be halted in the same way [17]. Cortisol can also be eliminated from the body with adrenalectomy. In addition, cortisol (corticosterone (CORT) in rats) synthesis is suppressed with the administration of metyrapone [18]. The above information from the literature suggests that adrenal medulla hormones are also involved in the duration of the effect of ketamine. We hypothesised that the suppression of endogenous release of adrenal gland hormones including adrenalin, noradrenalin and dopamine may provide longer duration of anesthesia with low dose of ketamine. Therefore, this experimental study was designed to investigate whether the strength and duration of the anesthetic effect of ketamine in rats associated with adrenal gland hormones.

Section snippets

Animals

All procedures were approved by the Ataturk University Institutional Animal Care and Use Committee and all studies were performed in accordance with the ethical guidelines set out by the local ethical committee that were fully compatible with the “NIH Guide for the Care and Use of Laboratory Animals”. The protocols and the procedures were approved by the local Animal Experimentation Ethics Committee (Date: 25. 09. 2013, meeting no: 4, decision number: 109). Ninety-six male Wistar rats weighing

Test I experimental results (Intact animals)

As shown in Table 1, no sleep state or anesthesia was observed in the intact rat groups receiving ketamine at doses of 15 (IK-15) or 30 mg/kg (IK-30, IMTK-30). These animals (IK-15, IK-30 and IMTK-30) moved little and exhibited imbalance in their movements. However, the rats in the IK-60, IMK-30, IMK-60 and IMTK-60 groups remained immobile in the supine position for 11.1 ± 0.5, 24.1 ± 0.9, 47.6 ± 3 and 10.6 ± 0.6 min. During these times when rats remained immobile, a 1 cm vertical incision was made to the

Discussion

This study investigated whether the anesthetic power and duration of ketamine were associated with adrenal gland hormones. Our experimental results showed that ketamine at 30 mg/kg did not induce anesthesia in intact rats, while at 60 mg/kg it induced anesthesia for only 11 min. However, significant anesthesia was seen even at a dose of 30 mg/kg in animals with endogenous ADR levels suppressed at a level of 45–47%. At a dose of 60 mg/kg, ketamine prolonged duration of anesthesia 4.3-fold. Ketamine

Conflict of interest

All authors declare that they have no conflicts of interest.

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