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However, although the individual molecule has no pressure, the individual patient does have an explicit treatment effect. This extreme example may be seen as simply the knocking down of a straw man; but in evidence-based medical practice there seems to be an all-pervasive, unquestioned assumption that individual probability is equal to the frequentist population probability - the average treatment effect. Using frequentist methods, all the variation in individual (between-patient) response is assigned to the random-error term in the analysis - and ever more precise estimates of average treatment effect are sought by designing ever larger trials. An eloquent paper by Gill et al. entitled " I Why clinicians are natural bayesians i " [4] showed how this process is used for diagnosis of patients, but the same reasoning can also be applied to patient treatment. [Extracted from the article]

Methoxyflurane, an agent formerly used as a volatile anaesthetic but that has strong analgesic properties, will soon become available again in the UK and Europe in the form of a small hand-held inhaler. We describe our experience in the use of inhaled methoxyflurane for procedural analgesia within a large tertiary hospital. In a small pilot crossover study of patients undergoing burns-dressing procedures, self-administered methoxyflurane inhalation was preferred to ketamine-midazolam patient-controlled analgesia by five of eight patients. Patient and proceduralist outcomes and satisfaction were recorded from a subsequent case series of 173 minor surgical and radiological procedures in 123 patients performed using inhaled methoxyflurane. The procedures included change of dressing, minor debridement, colonoscopy and incision-and-drainage of abscess. There was a 97% success rate of methoxyflurane analgesia to facilitate these procedures. Limitations of methoxyflurane include maximal daily and weekly doses, and uncertainty regarding its safety in patients with pre-existing renal disease. [ABSTRACT FROM AUTHOR]

The authors comment on the results of the 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland, which focuses on accidental awareness during general anesthesia (AAGA). They discuss the three papers that summarized the results of the NAP5 and the use of a human factors/root cause analysis in evaluating the reasons for cases of AAGA.

Background The highly selective α2-adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. Methods Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 μg/kg and maintenance infusion at doses from 10 to 0.6 μg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. Results All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 μg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 μg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation ( CV) 46.6.%] and volume of distribution was 3.37 l/kg ( CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. Conclusions Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications. [ABSTRACT FROM AUTHOR]

Gap junction blockade is a possible mechanism by which general anaesthetic drugs cause unconsciousness. We measured the sensitivity of connexin36 knockout mice to the hypnotic effects of isoflurane and propofol. The experimental endpoint was recovery of the righting reflex of the anaesthetised animals during 0.2% step-reductions in isoflurane concentration, or following intraperitoneal injection of propofol (100 mg.kg). Connexin36 knockout animals were more sensitive to the hypnotic effects of isoflurane than 'normal' wild-type animals. The half maximal effective concentration (EC50) for recovery of righting reflex was 0.37% for connexin36 knockout vs 0.49% for wild-type animals (p < 0.001). For propofol, connnexin36 knockout animals showed more rapid loss of righting reflex than wild-type animals (mean (SD) 2.8 (0.13) vs 3.8 (0.27) min); and young (< 60 days) connexin36 knockout animals remained anaesthetised for longer than young wild-type mice (47.2 (2.9) vs 30.5 (1.7) min; p < 0.00001). These findings suggest that the hypnotic effects of anaesthetic drugs may be moderately enhanced by gap junction blockade. [ABSTRACT FROM AUTHOR]

Background: Different volatile anesthetic agents have differing propensities for inducing seizures. A measure of the predilection to develop seizures is the presence of interictal spike discharges (spikes) on the electrocorticogram (ECoG). In this study, we investigated the propensity of desflurane to induce cortical spikes and made a direct objective comparison with enflurane, isoflurane, and sevoflurane. The ECoG effects of desflurane have not been previously reported. Methods: After establishment of invasive monitoring and a parasagittal array of eight electrodes to record the ECoG; eight adult merino sheep were given a series of short inhalational anesthetics (using desflurane, enflurane, sevoflurane and isoflurane); each titrated to ECoG burst suppression. Anesthetic effect was estimated by the effects on the approximate entropy of the ECoG. The effect of anesthetic on the spike-rate in the ECoG was analyzed using a non-linear mixed-effect method with a sigmoid Emax model. Results: A similar ‘depth of anesthesia’ was achieved for each agent, as estimated by the approximate entropy. The mean (SD) values of Emax for the spike-rate vs. approximate entropy relationship were desflurane 0.5 (0.9), enflurane 17.2 (4.0), isoflurane 0.7 (1.2), and sevoflurane 5.3 (1.2) spikes/min. The spike rate caused by desflurane was similar to isoflurane and significantly lower than that of enflurane ( P < 0.001), and sevoflurane ( P = 0.009). Conclusion: Desflurane induces minimal cerebral cortical spike activity when administered to burst suppression, consistent with its low propensity for inducing seizures in non-epileptic brains. The agents can be ranked by their relative ability to cause spike activity: enflurane >> sevoflurane > isoflurane = desflurane. [ABSTRACT FROM AUTHOR]

Background: Postoperative respiratory disturbances may be the result either of depression of respiratory drive, or alteration of respiratory pattern.Methods: Using an inductance plethysmograph, we continuously recorded the breathing in 52 patients for 4 h after major thoracic, abdominal, and body surface surgery. The ventilatory response to hypercapnia was measured preoperatively, and at the start and end of the observation period.Results: From a variety of statistical measures of respiratory depression, it was found that the occurrence of apnoeas (breath times >10 s), did not correlate with measures of respiratory drive, or with dose or route of administration of opioid, site of surgery, pain, or drowsiness. Instead, the incidence of apnoeas correlated most closely with measures of respiratory pattern (standard deviation of breath times (r=0.72), the mean breath time (r=0.63), approximate entropy of the breath times (r= -0.32)). Twenty-nine percent of patients had some breath times (Ttot) longer than 20 s.Conclusion: We would conclude that changes in respiratory pattern are not closely correlated with changes in traditional measures of respiratory drive. [ABSTRACT FROM AUTHOR]

Eight patients were given a propofol infusion until they no longer responded to loud verbal stimuli, a sedation score of two (modified Observer Assessment of Alertness and Sedation Scale). After receiving 15 µg of intravenous epinephrine, changes in sedation score and bispectral index (BIS) were observed. Mean pulse rate increased from 68 to 96 (SD 10) beat.min-1, mean blood pressure increased from 107/60 (SD 10/8) mmHg to 140/70 (SD 27/14) mmHg, and mean BIS level rose from 63 to 76 (p < 0.005). Sedation scores increased in six of the eight patients. Exogenous catecholamines seem to have an arousal effect on lightly anaesthetised patients. This could be due to changes in neurotransmitter levels in the brain, or due to the effects consequent on increased cardiac output. [ABSTRACT FROM AUTHOR]

Three different dosage regimens of alfentanil were compared with boluses of fentanyl in 80 patients who underwent a variety of surgical procedures. Alfentanil given by infusion at a rate of 7.5 micrograms/kg/minute for 10 minutes followed by 0.75 micrograms/kg/minute, was shown to provide a stable anesthetic which minimises the use of a volatile agent for surgery that lasts more than 45 minutes.