Basics

Ketamine is a water and lipid soluble phencyclidine derivative used for anesthesia and sedation. It contains a chiral carbon center, thus enabling two different steric configurations. The two enantiomers have different affinities for the different receptors and consequently somewhat different clinical profiles [1]. S(+)-ketamine influences many cellular processes. Firstly, it is a non-competitive inhibitor of the N‑methyl-D-aspartate (NMDA) receptor via at least two distinct mechanisms, acting both as a channel blocker (effectively shortening the open time) and as an allosteric modulator, reducing the frequency of channel opening. S(+)-ketamine slowly dissociates from the receptor (slow off-rate), even after glutamate has dissociated, and thus causes a persistent blockade. In addition, it is known to interact with opioid receptors, monoamine receptors, adenosine receptors and other purinergic receptors and local anesthetic effects mediated by several ion channels have also been described. The hypnotic effects of S(+)-ketamine are most likely due to the rapid blockade of NMDA and of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN-1 receptors). Sedative and analgesic effects are probably related to both positive and negative modulation of the cholinergic and aminergic systems, resulting in sensitization of the opioid system combined with enhanced activity of endogenous antinociceptive systems [2]; however, the different systems do not act in isolation but are part of an integrated nervous system with a myriad of interactions on all levels (Fig. 1).

Fig. 1 Mechanisms of action of S(+)-ketamine. NMDA N-methyl-D aspartate, HCN1 hyperpolarization-activated cyclic nucleotide channel, ACh acetylcholine, nACh nicotinergic acetylcholine receptor, AMPA α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, mGluR metabotropic glutamate receptor, ERK1/2 extracellular signal-regulated kinases, NOX NADPH oxidase, BDNF brain-derived neurotrophic factor, mTOR mammalian target of rapamycin, Rgs4 regulator of G protein signalling 4, L-type Ca 2 + L-type calcium channel, GFAP glial fibrillary acidic protein. (Figure used by courtesy of Jamie Sleigh et al. [2] with permission of Elsevier GmbH) Full size image

Immediate and delayed effects

The immediate effects of ketamine include the non-competitive blockade of the NMDA subtype of the glutamate receptor, tonic inhibition of voltage-dependent sodium channels (hypnotic and local anesthetic effects) and blockade of acetylcholine receptors (bronchodilatory effect). Also, at high doses mechanisms involving opiate receptors (δ, μ) lead to potentiation of opiate effects. Effects on α‑amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, metabotropic glutamate receptors (mGluR) and L‑type calcium canals have also been described. Another immediate effect is the release of dopamine and noradrenaline. Delayed effects include inhibition of transcription factor expression (c-fos, c‑jun), modulation of the phosphorylation of the NMDA receptor and inhibition of the activation of astrocytes and microglia. The most relevant receptor activities of S(+)-ketamine are depicted in Table 1; [3].

Table 1 S (+) -ketamine: receptor interactions and clinical effects [3] Full size table

Effects of S(+)-ketamine on other physiological systems

Administration of S(+)-ketamine increases muscle tone and salivation [4]. The swallowing reflex, blinking reflex, coughing reflex and gag reflex remain functional. In the cardiovascular system, ketamine has a dose-dependent stimulatory effect, mainly mediated by the sympathetic nervous system: heart rate, blood pressure and cardiac output all increase. Accordingly, temporary increases in heart rate and blood pressure are cited as common side effects. On the other hand, there is hardly any change in the resistance of the peripheral vasculature. In principle, the central respiratory drive is affected only marginally, although at high doses or with very fast administration of the drug, a depression of breathing may occur. Increased secretion of mucus and a possible increase of resistance in the pulmonary vasculature are also described. Direct effects on smooth muscle cells via voltage-dependent L‑type calcium channels receptors lead to bronchodilation [5]. Besides this, an anti-inflammatory effect has been described [6,7,8,9], which may be responsible for the antihyperalgesic effects of ketamine [1]. In sepsis, suppression of the induction of NO synthase and expression of proteins by endotoxins have been observed [10]. The significance of anti-inflammatory effects in daily clinical use of S(+)-ketamine is still under discussion, although experimental data have clearly shown benefits over more than a decade. In addition, current research concerning the antidepressant effects of S(+)-ketamine also revealed that the antinociceptive and anti-inflammatory effects, especially in decreasing inducible Nitric Oxide Synthases (iNOS) are strongly associated with its antidepressant response [11]. No effects of S(+)-ketamine on metabolism, the endocrine system, liver, kidneys, gut function or on blood coagulation are known. In the central nervous system, S(+)-ketamine has cataleptic, potently analgesic and dose-dependent anesthetic effects. Concerns over a drug-induced increase in intracranial pressure using ketamine in the neurosurgical and acute brain injury patients have been present for a long time. Langsjö et al. showed in a prospective observational study during S(+)-ketamine infusion targeted to subanesthetic (150 ng/ml) as well as anesthetic (1500–2000 ng/ml) concentrations by using positron emission tomography (PET) that S(+)-ketamine increases cerebral blood flow (CBF), exceeding the minor changes in metabolic rate of oxygen (CMRO 2 ) and glucose metabolic rate (GMR) during anesthesia [12]. Anesthetic doses of ketamine have an effect on cerebral vascular tone; this can increase intracranial pressure in patients with severe traumatic brain injury, especially in combination with hypoventilation and hypertension. This effect can be controlled by normoventilation, which should always be maintained, especially as long as monitoring of intracranial pressure (ICP) is not available. Psychotomimetic effects, which are a major drawback of the racemate and the R(+) enantiomer, are rare at low dosages of S(+)-ketamine (0.125–0.25 mg/kg bodyweight [BW]) but at higher doses they are a frequent problem occurring in up to 12% of cases [13]. At anesthetic doses (0.5–1 mg/kg BW i. v.) S(+)-ketamine gives rise to a characteristic form of dissociative anesthesia: the cataleptic effect leads to an akinetic state with loss of reaction to painful stimuli, but apparently without a complete loss of consciousness. Some patients have their eyes open, some exhibit spontaneous movements, and reflexes such as the corneal reflex, the cough reflex or the swallowing reflex remain functional. Tears and saliva may flow but the patient does not remember the operation or the anesthesia. Occasionally, vivid and possibly unpleasant dreams, sometimes pronounced hallucinations, are triggered; however, these phenomena are considerably less frequent with S(+)-ketamine than with the racemate [14] and can generally be completely suppressed by suitable comedication with propofol or midazolam. Other, more frequent side effects of S(+)-ketamine include nausea or vomiting, impaired vision, dizziness and motor agitation. These effects can, however, almost always be satisfactorily controlled with comedications, such as 5HT3 receptor antagonists or dimenhydrinate. The mechanism of this remains unclear, but could be caused by a dose-dependent interaction of S(+)-ketamine and 5‑HT3 receptor antagonists on this type of receptor [15].

Neuroprotection

S(+)-ketamine has a potent and clinically useful neuroprotective effect, because the activation of NMDA receptors is central to the pathophysiological processes that lead from ischemia to apoptosis. Inhibition of the calcium influx into the cell via the antagonistic effect on the NMDA receptor therefore has protective effects on neurons. In cases of severe brain trauma, but also following spontaneous subarachnoid hemorrhage, intracerebral hemorrhage or a space-occupying infarction of the middle cerebral artery, so-called spreading cortical depolarizations can occur (incidence 54–100%). This was first described in 1944 [16] and also plays a key role in the pathophysiology of migraine [17]. These waves of depolarization spread at a rate of 2–7 mm per min across the cortex. They are characterized by a loss of normal ionic homeostasis and especially in cases of severe brain damage, may occur in clusters (>1/h) and lead to neurovascular decoupling, and thus to a secondary phase of brain damage through ischemia and necrosis [18]. Particularly in severe brain trauma, spreading depolarizations, which result in a loss of neuronal activity, are an independent predictor of poor outcome [19]. A retrospective study of 115 patients with acute brain trauma that required surgery investigated the effect of different sedatives and analgesics on spreading depolarizations. S(+)-ketamine yielded a greater reduction of spreading depolarizations than the other substances tested, which were midazolam, fentanyl, propofol and morphine (Fig. 2; [20]). Univariate analysis found a significant correlation between therapy with S(+)-ketamine and the reduction of spreading depolarizations following traumatic brain damage, subarachnoid hemorrhage and malignant hemispheric infarction. In a recently published case report, Schiefecker et al. presented a patient with severe intracerebral bleeding in whom both spreading depolarizations and the concentration of the excitatory neurotransmitter glutamate in the cerebral microdialysate were reduced on treatment with S(+)-ketamine [21]. A possible explanation could be that cortical spreading depolarizations may be suppressed and the cerebral energy utilization is improved by ketamine, which may help maintain the electrochemical ion gradient. It should be mentioned that these findings still have to be proven in prospective randomized controlled trials, and that there is also an ongoing discussion about potential neurotoxic effects of S(+)-ketamine, especially in the context of its anesthetic use in small children [22]. The latter topics will be discussed in more detail in part two of this review.

Fig. 2 Reduction of relative probability of spreading depolarization (CI confidence interval). Figure used by courtesy of D.N. Hertle and J.P. Dreier [20], with permission of Oxford University Press Full size image

Neurotoxicity

Experimental data and animal models raised concern that S(+)-ketamine may be neurotoxic for the developing brain [22, 23]. This seems to be caused by an increase in NMDA receptor NR1 subunit expression, especially when the agent is given repeatedly and in high doses (≥20 mg/kg BW). Consecutive and fulminant influx of Ca++ could then lead to apoptotic cell death. Thus, there is on-going discussion about neurofunctional impairment after repeated high-dose ketamine-based anesthesia in (premature) neonates, based on elevated S‑100B levels as well as on clinical findings like a reduction in Bayley scales of infant development (BSID-II) [24]; however, to date no clinical or human data could clearly prove this assumption [22].

Effect on potential neuronal chronification mechanisms

A further favorable characteristic of S(+)-ketamine is that it helps prevent chronic pain. This effect appears to be due to the suppression of long-term potentiation (LTP). Pain stimuli can cause a sustained overactivation in the sensitive synapses of the pain-conducting C‑fibres that lead into the posterior horn of the spinal cord [25]. The effect is explained in terms of an increased calcium influx into the cells via the NMDA receptors [2], which is largely due to the supraspinal block of the NR2B-NMDA subunit. S(+)-ketamine effectively prevents development of an LTP due to pain stimuli, and this effect has been observed even at doses far below the anesthetic range (0.25 mg/kg BW). This removes a major factor in the emergence of chronic pain and the pain memory.

Opioids promote the excitability of NMDA receptors via activation of µ opioid receptors and in this way they can contribute to a hyperalgesia based on LTP. This can be pre-empted by administering a low dose of S(+)-ketamine before the opioids. At this dose, S(+)-ketamine acts directly on the δ opioid receptor and improves the µ receptor function [2]. It also reinforces the endogenous antinociceptive system independently of the opioid effect by activating the aminergic system (serotonin, noradrenaline) and inhibiting reuptake into the cells. Control of chronic pain is also supported by the effect of S(+)-ketamine on the gene expression cascade linked to pain development. It affects the expression of NMDA receptors, the activation of microglia and astrocytes and synaptic structure and function. Altogether, S(+)-ketamine limits the chronification of pain through all of these mechanisms, but NMDA receptor-related mechanisms play a much stronger role than in acute short-term pain sensations.