Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anaesthetics and succinylcholine (SC) characterized by hypercapnia, hypermetabolism and muscle breakdown. MH is commonly caused by mutations in RYR1, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between risk genotypes and actual MH incidence remains unexplained. We hypothesized that MH is a compound event, reflecting a synergistic effect of predisposing genotype, triggering anaesthetic, and exercise and/or pyrexia as modifying factors. We performed a retrospective case study in 5 international MH centres and identified 41 patients with a history of exercise and/or pyrexia within 72 hours prior to an MH event. 35 patients had a causative RYR1 variant, in 6 MH susceptibility was confirmed on contracture testing. We compared the frequency of a history of exercise and/or pyrexia within 72 hours of the triggering agent in general anaesthesia with MH (GA+MH) (n=41) and without MH (GA-MH)(n=51) in the index cases and/or their MH susceptible relatives. Indications for and urgency of surgery, and SC use were also recorded. In GA+MH, there was a history of exercise and/or pyrexia within 72 hours prior to the anaesthetic in 24 and 21 patients, compared to 0 and 1 in GA-MH(p=0.000). Trauma and acute abdomen as surgery indications, emergency surgery and SC use were also more common in GA+MH (p=0.000). Exercise and/or pyrexia prior to GA are modifying factors for MH. Emergency surgery and the use of succinylcholine carry a particularly high risk. Rhabdomyolysis may mimic an acute abdomen (in particular appendicitis), leading to the potentially high-risk situation of a triggering anaesthetic given on the background of a pre-damaged musculature. Trauma surgery may carry a specific risk due to additional muscle damage. These observations should inform perioperative guidelines with substantial potential to reduce fatal anaesthesia-associated mortality and morbidity.

This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r(2)=0.95, p=0.002, and r(2)=0.97, p<0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r(2)=0.22, p=0.04) and ratios of Glu to Cr (r(2)=0.30, p=0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma. Copyright (c) 2014 John Wiley & Sons, Ltd.

BACKGROUND:The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity.METHODS:Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity.RESULTS:The mean [standard deviation (SD)] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) μg ml(-1). The maximum detected concentration in any patient was 3.76 μg ml(-1) (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean (SD) peak levels were elevated in these patients, 2.70 (0.46) µg ml(-1).CONCLUSIONS:TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity.

AIM:The aim of this study was to document exercise capacity and serial electrocardiogram and echocardiograph findings in a cohort of Australian patients with Fabry disease, in relation to their history of enzyme replacement therapy (ERT).BACKGROUND:Fabry disease has multifactorial effects on the cardiovascular system. Most previous studies have focused on electrocardiographic and echocardiographic parameters. Exercise capacity can be used as an integrated measure of cardiovascular function and allows the effects of treatment to be monitored.METHODS:A total of 38 patients (30 men and 8 women) with Fabry disease were monitored by 12-lead electrocardiograms every 6-12 months, and by annual standardized-protocol echocardiograms. Bicycle stress tests with VO(2) max measurement and once-only 6 minutes' walk tests were also carried out in subsets of patients whose general health status allowed testing.RESULTS:Seventy per cent of patients met electrocardiogram criteria for left ventricular hypertrophy. Left ventricular hypertrophy on echocardiograph was present in 64% of patients (80% of men). Exercise capacity was reduced in patients with Fabry disease compared with that predicted from normative population data. Mild improvement in anaerobic threshold was seen in the first year of ERT (14.1 +/- 3.0 to 15.8 +/- 3.0, P = 0.02), but no consistent further increase was seen beyond the first year. Most patients had resting bradycardia, with impaired ability to increase heart rate during exercise. Serial testing on ERT showed an improvement in anaerobic threshold but no significant change in VO(2) max.CONCLUSIONS:Male patients with Fabry disease were unable to attain predicted maximal heart rate on exercise or to achieve normal exercise levels. ERT was associated with a small improvement in anaerobic threshold over the first year.

BACKGROUND:We tested the hypothesis that there is greater suppression of autonomic reflexes during general anaesthesia when fentanyl is administered epidurally than when it is given intravenously.METHODS:Ten volunteers were anaesthetized with desflurane. Noxious stimuli of variable intensity were then delivered by tetanic electrical stimuli. Heart rate, arterial pressure, and pupillary dilation in response to these stimuli defined nociception. Seven of these volunteers participated twice using a crossover design: they received i.v. fentanyl on one study day and epidurally on the other. Autonomic responses to alternative tetanic stimuli at L4 and C5 dermatomes were measured every 5 min for 3 h after fentanyl administration.RESULTS:After a brief redistribution period, plasma fentanyl concentrations were virtually identical on both days. After stimulation of the L4 dermatome only, block of pupillary reflex dilation was greater by 47 (22)% after epidural fentanyl compared with i.v. fentanyl. Time to maximal depression of reflex dilation after L4 stimulation was 41 (13) min. Arterial pressure and heart rate decreased after fentanyl by either route but there were no differences observed between L4 and C5 stimulations.CONCLUSION:We conclude that during general anaesthesia, epidural fentanyl enhances antinociception by a spinal mechanism which can be detected by pupillary dilation but not by changes in arterial pressure or heart rate.

Areas of insensibility produced by neuraxial anesthesia or peripheral nerve blocks can be detected during general anesthesia by failure of noxious stimulation to trigger pupillary reflex dilation. We examined the latency of pupillary reflex dilation and the effect of fentanyl on the latency of reflex dilation during anesthesia in nine volunteers. We hypothesized that the reflex was generated by slowly conducting C nociceptive fibers and would be significantly delayed if a distal dermatome (L(4)) was stimulated compared with a proximal dermatome (C(5)). We also hypothesized that fentanyl would prolong the latency and alter the shape of the reflex. After induction of general anesthesia, pupillary reflex dilation was measured with an infrared pupillometer every 5 min after stimulations of the L(4) and C(5) dermatomes. Fentanyl (3 microg/kg) was then given intravenously. Pupillary reflex dilation latencies were calculated by examining each individual measurement. After 3 h, naloxone (400 microg) was given intravenously; anesthesia was then discontinued. Pupillary reflex dilation had a long latency and consisted of distinct early and late phases. No differences were found between latencies of reflex dilation after simulation of L(4) and C(5) dermatomes either before or after fentanyl administration. Fentanyl at high concentrations essentially eliminated pupillary reflex dilation; but over the 180-min observation period, first early and then late dilation returned. Fentanyl produced a small increase in the latency of the initial early dilation. We conclude that pupillary reflex dilation during anesthesia is not initiated by slowly conducting C fibers and that fentanyl depresses the reflex in a stereotypical manner.

UNLABELLED:Dantrolene is used for treatment of life-threatening hyperthermia, yet its thermoregulatory effects are unknown. We tested the hypothesis that dantrolene reduces the threshold (triggering core temperature) and gain (incremental increase) of shivering. Healthy volunteers were evaluated on 2 random days: control and dantrolene (approximately 2.5 mg/kg plus a continuous infusion). In Study 1, 9 men were warmed until sweating was provoked and then cooled until arteriovenous shunt constriction and shivering occurred. Sweating was quantified on the chest using a ventilated capsule. Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography. A sustained increase in oxygen consumption identified the shivering threshold. In Study 2, 9 men were given cold lactated Ringer's solution i.v. to reduce core temperature approximately 2 degrees C/h. Cooling was stopped when shivering intensity no longer increased with further core cooling. The gain of shivering was the slope of oxygen consumption versus core temperature regression. In Study 1, sweating and vasoconstriction thresholds were similar on both days. In contrast, shivering threshold decreased 0.3 +/- 0.3 degrees C, P = 0.004, on the dantrolene day. In Study 2, dantrolene decreased the shivering threshold from 36.7 +/- 0.2 to 36.3 +/- 0.3 degrees C, P = 0.01 and systemic gain from 353 +/- 144 to 211 +/- 93 mL.min(-1).degrees C(-1), P = 0.02. Thus, dantrolene substantially decreased the gain of shivering, but produced little central thermoregulatory inhibition. IMPLICATIONS:Dantrolene substantially decreases the gain of shivering but produces relatively little central thermoregulatory inhibition. It thus seems unlikely to prove more effective than conventional muscle relaxants for treatment of life-threatening hyperthermia.