J.W. Sear

Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis.

Background:There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods:The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results:Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2–5.2), but there was substantial heterogeneity (I2 = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (≤ 12 months) mortality was an OR = 6.7 (95% CI 4.1–10.9, I2 = 0%) and in the 4 studies that assessed long-term (more than 12 months) mortality was an OR = 1.8 (95% CI 1.4–2.3, I2 = 0%; P < 0.001 for test of interaction). Four studies, including 1,165 patients and 202 deaths, demonstrated an independent association between an increased creatine kinase muscle and brain isoenzyme measurement after surgery and mortality (OR 2.5, 95% CI 1.5–4.0, I2 = 4%). Conclusions:An increased troponin measurement after surgery is an independent predictor of mortality, particularly within the first year; limited data suggest an increased creatine kinase muscle and brain isoenzyme measurement also predicts subsequent mortality. Monitoring troponin measurements after noncardiac surgery may allow physicians to better risk stratify and manage their patients.

Systemic uptake of buprenorphine by cats after oral mucosal administration

The plasma concentration of buprenorphine was measured by radioimmunoassay in six female cats after the administration of 0.01 mg/kg (0.033 ml/kg) buprenorphine hydrochloride solution into the side of the cats mouth. Blood samples were taken through a preplaced jugular catheter before and one, two, four, six, 10, 15, 30, 45 and 60 minutes, and two, four, six, 12 and 24 hours after the dose was administered. The buprenorphine was accepted well by all the cats and did not cause salivation or vomiting. Its median peak plasma concentration was 7.5 ng/ml and was reached after 15 minutes. The pharmacokinetic data were similar to the pharmacokinetic data obtained after the intramuscular and intravenous administration of buprenorphine to cats from the same colony, suggesting that the mucosal route of administration should be as effective as intravenous and intramuscular injections. In addition, the pH of the oral cavity of 26 cats was measured with pH paper, and 100 cat owners were asked their preferred method of administering drugs to cats. The pH of the cats mouths was between 8 and 9, and the technique preferred by the cat owners was the use of drops placed in the mouth.

Neuraxial block, death and serious cardiovascular morbidity in the POISE trial

BACKGROUNDnThis post hoc analysis aimed to determine whether neuraxial block was associated with a composite of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal cardiac arrest within 30 days of randomization in POISE trial patients.nnnMETHODSnA total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to β-blocker or placebo. Neuraxial block was defined as spinal, lumbar or thoracic epidural anaesthesia. Logistic regression, with weighting using estimated propensity scores, was used to determine the association between neuraxial block and primary and secondary outcomes.nnnRESULTSnNeuraxial block was associated with an increased risk of the primary outcome [287 (7.3%) vs 229 (5.7%); odds ratio (OR), 1.24; 95% confidence interval (CI), 1.02-1.49; P=0.03] and MI [230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07-1.64; P=0.009] but not stroke [23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44-1.33; P=0.34], death [96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65-1.17; P=0.37] or clinically significant hypotension [522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99-1.30; P=0.08]. Thoracic epidural with general anaesthesia was associated with a worse primary outcome than general anaesthesia alone [86 (12.1%) vs 119 (5.4%); OR, 2.95; 95% CI, 2.00-4.35; P<0.001].nnnCONCLUSIONSnIn patients at high risk of cardiovascular morbidity, neuraxial block was associated with an increased risk of adverse cardiovascular outcomes, which could be causal or because of residual confounding.

Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats

OBJECTIVEnTo describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (SC) buprenorphine in cats.nnnSTUDY DESIGNnRandomized, prospective, blinded, three period crossover experiment.nnnANIMALSnSix healthy adult cats weighing 4.1±0.5 kg.nnnMETHODSnBuprenorphine (0.02 mg kg(-1)) was administered i.v., i.m. or s.c.. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p<0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the i.v. data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.nnnRESULTSnTT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after i.v. and i.m. administration, respectively (p<0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60 minutes (i.v.), 4.6±2.8°C at 45 minutes (i.m.) and 1.9±1.9°C at 60 minutes (s.c.). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after i.v. administration compared to i.m. and s.c., respectively. I.v. and i.m. buprenorphine concentration-time data decreased curvilinearly. S.c. PK could not be modeled due to erratic absorption and disposition. I.v. buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t(1/2) k(e0)=47.4 minutes) and receptor binding (k(on)=0.011 mL ng(-1) minute(-1)). Persistence of thermal antinociception was due to slow receptor dissociation (t(1/2) k(off)=18.2 minutes).nnnCONCLUSIONS AND CLINICAL RELEVANCEnI.v. and i.m. data followed classical disposition and elimination in most cats. Plasma concentrations after i.v. administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the i.v. route should be preferred over the i.m. and s.c. routes when buprenorphine is administered to cats.

Use of a transdermal matrix patch of buprenorphine in cats: preliminary pharmacokinetic and pharmacodynamic data

Six domestic shorthair cats, aged three to four years and weighing 5·1 to 7·4 kg, were used to assess the thermal antinociceptive effect of a transdermal buprenorphine patch, designed to supply 35 μg buprenorphine/hour, which was applied to the shaved thorax. The cats thermal thresholds were tested before the patch was applied and two, four, six, eight, 10, 12, 14 and 16 hours after it had been applied, and then every six hours until it was removed after 72 hours, and for a further 24 hours afterwards. Blood was collected at each time to measure the plasma concentration of buprenorphine. The patches did not produce a significant change in the thermal thresholds of the cats throughout the testing period. The mean (sd) peak plasma buprenorphine concentration was 10 (0·81) ng/ml.

Nitrous Oxide and Serious Morbidity and Mortality in the POISE Trial

BACKGROUND:In this post hoc subanalysis of the Perioperative Ischemic Evaluation (POISE) trial, we sought to determine whether nitrous oxide was associated with the primary composite outcome of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal cardiac arrest within 30 days of randomization. METHODS:The POISE trial of perioperative &bgr;-blockade was undertaken in 8351 patients. Nitrous oxide anesthesia was defined as the coadministration of nitrous oxide in patients receiving general anesthesia, with or without additional neuraxial blockade or peripheral nerve blockade. Logistic regression, with inverse probability weighting using estimated propensity scores, was used to determine the association of nitrous oxide with the primary outcome, MI, stroke, death, and clinically significant hypotension. RESULTS:Nitrous oxide was administered to 1489 (29%) of the 5133 patients included in this analysis. Nitrous oxide had no significant effect on the risk of the primary outcome (112 [7.5%] vs 248 [6.9%]; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.82–1.44; 99% CI, 0.75–1.57; P = 0.58), MI (89 [6.0] vs 204 [5.6]; OR, 0.99; 95% CI, 0.75–1.31; 99% CI, 0.69–1.42; P = 0.94), stroke (6 [0.4%] vs 28 [0.8%]; OR, 0.85; 95% CI, 0.26–2.82; 99% CI, 0.17–4.11; P = 0.79), death (40 [2.7%] vs 100 [2.8%]; OR, 1.04; 95% CI, 0.6–1.81; 99% CI, 0.51–2.15; P = 0.88) or clinically significant hypotension (219 [14.7%] vs 544 [15.0%]; OR, 0.92; 95% CI, 0.74–1.15; 99% CI, 0.70–1.23; P = 0.48). CONCLUSIONS:In this post hoc subanalysis, nitrous oxide was not associated with an increased risk of adverse outcomes in the POISE trial patients. This analysis was limited by the observational nature of the data and the lack of information on the concentration and duration of nitrous oxide administration. Further randomized controlled trial evidence is required.

Propofol anaesthesia for surgery in late gestation pony mares

OBJECTIVEnTo characterize propofol anaesthesia in pregnant ponies.nnnANIMALSnFourteen pony mares, at 256 ± 49 days gestation, undergoing abdominal surgery to implant fetal and maternal vascular catheters.nnnMATERIALS AND METHODSnPre-anaesthetic medication with intravenous (IV) acepromazine (20 µg kg-1), butorphanol (20 µg kg-1) and detomidine (10 µg kg-1) was given 30 minutes before induction of anaesthesia with detomidine (10 µg kg-1) and ketamine (2 mg kg-1) IV Maternal arterial blood pressure was recorded (facial artery) throughout anaesthesia. Arterial blood gas values and plasma concentrations of glucose, lactate, cortisol and propofol were measured at 20-minute intervals. Anaesthesia was maintained with propofol infused initially at 200 µg kg-1 minute-1, and at 130-180 µg kg-1 minute-1 after 60 minutes, ventilation was controlled with oxygen and nitrous oxide to maintain PaCO2 between 5.0 and 6.0 kPa (37.6 and 45.1 mm Hg) and PaO2 between 13.3 and 20.0 kPa (100 and 150.4 mm Hg). During anaesthesia flunixin (1 mg kg-1), procaine penicillin (6 IU) and butorphanol 80 µg kg-1 were given. Lactated Ringers solution was infused at 10 mL kg-1 hour-1. Simultaneous fetal and maternal blood samples were withdrawn at 85-95 minutes. Recovery from anaesthesia was assisted.nnnRESULTSnArterial blood gas values remained within intended limits. Plasma propofol levels stabilized after 20 minutes (range 3.5-9.1 µg kg-1); disposition estimates were clearance 6.13 ± 1.51 L minute-1 (meanu200a±u200aSD) and volume of distribution 117.1 ± 38.9 L (meanu200a±u200aSD). Plasma cortisol increased from 193 ± 43 nmol L-1 before anaesthesia to 421 ± 96 nmol L-1 60 minutes after anaesthesia. Surgical conditions were excellent. Fetal umbilical venous pH, PO2 and PCO2 were 7.35 ± 0.04, 6.5 ± 0.5 kPa (49 ± 4 mm Hg) and 6.9 ± 0.5 kPa (52 ± 4 mm Hg); fetal arterial pH, PO2 and PCO2 were 7.29 ± 0.06, 3.3 ± 0.8 kPa (25 ± 6 mm Hg) and 8.7 ± 0.9 kPa (65 ± 7 mm Hg), respectively. Recovery to standing occurred at 46 ± 17 minutes, and was generally smooth. Ponies regained normal behaviour patterns immediately.nnnCONCLUSIONS AND CLINICAL RELEVANCEnPropofol anaesthesia was smooth with satisfactory cardiovascular function in both mare and fetus; we believe this to be a suitable anaesthetic technique for pregnant ponies.

Ketamine hepato-toxicity in chronic pain management: Another example of unexpected toxicity or a predicted result from previous clinical and pre-clinical data?

This issue of PAIN reports on a series of patients being treated with S(+)ketamine for relief of chronic pain [11]. In three of the patients, abnormalities occur following repeat exposure to ketamine with the liver enzyme values returning below the upper reference limit of normal range (URL) on cessation of the drug. Ketamine has been used worldwide and shown to be a useful agent for induction and maintenance of anesthesia (especially in children) in the elective surgical scene and in emergency out-of-hospital medicine, as well as providing analgesia in the intraand post-operative period. Ketamine is also becoming popular as a drug of recreational abuse, and in the latter scenario, liver toxicity has been reported. In a review of 233 patients presenting to the Hong Kong Poisons Information Center, 178 had liver function tests recorded with abnormal values of ALP and ALT in 29 patients (16.3%) [10]. Other sites of ketamine toxicity are the bladder and urinary tract. One or more ketamine metabolites may be the toxic agent(s) [25]. In general, drug-related hepatotoxicity may be manifest in one of several ways – clinically as hepatitis or cholestasis, as an increase in plasma activity of intracellular enzymes (such as the transaminases), or a decrease in the production of proteins (such as the factors associated with coagulation). The etiology of the liver damage also varies. This may relate to exposure of the hepatocyte to reactive drug metabolites formed during cytochrome P450 biotransformations; by general mechanisms of cell injury (due to non-covalent interactions resulting in lipid peroxidation, glutathione depletion and modification of the sulphydryl groups on key enzymes and structural proteins, increases in intracellular calcium ions secondary to increased cell membrane permeability); to cholestasis; or to immunological mechanisms. As well as causing loss of consciousness, all anesthetics have effects on other body organs and tissues – including the liver. Sometimes the occurrence of significant adverse side-effects of a drug is observed after licensing and while the drug is in widespread clinical use. The development of hepatotoxic damage may result in significant patient outcomes. Continuous infusion of most hypnotic agents (ketamine excepted) has effects on liver blood flow secondary to decreases in cardiac output and mean arterial pressure [13,17,21]. By contrast, ketamine has cardio-stimulatory properties with infusions having little effect on total hepatic blood flow. Neither hepatic arterial nor portal venous flows are significantly different from baseline values [20]. However ketamine causes a decrease

Pharmacokinetic and pharmacodynamic evaluation of high doses of buprenorphine delivered via high-concentration formulations in cats.

Objectives To evaluate the potential benefits of high-dose buprenorphine formulations for analgesia in cats, serial and crossover studies were undertaken to investigate their pharmacokinetics and thermal antinociceptive effects. Methods Twelve healthy adult domestic shorthair cats (6.0 ± 1.1 kg body weight) were studied. Aqueous solutions of buprenorphine hydrochloride at 0, 0.02, 0.06, 0.12 and 0.24 mg/kg body weight and formulations containing 0, 0.3, 0.6 and 1.2 mg/ml with and without preservatives were given subcutaneously. Blood samples were taken and thermal threshold (TT) measured prior to and at regular time points up to 72 h after dosing. Descriptive statistics and analyses of variance were applied as appropriate. Results Baseline TT was 47.6 ± 4.1°C, which increased in all groups treated with all buprenorphine dosages and formulations. After doses of 0.12 mg/kg and above, TT was significantly higher than baseline at most time points from 1–30 h post-treatment. The time to maximum effect (Tmax) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (Cmax) were 1.01–1.72 ng/ml after the 0.02 mg/kg dose, 1.4–4.9 ng/ml after the 0.06 mg/kg dose, 4.6–51.4 ng/ml after the 0.12 mg/kg dose and 5.3–22.3 ng/ml after the 0.24 mg/kg dose. The range of estimates for the buprenorphine elimination half-life were as follows: 0.02 mg/kg = 1.35–5.33 h; 0.06 mg/kg = 16.1–31.2 h; 0.12 mg/kg = 10.1–34.0 h; and 0.24 = mg/kg 16.1–31.6 h. The mean ‘plasma concentration for the offset of analgesia’ was 2.3 ± 2.0 ng/ml. No adverse effects were seen. The addition of preservatives to a high-concentration buprenorphine formulation had no impact on antinociception nor any side effects. Conclusions and relevance Aqueous high-concentration buprenorphine formulations administered at 0.12 or 0.24 mg/kg have potential for clinical use in cats, providing prolonged antinociception in a single subcutaneous injection of minimal dose volume.

Pharmacokinetic-pharmacodynamic modelling of intravenous buprenorphine in conscious horses

OBJECTIVEnDescribe the pharmacokinetics of buprenorphine and norbuprenorphine in horses and to relate the plasma buprenorphine concentration to the pharmacodynamic effects.nnnSTUDY DESIGNnSingle phase non-blinded study.nnnANIMALSnSix dedicated research horses, aged 3-10xa0years and weighing 480-515xa0kg.nnnMETHODSnThermal and mechanical nociceptive thresholds, heart and respiratory rates and locomotor activity were measured before and 15, 30, 45 & 60xa0minutes and 2, 4, 6, 8, 12 & 24xa0hours post-administration of 10xa0μgxa0kg(-1) buprenorphine IV. Intestinal motility was measured 1, 6, 12 & 24xa0hours after buprenorphine administration. Venous blood samples were obtained before administration of buprenorphine 10xa0μgxa0kg(-1) IV and 1, 2, 4, 6, 10, 15, 30, 45 & 60xa0minutes, and 2, 4, 6, 8, 12 & 24xa0hours afterwards. Plasma buprenorphine and norbuprenorphine concentrations were measured using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay with solid-phase extraction. A non-compartmental method was used for analysis of the plasma concentration-time data and plasma buprenorphine concentrations were modelled against two dynamic effects (change in thermal threshold and mechanical threshold) using a simple Emax model.nnnRESULTSnPlasma buprenorphine concentrations were detectable to 480xa0minutes in all horses and to 720xa0minutes in two out of six horses. Norbuprenorphine was not detected. Thermal thresholds increased from 15xa0minutes post-buprenorphine administration until the 8-12xa0hour time points. The increase in mechanical threshold ranged from 3.5 to 6.0xa0Newtons (median: 4.4xa0N); and was associated with plasma buprenorphine concentrations in the range 0.34-2.45xa0ngxa0mL(-1) .nnnCONCLUSIONS AND CLINICAL RELEVANCEnThe suitability of the use of buprenorphine for peri-operative analgesia in the horse is supported by the present study.