Single Dose Of Ketamine Research Articles

Modeling the norketamine metabolite in children and the implications for analgesia

Norketamine, a metabolite of ketamine, is an analgesic with a potency one-third that of ketamine. The aim of this study was to describe norketamine pharmacokinetics in children in order to predict time-concentration profiles for this metabolite after racemic ketamine single dose and infusion administration. The possible analgesic potential resulting from norketamine concentration may then be predicted using simulation. Ketamine and norketamine data were available from two sources: (i) children presenting for procedural sedation in an emergency department given ketamine 1-1.5 mg.kg(-1) IV as a bolus dose; and (ii) a literature search of those studies describing ketamine and norketamine time-concentration profiles after either IV or IM single-dose ketamine in adults and children. A population pharmacokinetic analysis was undertaken using nonlinear mixed effects models (NONMEM). A two-compartment (central, peripheral) linear disposition model was used to fit the parent drug. An additional metabolite compartment was linked to the central compartment by series of intermediate compartments to account for norketamine delayed formation. Norketamine volume of distribution was fixed equivalent to central volume. Simulation was used to predict norketamine time-concentration profiles in children given either ketamine as an i.v. bolus 2 mg.kg(-1) or as an analgesic infusion 0.2 mg.kg(-1).h(-1) for 24 h. The analysis comprised 621 observations from 70 subjects. There were 57 children (age 8.3, sd: 3.5 years, range: 1.5-14; weight 32.5, sd: 15.6 kg, range: 10.8-74.8) and 13 adults. Population parameter estimates for the parent drug, standardized to a 70 kg person using allometric models were central volume (V1) 22 (BSV 89.6%) l.70 kg(-1), peripheral volume of distribution (V2) 129 (30.9%) l.70 kg(-1), clearance other than that metabolized to norketamine (CLother) 47.8 (37.7%) l.h(-1).70 kg(-1) and intercompartment clearance (Q) 216 (54.5%) l.h(-1).70 kg(-1). The norketamine formation clearance (CL2M) was 12.4 (127%) l.h(-1).70 kg(-1), elimination clearance (CLM) was 13.5 (145%) l.h(-1).70 kg(-1), and the rate constant for intermediate compartments was 26.5 (59.1%) h(-1). Ketamine has a longer elimination half-life (2.1 h) than norketamine (1.13 h). Simulation suggested that norketamine contributes to analgesia for 4 h after 2 mg.kg(-1) i.v. bolus, provided the assumption that a norketamine concentration above 0.1 mg.l(-1) contributes analgesia is true. Similarly, the norketamine metabolite may contribute to analgesia for 1.5 h after low-dose infusion (0.2 mg.kg(-1).h(-1)) cessation.

Pharmacokinetics of Intramuscular Ketamine in Young Ostriches Premedicated with Romifidine

Ketamine is a short-acting dissociative anaesthetic for chemical restraint and surgical anaesthesia in domestic and non-domestic animals. The present study was designed to determine the pharmacokinetics of a single dose of ketamine (10 mg/kg) after intramuscular (i.m.) administration to young ostriches premedicated with romifidine. Ketamine was rapidly absorbed after i.m. administration. Maximal ketamine concentration (C(max)) of 2.93 +/- 0.61 microg/ml was reached at 12.5 +/- 2.50 min and thereafter ketamine concentrations decreased rapidly. The elimination half-life (t(1/2 z)) obtained was 62.37 +/- 17.37 min and mean residence time (MRT) was 77.33 +/- 19.12 min. The area under the curve (AUC) was 114.19 +/- 15.76 microg x min/ml.

Behavioral effects of ketamine and toxic interactions with psychostimulants

BackgroundThe anesthetic drug ketamine (KT) has been reported to be an abused drug and fatal cases have been observed in polydrug users. In the present study, considering the possibility of KT-enhanced toxic effects of other drugs, and KT-induced promotion of an overdose without making the subject aware of the danger due to the attenuation of several painful subjective symptoms, the intraperitoneal (i.p.) KT-induced alterations in behaviors and toxic interactions with popular co-abused drugs, the psychostimulants cocaine (COC) and methamphetamine (MA), were examined in ICR mice.ResultsA single dose of KT caused hyperlocomotion in a low (30 mg/kg, i.p.) dose group, and hypolocomotion followed by hyperlocomotion in a high (100 mg/kg, i.p.) dose group. However, no behavioral alterations derived from enhanced stress-related depression or anxiety were observed in the forced swimming or the elevated plus-maze test. A single non-fatal dose of COC (30 mg/kg, i.p.) or MA (4 mg/kg, i.p.) caused hyperlocomotion, stress-related depression in swimming behaviors in the forced swimming test, and anxiety-related behavioral changes (preference for closed arms) in the elevated plus-maze test. For the COC (30 mg/kg) or MA (4 mg/kg) groups of mice simultaneously co-treated with KT, the psychostimulant-induced hyperlocomotion was suppressed by the high dose KT, and the psychostimulant-induced behavioral alterations in the above tests were reversed by both low and high doses of KT. For the toxic dose COC (70 mg/kg, i.p.)- or MA (15 mg/kg, i.p.)-only group, mortality and severe seizures were observed in some animals. In the toxic dose psychostimulant-KT groups, KT attenuated the severity of seizures dose-dependently. Nevertheless, the mortality rate was significantly increased by co-treatment with the high dose KT.ConclusionOur results demonstrated that, in spite of the absence of stress-related depressive and anxiety-related behavioral alterations following a single dose of KT treatment, and in spite of the KT-induced anticonvulsant effects and attenuation of stress- and anxiety-related behaviors caused by COC or MA, the lethal effects of these psychostimulants were increased by KT.

Effects of peritraumatic ketamine medication on early and sustained posttraumatic stress symptoms in moderately injured accident victims

Ketamine, an N-methyl-D: -aspartate receptor antagonist, produces transient dissociative and psychotic states in healthy humans that resemble symptoms shown by subjects with acute and chronic posttraumatic stress disorder (PTSD). Since ketamine is widely used as an analgesic and sedative in emergency care, it might be one factor triggering, modulating, or exacerbating PTSD in accident victims when given in the acute trauma phase. The purpose of the present study was to determine whether the peritraumatic administration of ketamine affects acute and sustained PTSD symptoms in accident victims. A sample of 56 moderately injured accident victims was screened retrospectively for acute (Peritraumatic Dissociative Experiences Questionnaire; Acute Stress Disorder Scale) and for current PTSD symptoms (Impact of Event Scale) approximately 1 year postaccident. All subjects had received a single or fractionated dose of either racemic ketamine (n = 17), (S)-ketamine (n = 12), or opioids (n = 27) during emergency ambulance transportation. Retrospectively assessed acute symptomatology was strongly increased in (S)-ketamine subjects in terms of dissociation, reexperiencing, and avoidance, and slightly heightened in racemic ketamines. Current PTSD symptoms were substantially elevated in (S)-ketamine subjects, while there was no difference observed between opioids and racemic ketamines. Medication groups did not differ in regard to demographic variables, previous or postaccidental traumatic events, time between accident and investigation, and injury severity. The data provide first evidence for a modulating effect of a single-dose ketamine on the severity and duration of posttraumatic stress symptoms in accident victims.

Of Mice and Men: Should We Extrapolate Rodent Experimental Data to the Care of Human Neonates?

Of Mice and Men: Should We Extrapolate Rodent Experimental Data to the Care of Human Neonates?

Detection of Ketamine and Norketamine in Urine of Nonhuman Primates after a Single Dose of Ketamine using Microplate Enzyme-Linked Immunosorbent Assay (ELISA) and NCI-GC-MS

The general anesthetic ketamine (Ketalar, Ketaject, Vetalar) (KET) is used in human and veterinary medicine for induction of anesthesia for short surgical procedures and routine veterinary examination. Its illicit use by teenagers in rave parties has been reported, and it has recently been identified as a substance associated with sexual assault. One aim of this paper was to study the elimination of KET and its major metabolite norketamine (NKET) in urine collected from five nonhuman primates that received a single dose (5 mg/kg, I.M.) of KET and to study elimination patterns to determine how long after drug administration KET and NKET can be detected. Another aim of this study was to develop and validate a highly sensitive negative ion chemical ionization-gas chromatography-mass spectrometry (NCI-GC-MS) method for the simultaneous quantitation of KET and its major metabolite NKET in urine and to analyze urine samples collected from the animals. The last aim of this study was to apply and evaluate a newly developed ELISA screening methodology for detection of KET and its metabolites in the same urine samples collected from primates which received a single dose of KET. In two monkeys, KET was detected in urine up to 3 days after drug administration (32-7070 ng/mL); in one monkey, it was detected up to 4 days (65-13,500 ng/mL); in one monkey, it was detected only on days 1 and 2 (4000 and 70 ng/mL, respectively); and in one monkey, it was detected 10 days after KET injection (22-35,000 ng/mL). NKET concentrations ranged from 63 pg/mL to 1.75 microg/mL, and it remained in the urine throughout the entire 35-day study period in 4 out of 5 animals. In one monkey, NKET was detected up to 31 days after KET administration. Urine analysis using ELISA revealed that KET and NKET can be easily detectable at 25 ng/mL. In one monkey, KET and its metabolites were detected in urine up to 4 days after drug administration, up to 7 days in two monkeys, up to 11 days in one monkey, and 16 days after KET injection in one monkey. Urine extraction followed by screening using ELISA methodology allowed for significant extension of the detection period in all animals from the study. It is believed that the KET elimination in urine of nonhuman primates is slightly faster than in humans. We propose that NCI-GC-MS be employed to detect NKET as a target compound in urine in toxicological investigations of drug-facilitated sexual assault when KET use by the perpetrator is suspected.

Use of intramuscular ketamine for endoscopy sedation in children.

To report the experience of the use of intramuscular (IM) ketamine for endoscopy sedation in children. Children over 6 months of age scheduled for elective endoscopy - esophagogastroduodenoscopy (EGD), bronchoscopy and nasopharyngolaryngoscopy (NPL) were enrolled for (2 mg/kg to 3 mg/kg) intramuscular ketamine sedation. A repeated dose of 2 mg/kg intramuscular ketamine was administered to those who failed the first sedation. Alternative sedation (intravenous midazolam and fentanyl) was given to children who failed ketamine sedation twice. Sedation was regarded as successful if the procedure was completed by endoscopist with a single dose of ketamine. Sixty children were enrolled for the study. Overall success rate in our patients was 78.3%. Failure rate in infants was 50%, i.e. 4 out of 8. For children aged 1-7, the failure rate was 32%. Failure rate dropped markedly to 6.7% for those older than 7 years of age, and it showed significant difference when compared with the other two groups. Two cases of laryngospasm were experienced in the present study. Intramuscular ketamine is an effective medication for sedation in endoscopy undertaken in children over age 7 years, but it should be avoided with children under age 7 because of the high failure rate.

Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain.

This study was conducted to investigate, in vivo, the dose and duration effects of ketamine administration on neuronal degeneration in the developing rat brain. Seven-day-old (P7) Sprague-Dawley rats were treated with intraperitoneal injections of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist. Degenerating neurones were identified by the cupric-silver stain from 10 brain regions using the stereological disector method. A single dose of ketamine (25, 50 and 75 mg.kg-1) did not increase neuronal degeneration compared with the saline-treated control. However, repeated doses of ketamine (25 mg.kg-1) at 90-min intervals over 9 h increased degenerating neurones in seven out of 10 brain regions. These findings suggest that the duration of ketamine exposure correlates with increased neuronal degeneration in the developing rat brain.

NMDA receptor antagonists extend the sensitive period for imprinting

Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the α 2-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine–xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases

Study objective: To determine the safety of intramuscular ketamine when administered by emergency physicians for pediatric procedures in accordance with a defined protocol. Methods: We assembled a consecutive case series of children aged 15 years or younger who were given ketamine in the emergency departments of a university medical center and an affiliated county hospital over a 9-year period. A protocol for ketamine use (4 mg/kg, intramuscularly) was followed. Treating physicians were instructed to complete data forms recording complications and adequacy of sedation concurrent with patient care. Subsequent chart review was used to determine indications, adjunctive drugs, time to discharge, and adverse reactions for all patients. Results: Intramuscular ketamine was administered 1,022 times, mainly for laceration repair and fracture reduction. Physicians completed data forms for 431 of treated children (42%). Transient airway complications occurred in 1.4%: airway malalignment (n=7), laryngospasm (n=4), apnea (n=2), and respiratory depression (n=1). All were quickly identified and treated without intubation or sequelae. Emesis occurred in 6.7%, without evidence of aspiration. Mild recovery agitation occurred in 17.6%, moderate to severe agitation in 1.6%. No child required hospitalization for complications caused by ketamine. Ketamine produced acceptable sedation in 98% of patients. The median time from injection to emergency department discharge was 110 minutes for children given a single dose of ketamine. Conclusion: Intramuscular ketamine may be administered safely by emergency physicians to facilitate pediatric procedures in accordance with a defined protocol and with appropriate monitoring. Ketamine is highly effective, has a wide margin of safety, does not require intravenous access, and uniquely preserves protective airway reflexes. [Green SM, Rothrock SG, Lynch EL, Ho M, Harris T, Hestdalen R, Hopkins GA, Garrett W, Westcott K: Intramuscular ketamine for pediatric sedation in the emergency department: Safety profile in 1,022 cases. Ann Emerg Med June 1998;31:688-697.]

Anesthesia and Immunosuppression in an Experimental Model

The purpose of the present work was to study: (1) if anesthesia induces changes in the helper/cytotoxic/suppressor T cell ratio in the rat spleen, and (2) if there is any difference between two anesthetic methods usually employed in rat experimentation. 50 Fisher 344 rats were allotted into 5 groups. In group A (control), a splenectomy was performed in an average time of 3 min under ether anesthesia. In groups B1 and B2, the rats anesthetized for 1 h with ether (group B1) or with one single dose of ketamine + atropine + diazepam (group B2) and then underwent splenectomy. Groups C1 and C2 were similar to groups B1 and B2 but splenectomy was performed 24 h later, under ether anesthesia during 3 min. T helper (Th) and T cytotoxic-suppressor (Ts-c) cells were identified in periarterial and follicular spleen tissue by means of an immunohistologic analysis using an immunoperoxidase technique with monoclonal antibodies. In periarterial tissue the Th/Ts-c ratio (mean +/- SE) was: group A, 1.61 +/- 0.11; group B1, 1.10 +/- 0.1; group B2, 1.28 +/- 0.11; group C1, 0.85 +/- 0.08, and group C2, 1.23 +/- 0.12. The differences between groups A and B1, C1 and C2 were statistically significant (t = 2.2833) as well as the difference between groups C1 and C2 (t = 2.5223). The Th/Ts-c ratio was also compared when equal to 1 or less than 1. The difference between groups A and C1 was statistically significant (p less than 0.05) as well. In follicular tissue the ratio was 1 in all the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of ketamine on cardiovascular dynamics during halothane and enflurane anesthesia.

The cardiovascular effects of a single dose of ketamine administered during halothane or enflurane anesthesia were studied in 24 patients. During halothane anesthesia, ketamine caused a rapid and significant increase in arteriolar peripheral resistance (p less than 0.01) and a decrease in cardiac output, stroke volume, and systolic diastolic, and mean arterial blood pressures. Heart rate was not significantly changed. Ketamine resulted in similar, though less dramatic and slower developing, changes in patients anesthetized with enflurane. These results demonstrate that general anesthesia blocks the cardiovascular-stimulating properties of ketamine. They also indicate that ketamine has significant cardiovascular-depressant qualities when used during halothane or enflurane anesthesia.

Ketamine prevention of penile turgescence.

ABSTRACT To the Editor.— Cystoscopy and operative procedures on the penis can be rendered difficult, if not impossible, if an erection occurs. Since the latter is not uncommon, in spite of general and even regional anesthesia, a method to prevent or reverse this condition would be helpful. Since the turgescence seems to occur in response to external stimuli, it was thought that a dissociative anesthetic such as ketamine might prevent such a response.A limited number of patients (25) were given a does of 1 mg/lb of body weight at the time of induction. Anesthesia was induced and maintained in the usual manner with thiopental and nitrous oxide with a narcotic (anileridine) or halothane. In no case did an erection occur, even though only a single dose of ketamine was administered and the procedure lasted an hour or more. In two additional cases, the same dose of ketamine was administered after