Anesthetic Doses Of Ketamine Research Articles

Convergent effects of different anesthetics on changes in phase alignment of cortical oscillations.

Many anesthetics cause loss of responsiveness despite having diverse underlying molecular and circuit actions. To explore the convergent effects of these drugs, we examined how anesthetic doses of ketamine and dexmedetomidine affected oscillations in the prefrontal cortex of nonhuman primates. Both anesthetics caused increases in phase locking in the ventrolateral and dorsolateral prefrontal cortex, within and across hemispheres. However, the nature of the phase locking varied. Activity in different subregions within a hemisphere became more anti-phase with both drugs. Local analyses within a region suggested that this finding could be explained by broad cortical distance-based effects, such as large traveling waves. By contrast, homologous areas across hemispheres became more in-phase. Our results suggest that both anesthetics induce strong patterns of cortical phase alignment that are markedly different from those in the awake state, and that these patterns may be a common feature driving loss of responsiveness from different anesthetic drugs.

Role of Different Doses of Ketamine in Postoperative Neurocognitive Function in Aged Mice Undergoing Partial Hepatectomy by Regulating the Bmal1/NMDA/NF-Κb Axis

Background: The current study set out to probe the function of different doses of ketamine in postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) with the involvement of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1)/n-methyl-D-aspartate (NMDA)/nuclear factor-kappa B (NF-κB) axis. Methods: First, aged mice were intraperitoneally injected with different doses of ketamine prior to surgery, followed by hepatic lobectomy. Afterward, mice cognitive function was assessed. In addition, Bmal1 mRNA expression patterns were quantified, while NMDA 2B receptor, NF-κB p65, synapsin 1, and postsynaptic density 95 (PSD95) levels were determined; the release of inflammatory factors was detected, and ionized calcium-binding adapter molecule-1 expression was measured to quantify microglia activation. In addition, Bmal1-knockout (Bmal1-KO) mice were intraperitoneally injected with a subanesthetic dose of ketamine to verify the mechanism of Bmal1 in regulating the NMDA 2B subunit (NR2B)/NF-κB axis to affect PH in aged patients. Results: After PH, hippocampal-dependent memory was impaired, and synapsin 1 and PSD95 levels were downregulated. On the other hand, PH diminished Bmal1 expression but elevated NR2B and NF-κB p65 levels and anesthetic doses of ketamine further regulated the Bmal1/NMDA/NF-κB axis. In Bmal1-KO mice, the NMDA/NF-κB axis was activated, the release of inflammatory cytokines was promoted, and hippocampus-dependent memory was impaired, which were reversed by a subanesthetic dose of ketamine. Conclusion: Altogether, findings obtained in our study indicated that a subanesthetic dose of ketamine activated Bmal1, downregulated the NMDA/NF-κB axis, and reduced inflammation and microglia activation to alleviate PND in aged mice undergoing PH.

Ketamine inhibits neuronal differentiation by regulating brain-derived neurotrophic factor (BDNF) signaling

Ketamine is widely used in pediatric anesthesia, perioperative sedation, and analgesia. Knowledge of anesthesia neurotoxicity in humans is currently limited by the difficulty of obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. However, mouse embryonic stem cells (mESCs) derived from embryos at the preimplantation stage demonstrate an unlimited ability to self-renew and generate different cell types and are a valuable tool for clinical research. Thus, in this study, a model was employed to investigate the mechanism by which ketamine (200 nM) influences the neuronal differentiation of mESCs. Mouse ESCs were treated with an anesthetic dose of ketamine, and neuronal differentiation was significantly inhibited on day 5. Downregulation of brain-derived neurotrophic factor (BDNF) by shRNA was found to have the same inhibitory effect. Furthermore, a rescue experiment indicated that BDNF overexpression markedly restored the neuronal differentiation inhibited by ketamine in the ketamine/BDNF group on day 5. Taken together, these data suggested that ketamine inhibited the neuronal differentiation of mESCs, possibly by interfering with BDNF. The results of the current study may provide novel ideas for preventing ketamine toxicity in the developing fetus.

Effects of Ketamine on Learning and Memory in the Hippocampus of Rats through ERK, CREB, and Arc.

Ketamine has become a popular recreational drug due to its neuronal anesthesia effect and low price. The process of learning and memory is part of the distinctive high-level neural activities in animals. We investigated the effects of subanesthetic and anesthetic doses of ketamine on the learning and memory-related signal transduction mechanisms. We used the Morris water maze test to execute rats’ learning and memory ability and detected changes of Arc mRNA and Arc, cAMP-response element-binding protein (CREB), phospho-CREB (p-CREB), extracellular signal-regulated kinase (ERK), and phospho-ERK (p-ERK) protein expression in the hippocampus 10 min and 24 h after administration. Ten min after ketamine injection, the Arc gene and the protein expression levels increased in all groups; p-ERK only increased in the chronic subanesthetic dose group. After 24 h, the Arc gene and the protein expression levels of the subanesthetic dose group increased, but those of the chronic subanesthetic dose group and anesthetic dose group decreased. However, p-ERK increased in all groups. A chronic subanesthetic dose of ketamine could increase learning and memory ability through ERK, CREB, and Arc in a short time, and the high body temperature after the subanesthetic dose of ketamine injection was the main factor leading to changes in Arc. The subanesthetic dose of ketamine regulated learning and memory through ERK, CREB, and ARC 24 h after injection.

Cortical dynamics during psychedelic and anesthetized states induced by ketamine

Ketamine is a unique drug that has psychedelic and anesthetic properties in a dose-dependent manner. Recent studies have shown that ketamine anesthesia appears to maintain the spatiotemporal complexity of cortical activation evoked by transcranial magnetic stimulation, while a psychedelic dose of ketamine is associated with increased spontaneous magnetoencephalographic signal diversity. However, a systematic investigation of the dose-dependent effects of ketamine on cortical complexity using the same modality is required. Furthermore, it is unknown whether the complexity level stabilizes or fluctuates over time for the duration of ketamine exposure. Here we investigated the spatiotemporal complexity of spontaneous high-density scalp electroencephalography (EEG) signals in healthy volunteers during alterations of consciousness induced by both subanesthetic and anesthetic doses of ketamine. Given the fast transient spectral dynamics, especially during the gamma-burst pattern after loss of consciousness, we employed a method based on Hidden Markov modeling to classify the EEG signals into a discrete set of brain states that correlated with different behavioral states. We characterized the spatiotemporal complexity specific for each brain state as measured through the Lempel-Ziv complexity algorithm. After controlling for signal diversity due to spectral changes, we found that the subanesthetic dose of ketamine is associated with an elevated complexity level relative to baseline, while the brain activity following an anesthetic dose of ketamine is characterized by alternating low and high complexity levels until stabilizing at a high level comparable to that during baseline. Thus, spatiotemporal complexity associated with ketamine-induced state transitions has features of general anesthesia, normal consciousness, and altered states of consciousness. These results improve our understanding of the complex pharmacological, neurophysiological, and phenomenological properties of ketamine.

Sub-anaesthetic bolus dose of intravenous ketamine for postoperative pain following caesarean section

Background: Effective postoperative analgesia following Caesarean Section is important because parturients are at a higher risk for thromboembolic events due to immobility, increased likelihood of developing postpartum depression (PPD) following inadequate pain control which also can interrupt breastfeeding. Ketamine at sub anesthetic doses has been considered to reduce postoperative pain and analgesic consumption following caesarean section. Aims: The aim of this study was to evaluate the efficacy of sub anesthetic doses of ketamine on post caesarean analgesia. Material and Methods: This randomized double blind, placebo controlled study was conducted on 108 parturients, divided into three groups (36 in each group);Group C- received 2 ml of 0.9% normal saline; Group Ka- received 0.15 mg/kg of ketamine (2 ml) and Group Kb- 0.3 mg/kg of ketamine (2 ml) after 5 min of delivery. Postoperatively VAS score, consumption of rescue analgesic in 24 h and adverse effects were recorded. Statistical analysis was done with Analysis of variance (ANOVA) for continuous variables and Chi-square test for categorical scale. P values less than 0.05 were considered significant. Results: Postoperative VAS scores were significantly higher in control group while the time to the first analgesic requirement was significantly prolonged in Ka group (5.44 ± 1.45 h) and Kb group (6.18 ± 1.61 h) as compared to the control group (4.97 ± 1.48 h). The total number of doses and total dose of rescue analgesic (tramadol) required in 24 hours was significantly less in the Ka group (194.44 ± 53.15 mg) and Kb group (152.78 ± 50.63 mg) as compared to group C (136.11 ± 48.71 mg. Conclusion: Administration of sub-anesthetic doses (0.15 mg/kg and 0.3 mg/kg) of intravenous ketamine enhanced postoperative analgesia and reduced the total rescue analgesic consumption in first 24 h following CS. Ketamine 0.3 mg/kg also increased the time to first postoperative rescue analgesic request.

Ketamine NMDA receptor-independent toxicity during zebrafish (Danio rerio) embryonic development

Concerns have been raised that the effect of anaesthetic drugs on the central nervous system may result in long-term impairment, namely when ketamine is used during embryogenesis. In addition, the cell and molecular basis of anaesthetics teratology and toxicity are still uncertain and its implications in the development remain to be clarified. More recently, the potential risks for human, and animal, exposure through environmental contamination also became an important question. In this study, the effects of sub- and over anaesthetic doses of ketamine were investigated during zebrafish (Danio rerio) embryonic development by exposing zebrafish embryos to ketamine concentrations (0.2, 0.4 and 0.8mgmL−1) for a period of 20min during the blastula stage. Ethanol 2% was used as a positive control. Morphological parameters, the overall pattern of cell death using acridine orange and overall degree of oxidative stress levels by 2,7-dichlorodihydrofluorescein-diacetate were determined. Lethality and/or developmental anomalies were measured based on specific time endpoints until 144h post fertilisation. Results showed a concentration-dependent increase in anomalies and mortality. Cephalic disorders, enlarged organs and tail/spine anomalies were the most prominent deformities observed at 144hpf. Acridine orange images revealed no differences in cellular death pattern in exposed embryos at 24hpf. At the same time point, the cellular redox processes were found to be similar among groups. In summary, this study shows that ketamine is teratogen and toxic, interfering with the normal developmental pathways of embryogenesis, suggesting that ketamine exerts an independent NMDA receptor action during the zebrafish blastula stage.

Ketamine does not impair heat tolerance in rats

Exposure to organophosphorus compounds, either pesticides or chemical warfare agents such as soman or sarin, represents a major health problem. Organophosphorus poisoning may induce seizures, status epilepticus and even brain lesions if untreated. Ketamine, an antagonist of glutamatergic receptors, was recently proved to be effective in combination with atropine sulfate as an anticonvulsant and neuroprotectant in mice and guinea pigs exposed to soman. Organophosphorus exposure may also occur in conditions of contemporary heat exposure. Since both MK-801, a more potent glutamatergic antagonist than ketamine, and atropine sulfate are detrimental for thermoregulation, we evaluated the pathophysiological consequences of ketamine/atropine combinations in a hot environment. Male wistar rats were exposed to 38°C ambient temperature and treated with atropine sulfate and/or ketamine (anesthetic and subanesthetic doses). The abdominal temperature and spontaneous locomotor activity were continuously monitored using telemetry. At the end of heat exposure, blood chemistry and the mRNA expression of some specific genes in the brain were assessed. Unlike MK-801, ketamine did not induce any deleterious effect on thermoregulation in rats. Conversely, atropine sulfate led to heatstroke and depressed the heat-induced blood corticosterone increase. Furthermore, it induced a dramatic increase in Hsp70 and c-Fos mRNA levels and a decrease in IκBα mRNA expression, both suggesting brain aggression. When combined with the anesthetic dose of ketamine, some of the atropine-induced metabolic disturbances were modified. In conclusion, ketamine can be used in hot environment and may even limit some of the biological alterations induced by atropine sulfate in these conditions.

The Effect of Ketamine Anesthesia on the Immune Function of Mice with Postoperative Septicemia

It is unknown how ketamine anesthesia immunologically affects the outcome of patients with postoperative septicemia. We investigated the effects of ketamine anesthesia on mice with an Escherichia coli or lipopolysaccharide (LPS) challenge after laparotomy, focusing on phagocytosis by liver macrophages (Kupffer cells) and cytokine production. C57BL/6 mice received ketamine or sevoflurane anesthesia during laparotomy, which was followed by an E. coli or LPS challenge; thereafter, mouse survival rates and cytokine secretions were examined. The effects of a β-adrenoceptor antagonist, nadolol, on ketamine anesthesia were also assessed to clarify the mechanisms of ketamine-induced immunosuppressive effects. Ketamine anesthesia increased the mouse survival rate after LPS challenge after laparotomy compared with sevoflurane anesthesia, whereas such an effect of ketamine was not observed after E. coli challenge. Ketamine suppressed tumor necrosis factor (TNF) and interferon (IFN)-γ secretion after LPS and E. coli challenge. When bacterial growth was inhibited using an antibiotic, ketamine anesthesia effectively improved mouse survival after E. coli challenge compared with sevoflurane anesthesia. Neutralization of TNF also improved survival and decreased IFN-γ secretion after bacterial challenge in antibiotic-treated mice with sevoflurane anesthesia, suggesting that ketamine's suppression of TNF may improve survival. Ketamine also suppressed in vivo phagocytosis of microspheres by Kupffer cells in LPS-challenged mice. Concomitant use of nadolol with an anesthetic dose of ketamine did not restore TNF suppression in LPS-challenged mice, suggesting a mechanism independent of the β-adrenergic pathway. However, it restored TNF secretion under low-dose ketamine (10% anesthetic dose). In contrast, nadolol restored the decrease in phagocytosis by Kupffer cells, which was induced by the anesthetic dose of ketamine via the β-adrenergic pathway, suggesting distinct mechanisms. Ketamine suppresses TNF production and phagocytosis by Kupffer cells/macrophages. Therefore, unless bacterial growth is well controlled (by an antibiotic), postoperative infection might not improve despite reduction of the inflammatory response.

CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome

Background. Previous reports have indicated that ketamine anesthesia may produce significant improvement if not complete recovery of patients with complex regional pain syndrome (CRPS). Aims. Here we report on a patient who had CRPS affecting mainly the right side of her body who underwent functional magnetic resonance imaging (fMRI) scans prior to and in the months following apparent successful treatment with anesthetic doses of ketamine. Materials and Methods. The patient underwent two imaging sessions: one during her pain state (CRPS+) and 1 month after her ketamine treatment in her pain-free state (CRPS-). Both spontaneous and evoked (brush, cold, and heat) pain scores decreased from 7–9/10 on a visual analog scale prior to the treatment to 0–1 immediately following and for months after the treatment. For each imaging session, the identical mechanical (brush) and thermal (cold and heat) stimuli were applied to the same location (the skin of the dorsum of the right hand). Results. Comparison of CRPS+ vs CRPS- for the three stimuli showed significant changes throughout the cerebral cortex (frontal, parietal, temporal, cingulate, and hippocampus), in subcortical regions such as caudate nucleus, and in the cerebellum. In addition, resting state network analysis showed a reversal of brain network state, and the recovered state paralleled specific default networks in healthy volunteers. Discussion. The observed changes in brain response to evoked stimuli provide a readout for the subjective response. Conclusion. Future studies of brain function in these patients may provide novel insight into brain plasticity in response to this treatment for chronic pain.

Something new about ketamine for pediatric anesthesia?

This review discusses the place of the old anesthetic ketamine in pediatric anesthesia. Despite the availability of modern alternatives, ketamine remains a frequently used drug particularly for anesthesia in high-risk children and for procedures outside the operating room. In adult patients undergoing surgery, a renewed interest in this drug is noted. It is the consequence of recent demonstrations of the following effects. First, ketamine is highly effective against surgery and opiate-induced hyperalgesia. Second, it has original antiproinflammatory properties. In other words, it promotes self-limitation of the inflammatory response that follows surgery. In the pediatric population, these benefits wait to be confirmed. Finally, questions arise about the safety of ketamine anesthesia. Ketamine is a potent proapoptotic drug. In rodents treated during the critical period for central nervous system development, long-term behavioral deficits were noted after an anesthetic dose of ketamine. The exact consequences of these proapoptotic properties on human brain tissue development have to be exactly determined and are still debatable. Ketamine has not yet revealed all its interactions in humans. Recent discoveries indicate interesting properties on the one hand and potentially deleterious effects on the other.

The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome

Background Complex regional pain syndrome I (CRPS) is characterized by severe neuropathic pain that exceeds the severity of an injury and is refractory to traditional treatments. Recent experimental interventions include ketamine infusion therapy. Objective We sought to evaluate the physical, neurocognitive, and emotional effects of extended treatment with anesthetic doses of ketamine in refractory CRPS I patients. Methods Nine patients (eight females) received a neuropsychological evaluation pre- and 6 weeks post-treatment that evaluated intellectual and academic abilities, executive functioning/processing speed, attention, learning and memory, and motor functioning. Mood/affect and personality were also evaluated and patients completed an extensive pain questionnaire. Results There was a marked reduction in the report of both acute and overall pain after treatment. Brief attention and processing speed improved significantly post-treatment, whereas all other cognitive domains remained stable, with the exception of a mild decline in motor strength. Conclusions Findings suggest that, at least at a 6-week follow up: (1) deep ketamine therapy is effective for relief of pain CRPS I and (2) there were no adverse cognitive effects of extended treatment with deep ketamine infusion. No definitive conclusions could be drawn about the relationship between mood and personality factors and the presence of CRPS I.

Multi-Day Low Dose Ketamine Infusion for the Treatment of Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is characterized by pain that is out of proportion to the injury and is regional in distribution. A large body of literature supports a dynamic change in the physiology and structure of central pain projecting neurons mediated through the N-methyl-D-aspartate (NMDA) receptor. A critical factor in central sensitization seems to be the release of the magnesium block on the NMDA receptor with influx of calcium and initiation of intracellular cascades. Current literature supports the effectiveness of ketamine in blocking central sensitization through its effects on the NMDA receptor. Recent treatment with anesthetic doses of ketamine in severely ill patients with generalized CRPS prompted our interest in a lower dose therapy. To report on the efficacy of low dose outpatient ketamine infusion for the treatment of CRPS diagnosed by International Association for the Study of Pain (IASP) criteria in patients who have failed conservative treatment. Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine in the CRPS patient. Patients diagnosed with CRPS by a single neurologist were assigned to receive a 10-day outpatient infusion of ketamine supervised by an Anesthesiologist/Pain Management Specialist. The infusion was administered in a short procedure unit after each patient had been instructed on how to complete a pain questionnaire. Monitoring consisted of continuous ECG, pulse oximetry, and non-invasive blood pressure every 15 minutes. Patients made journal entries each day prior to the infusion of 40-80 mg of ketamine. The subjects were also asked to rate their pain intensity using a verbal analog pain scale of 0-10 and the affective component using a verbal scale of 0-4. There was a significant reduction in pain intensity from initiation of infusion (Day 1) to the 10th day, with a significant reduction in the percentage of patients experiencing pain by Day 10 as well as a reduction in the level of their "worst" pain. The nadirs of pain were lower by Day 10 with a significant reduction in the incidence of "punishing pain." Moreover, there was a significant improvement in the ability to initiate movement by the 10th day. A four-hour ketamine infusion escalated from 40-80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation.

Prolonged effect of an anesthetic dose of ketamine on behavioral despair

The present study investigated the effect of a single, anesthetic dose of ketamine, a noncompetitive N-methyl- d-aspartate (NMDA) glutamate receptor antagonist, on behavioral despair, an animal model of depression. Separate groups of male Wistar rats injected with an anesthetic dose of ketamine (160 mg/kg ip) and tested 3, 7, or 10 days later showed significantly less immobility in the second of two forced-swim tests compared to saline-injected controls. Ketamine- and saline-treated animals did not differ significantly in the swim tests with respect to other behavioral measures, namely diving, jumping, and head shakes. The present findings point to an ameliorative effect of ketamine on behavioral despair and support the view that NMDA antagonists may have a beneficial effect on depression.

Metabolic mapping of the rat brain after subanesthetic doses of ketamine: potential relevance to schizophrenia

Subanesthetic doses of ketamine have been shown to exacerbate symptoms in schizophrenia and to induce positive, negative, and cognitive schizophrenic-like symptoms in normal subjects. The present investigation sought to define brain regions affected by subanesthetic doses of ketamine, using high resolution autoradiographic analysis of 14C-2-deoxyglucose (2-DG) uptake and immunocytochemical staining for Fos-like immunoreactivity (Fos-LI). Both functional mapping approaches were used because distinct and complementary information is often obtained with these two mapping methods. Ketamine, at a subanesthetic dose of 35 mg/kg, substantially increased 2-DG uptake in certain limbic cortical regions, including medial prefrontal, ventrolateral orbital, cingulate, and retrosplenial cortices. In the hippocampal formation, the subanesthetic dose of ketamine induced prominent increases in 2-DG uptake in the dentate gyrus, CA-3 stratum radiatum, stratum lacunosum moleculare, and presubiculum. Increased 2-DG uptake in response to 35 mg/kg ketamine was also observed in select thalamic nuclei and basolateral amygdala. Ketamine induced Fos-LI in the same limbic cortical regions that exhibited increased 2-DG uptake in response to the subanesthetic dose of the drug. However, no Fos was induced in some brain regions that showed increased 2-DG uptake, such as the hippocampal formation, anterioventral thalamic nucleus, and basolateral amygdala. Conversely, ketamine induced Fos in the paraventricular nucleus of the hypothalamus and central amygdala, although no effect of the drug on 2-DG uptake was apparent in these regions. In contrast to the increase in 2-DG uptake observed in select brain regions after the subanesthetic dose, an anesthetic dose of ketamine (100 mg/kg) produced a global suppression of 2-DG uptake. By contrast, a robust induction of Fos-LI was observed after the anesthetic dose of ketamine that was neuroanatomically identical to that produced by the subanesthetic dose. Results of the present investigation show that anesthetic and subanesthetic doses of ketamine have pronounced effects on regional brain 2-DG uptake and induction of Fos-LI. The alterations in regional brain metabolism induced by the subanesthetic dose may be relevant to effects of ketamine to induce schizophrenic-like symptoms.

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.

Ketamine analgesia is not related to an opiate action in the periaqueductal gray region of the rat brain

Ketamine is an injectable anesthetic agent that has been shown to interact as an agonist at opiate receptors. In addition, its antinociceptive action in rats is antagonized by the narcotic receptor antagonist naloxone. Thus it was assumed that the anesthetic may activate the pain inhibitory pathway, originating in the periaqueductal gray (PAG) and descending into the spinal cord, in a manner similar to that of narcotics like morphine. In the present study, it was verified that the systemic administration of naloxone (3 mg/kg i.p.) antagonized the elevation in tail-flick latency produced by an anesthetic dose of ketamine (160 mg/kg i.p.), but did not alter the duration of anesthesia (defined as duration of the loss of the righting reflex). However, when naloxone (3 μg/0.5 μl/30 sec) was given by microinjection into the PAG it was found to be ineffective against the ketamine-induced elevation of the tail-flick latency. In contrast, the microinjection of the antagonist significantly attenuated (halved) the elevated latency in response to systemically administered morphine (4 mg/kg s.c.). It was also shown that ketamine was unable to elicit an increase in the latency of the tail-flick reflex when administered directly into the PAG over a wide range (0.10–100 μg) of doses. On the other hand, a local anesthetic-like effect of ketamine, known to occur when the drug is used in high concentration, was observed when doses exceeding 0.1 μg were injected into the PAG. This action interfered with opiate actions in the PAG and made data from the microinjection studies difficult to interpret. The descending, pain inhibitory neuronal system originating in the PAG does not appear to participate in the antinociceptive action of ketamine measured by the tail-flick reflex. Perhaps the drug's effects are associated with alternative opiate mechanisms and/or opiate receptor subtypes not present on the cells of origin of the descending nerves within the PAG.

Cardiovascular and metabolic sequelae of inducing anesthesia with ketamine or thiopental in hypovolemic swine.

If further sympathetic stimulation is neither possible nor desirable during moderate hypovolemia, anesthetic agents capable of sympathetic stimulation would not be advantageous for induction of anesthesia during hypovolemia. To test this hypothesis, 21 swine were studied during normovolemia and after 30% of their estimated blood volume was removed. Swine were divided randomly into three equal groups to receive no anesthetic or the minimal anesthetic dose of ketamine (6.65 +/- 0.38 mg/kg, iv) or thiopental (5.77 +/- 0.21 mg/kg, iv). After the initial response to hypovolemia, animals given no drug did not exhibit further changes during the hypovolemic period. Five minutes after induction of anesthesia in the hypovolemic state, ketamine, but not thiopental, caused large increases in plasma epinephrine, norepinephrine, and renin activity. Despite these differences, both anesthetics equally depressed systemic vascular resistance, mean systemic arterial blood pressure, heart rate, and cardiac output. Ketamine, but not thiopental, decreased stroke volume. Neither anesthetic affected oxygen consumption. Both anesthetics caused similar increases in blood lactate concentration. Thirty minutes after induction of anesthesia, plasma epinephrine, norepinephrine, and renin activity remained higher in animals given ketamine than in those given thiopental. Stroke volume, systemic vascular resistance, cardiac output, and oxygen consumption did not differ among groups; however, only the animals given ketamine showed further increase in blood lactate concentration and base-deficit. Thirty minutes after infusion of shed blood, cardiac output and blood lactate concentration were greater in the animals given ketamine than in those given thiopental or no anesthetic. Ninety minutes after infusion of shed blood, no differences existed among groups. The authors conclude that after moderate hemorrhage, further increase in circulating catecholamines is possible but that the levels achieved either exceed the maximal effective concentration at site(s) of action or their effects are overwhelmed by the depressant effects of ketamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Untoward Effects of Ketamine Combined with Diazepam for Supplementing Conduction Anaesthesia in Young and Middle-Aged Adults

Fifty-six young and 29 middle-aged adults who were scheduled for lower abdominal, anorectal or extremity surgery under epidural, sacral or brachial plexus blockades received intravenous analgesic or anaesthetic doses of ketamine, combined with diazepam, immediately before the start of the operation. Forty-one patients received no supplementary drugs for the conduction anaesthesia and were divided into two groups of controls. On the day following the operation, all the patients were asked about their postanaesthetic reactions and their acceptance of the anaesthetic technique, and the nursing staff expressed their opinion on the amount of work and supervision needed during the post-operative care of the patients. Administration of ketamine 0.5 mg/kg with diazepam 0.15 mg/kg to young or middle-aged patients was not associated with more side-effects or a greater need for post-operative care and supervision than in the control groups. Administration of anaesthetic doses of ketamine 1.5 mg/kg and 3.0 mg/kg with 0.15 mg/kg and 0.3 mg/kg of diazepam, respectively, caused significantly (P less than 0.05) more post-operative anxiety and confusion, as well as a significantly greater need for post-operative care and supervision than in the control patients. It is concluded that, in young or middle-aged patients, supplementing conduction anaesthesia with ketamine 0.5 mg/kg plus diazepam 0.15 mg/kg is not associated with the untoward effects which can be expected after anaesthetic doses of 1.5 mg/kg (or more) of ketamine.

Ketamine hydrochloride and its effect on a chronic cobalt epileptic cortical focus.

The effects of anesthetic and nonanesthetic doses of ketamine hydrochloride were studied in male adult rats in which a primary and a projected epileptic focus were induced with implantation of cobalt in the right or left frontal cortex. Electrical activity was recorded from the frontal, parietal, and occipital cortices. Nonanesthetic doses of ketamine were associated with activation or enhancement of primary and projected focal electrical activity, as well as turning behavior toward the side of the cobalt focus. Anesthetic doses of ketamine also enhanced or activated the primary and projected foci. These animals demonstrated turning behavior toward the side of the cobalt focus prior to and following the cataleptoid state. During catalepsy, forelimb twitching and oscillating movements of the vibrissae occurred. The activation of primary and projected foci by ketamine at anesthetic and nonanesthetic doses supports the clinical findings that ketamine is epileptogenic in certain patients with a seizure disorder.