Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats.
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For general anaesthesia, patients usually receive a combination of drugs, all of which are classified as gamma-amino-butyric acid (GABA) agonists, with two notable exceptions - ketamine and nitrous oxide (laughing gas, N(2)O) - which are antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors. At clinically relevant doses both ketamine and N(2)O, like other NMDA antagonists, have the potential to induce psychotomimetic reactions in humans and to cause pathomorphological changes in cerebrocortical neurons in rat brain. Because drug combinations used in clinical anaesthesia sometimes include both ketamine and N(2)O, we undertook experiments to evaluate whether augmented neurotoxicity results from their combined use. Ketamine and N(2)O were administered alone or in combination by various dosing regimens to adult female rats for a duration of 3 h and the severity of cerebrocortical neurotoxic changes was quantified histologically. Because GABA agonists are known to protect against the psychotomimetic and neurotoxic effects of NMDA antagonists, we also evaluated whether the combined neurotoxicity of ketamine+N(2)O can be prevented by certain commonly used GABA agonists. When ketamine and N(2)O were used in combination the neurotoxic reaction was enhanced to a degree much greater than can be explained by simple additivity. The apparent synergistic interaction was particularly striking when low doses of the agents were combined, the degree of toxic synergism at higher doses being masked by a ceiling effect. GABA agonists protected against ketamine/N(2)O neurotoxicity. It is recommended that this information be taken into consideration in the selection of drugs to be used in multi-agent protocols for general anaesthesia. (+info)
Stereospecific interaction of ketamine with nicotinic acetylcholine receptors in human sympathetic ganglion-like SH-SY5Y cells.
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BACKGROUND: Surprising clinical evidence suggests a block of sympathetic transmission by ketamine. The action of ketamine on nicotinic acetylcholine receptors (nAChRs) in human ganglions is unknown. Because ganglionic transmission depends on nAChRs, such information may help to clarify whether ketamine impairs ganglionic transmission in men. Because racemic ketamine as well as S(+)-ketamine are used clinically, the authors investigated stereospecific effects on human ganglionic nAChRs. Stereospecific psychomimetic effects have been attributed to voltage-dependent Kv channel inhibition; therefore the effects on nAChRs were compared with those on Kv channels present in the same cells. METHODS: Whole-cell currents through nAChRs and K channels were measured in SH-SY5Y cells with the patch-clamp technique by application of acetylcholine (1 mm, nAChRs) or by a step depolarization from a holding potential of -80 mV to +40 mV (K channels). Electrolyte conditions were identical for both currents. RESULTS: Racemic ketamine and the isomers inhibited nAChRs and K channels in a concentration-dependent and reversible manner. Racemic ketamine inhibited nAChRs and K channels, with the anesthetic concentration inducing the half-maximal effect being 1.4 and 300 micrometer, respectively. Only inhibition of the nAChRs was stereoselective. The half-maximal concentrations were 0.8 and 3.6 micrometer for S(+)- and R(-)-ketamine. The K channels were 350 and 70 times less sensitive to the effects of S(+)- and R(-)-ketamine. CONCLUSION: Ketamine at concentrations found during clinical anesthesia exerts stereospecific effects on human ganglionic nAChRs but not on voltage-dependent K channels. Our results support the view that ketamine impairs sympathetic ganglionic transmission. Nonspecific effects on voltage-dependent K channels may underlie psychomimetic side effects. (+info)
Effect of general anesthetics on IOP in rats with experimental aqueous outflow obstruction.
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PURPOSE: To determine the effect of several common general anesthetics on intraocular pressure (IOP) after experimental aqueous outflow obstruction in the rat. METHODS: A single episcleral vein injection of hypertonic saline was used to sclerose aqueous humor outflow pathways and produce elevated IOP in Brown Norway rats. Animals were housed in either standard lighting or a constant low-level light environment. Awake IOPs were determined using a TonoPen (Mentor, Norwell, MA) immediately before induction of anesthesia by either isoflurane, ketamine, or a mixture of injectable anesthetics (xylazine, ketamine, and acepromazine). For each anesthetic, IOPs were measured immediately after adequate sedation (time 0) and at 5-minute intervals, up to 20 minutes. RESULTS; Awake IOPs ranged from 18 to 52 mm Hg. All anesthetics resulted in a statistically significant (P: < 0.01) reduction in measured IOP at every duration of anesthesia when compared with the corresponding awake IOP. With increasing duration of anesthesia, measured IOP decreased approximately linearly for both the anesthetic mixture and isoflurane. However, with ketamine, IOP declined to 48% +/- 11% (standard lighting) and 60% +/- 7% (constant light) of awake levels at 5 minutes of anesthesia, where it remained stable. In fellow eyes, the SD of the mean IOP in animals under anesthesia was always greater than the corresponding SD of the awake mean. Anesthesia's effects in normal eyes and eyes with elevated IOP were indistinguishable. CONCLUSIONS: All anesthetics resulted in rapid and substantial decreases in IOP in all eyes and increased the interanimal variability in IOPs. Measurement of IOP in awake animals provides the most accurate documentation of pressure histories for rat glaucoma model studies. (+info)
Nonlinear dynamics of heart rate variability during experimental hemorrhage in ketamine-anesthetized rats.
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Indexes of heart rate variability (HRV) based on linear stochastic models are independent risk factors for arrhythmic death (AD). An index based on a nonlinear deterministic model, a reduction in the point correlation dimension (PD2i), has been shown in both animal and human studies to have a higher sensitivity and specificity for predicting AD. Dimensional reduction subsequent to transient ischemia was examined previously in a simple model system, the intrinsic nervous system of the isolated rabbit heart. The present study presents a new model system in which the higher cerebral centers are blocked chemically (ketamine inhibition of N-methyl-D-aspartate receptors) and the system is perturbed over a longer 15-min interval by continuous hemorrhage. The hypothesis tested was that dimensional reduction would again be evoked, but in association with a more complex relationship between the system variables. The hypothesis was supported, and we interpret the greater response complexity to result from the larger autonomic superstructure attached to the heart. The complexities observed in the nonlinear heartbeat dynamics constitute a new genre of autonomic response, one clearly distinct from a hardwired reflex or a cerebrally determined defensive reaction. (+info)
Analgesic effects of caudal and intramuscular S(+)-ketamine in children.
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BACKGROUND: Previous studies suggest that caudal administration of ketamine cause effective analgesia. The purpose of the current study was to compare the clinical effectiveness and plasma concentrations of S(+)-ketamine after caudal or intramuscular administration in children to distinguish between local and systemic analgesia. METHODS: After induction of general anesthesia, 42 patients, aged 1 to 7 yr, scheduled to undergo inguinal hernia repair randomly received a caudal (caudal group) or intramuscular (intramuscular group) injection of 1 mg/kg S(+)-ketamine. Intraoperatively, heart rate (HR), mean arterial pressure (MAP) and arterial oxygen saturation were measured. Postoperative measurements included duration of analgesia, a four-point sedation score, and hemodynamic and respiratory monitoring for 6 h in the recovery room. Analgesic requirements in the recovery room were assessed by an independent blinded observer using an observational pain/discomfort scale (OPS). Plasma samples for determination of ketamine concentrations were obtained before and 10, 20, 30, 45, 60, 90, 120, and 180 min after injection of S(+)-ketamine. RESULTS: A significantly longer duration of analgesia (P < 0.001) was observed after caudal administration (528 min [220-1,440 min]; median [range]) when compared with intramuscular administration (108 min [62-1,440 min]) of S(+)-ketamine. Plasma levels of ketamine were significantly lower from 10 to 45 min after caudal administration than after intramuscular injection. CONCLUSION: Caudal S(+)-ketamine provides good intra- and postoperative analgesia in children. Despite similar plasma concentrations during most of the postoperative observation period, caudal S(+)-ketamine provided more effective analgesia than did intramuscular S(+)-ketamine, indicating a local analgesic effect. (+info)
Discharge properties of neurons in subdivisions of the medial geniculate body of the guinea pig.
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The activity of 194 neurons was recorded in three subdivisions of the medial geniculate body (74 neurons in the ventral, 62 in the medial and 44 neurons in the dorsal subdivision, i.e. vMGB, mMGB and dMGB) of guinea pigs anesthetized with ketamine-xylazine. The discharge properties of neurons were evaluated by means of peristimulus time histograms (PSTHs), interval histograms (INTHs) and auto-correlograms (ACGs). In the whole MGB, the most frequent PSTH responses to pure tone stimuli were onset (43%) or chopper (32%). The onset responses were mostly present in the vMGB, whereas chopper responses dominated in the dMGB. In the whole MGB Poisson-like and bimodal INTHs were found in 46% and 40% of neurons, respectively. The mMGB revealed fewer bimodal and more symmetrical types of INTH. In the whole MGB, 60% of units were found to have ACGs typical for short bursts (<100 ms), 23% for long bursts (>100 ms) and 15% of units fired without bursts. Neurons in the vMGB were characterized by short bursting, whereas those in the mMGB and dMGB expressed more activity in the long bursts. The results demonstrate that the type of information processing in the vMGB, which belongs to the "primary" auditory system, is different from that in two other subdivisions of the MGB. (+info)
Reevaluation of rectal ketamine premedication in children: comparison with rectal midazolam.
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BACKGROUND: Results of previous studies of rectal ketamine as a pediatric premedication are clouded because of lack of dose-response relation, inappropriate time of assessing sedative effects, and previous administration or coadministration of benzodiazepines. Therefore, the authors reevaluated the efficacy of rectally administered ketamine in comparison with 1 mg/kg rectal midazolam. METHODS: Sixty-six infants and children (age, 7-61 months) who were American Society of Anesthesiologists physical status I and who were undergoing minor surgeries as in-patients were randomized to receive 5 mg/kg ketamine (n = 16), 7 mg/kg ketamine (n = 16), 10 mg/kg ketamine (n = 17), or 1 mg/kg midazolam (n = 17) via rectum. A blinded observer scored sedation 45 min and 15 min after administration of ketamine and midazolam, respectively, when children were separated from parent(s) for inhalational induction. All children underwent standardized general anesthesia with sevoflurane, nitrous oxide, and oxygen with endotracheal intubation. Blood pressure, heart rate, and oxyhemoglobin saturation were determined before, during, and after anesthesia. Postoperative recovery characteristics and incidence of adverse reactions were also assessed. RESULTS: Most children (88%) who received rectally 10 mg/kg ketamine or 1 mg/kg midazolam separated easily from their parents compared with those (31%) who received 7 or 5 mg/kg rectal ketamine (P < 0.05). Similarly, more children who received 10 mg/kg ketamine or 1 mg/kg midazolam underwent mask induction without struggling or crying compared with those who received 7 or 5 mg/kg ketamine (P < 0.05). There were no clinically significant changes in blood pressure, heart rate, and oxyhemoglobin saturation after administration of either drug. Immediately after surgery, more children receiving midazolam or 5 mg/kg ketamine were agitated compared with 7 or 10 mg/kg ketamine. Ketamine, 7 and 10 mg/kg, provided postoperative analgesia, but the largest dose of ketamine was associated with delayed emergence from general anesthesia. CONCLUSIONS: The results indicate that rectally administered ketamine alone produces dose-dependent sedative effects in children, when evaluated at its predicted peak plasma concentration. Ketamine, 10 mg/kg, has a delayed onset but is as effective as 1 mg/kg midazolam for sedating healthy children before general anesthesia. However, 10 mg/kg rectal ketamine is not recommended for brief surgeries because of prolonged postoperative sedation. (+info)
Neuroprotective effects of riluzole and ketamine during transient spinal cord ischemia in the rabbit.
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BACKGROUND: Massive release of central excitatory neurotransmitters is an important initial step in ischemic neuronal injury, and modification of this process may provide neuroprotection. We studied the protective effects of the voltage-dependent sodium channel antagonist riluzole and the N-methyl-d-aspartate receptor antagonist ketamine on hind limb motor function and histopathologic outcome in an experimental model of spinal cord ischemia. METHODS: Temporary spinal cord ischemia was induced by 29 min of infrarenal balloon occlusion of the aorta in 60 anesthetized New Zealand white rabbits. Animals were randomly assigned to one of four treatment groups (n = 15 each): group C, saline (control); group R, riluzole, 8 mg/kg intravenously; group K, ketamine, 55 mg/kg intravenously; group RK, riluzole and ketamine. After reperfusion, riluzole treatment was continued with intraperitoneal infusions. Normothermia (38 degrees C) was maintained during ischemia, and rectal temperature was assessed before and after intraperitoneal infusions. Neurologic function, according to Tarlov's criteria, was evaluated every 24 h, and infarction volume and the number of eosinophilic neurons and viable motoneurons in the lumbosacral spinal cord was evaluated after 72 h. RESULTS: Neurologic outcome was better in groups R and RK than in groups C and K. All animals in group C (100%) and all animals but one in group K (93%) were paraplegic 72 h after the ischemic insult versus 53% in group R and 67% in group RK (P < 0.01 each). More viable motoneurons were present in groups R and RK than in controls (P < 0.05). CONCLUSIONS: The data indicate that treatment with riluzole can increase the tolerance of spinal cord motoneurons to a period of normothermic ischemia. Intraischemic ketamine did not provide neuroprotection in this model. (+info)