Functional characterization of RYR1 variants identified in malignant hyperthermia susceptible individuals.

Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium channel of skeletal muscle. In this study, we performed functional analysis of 5 RYR1 variants identified in members from 8 families who had been diagnosed by the IVCT. Of the 68 individuals enrolled in the study, 43 were diagnosed as MHS, 23 as MHN, and 2 individuals were not tested. Here we demonstrate that the 5 RyR1 variants cause hypersensitivity to RyR1 agonist-mediated calcium release. According to the EMHG scoring matrix these five genetic variants can be classified as follows: c.8638G>A (p.E2880K) and c.11314C>T (p.R3772W) likely pathogenic, c.11416G>A (p.G3806R), c.14627A>G (p.K4876R) and c.14813T>C (p.I4938T), pathogenic (RefSeq NM_000540.3). We propose that the newly functionally characterized RYR1 variants, be included in the panel of variants to be used for the molecular diagnosis of MHS.

BMI and malignant hyperthermia pathogenic ryanodine receptor type 1 sequence variants in Switzerland: A retrospective cohort analysis.

BACKGROUND: Ryanodine receptor type 1 (RYR1) sequence variants are pathogenic for malignant hyperthermia. Variant carriers have a subtle increase in resting myoplasmic calcium concentration compared with nonaffected individuals, but whether this has metabolic effects in daily life is unknown. OBJECTIVES: We analysed the potential effect of malignant hyperthermia-pathogenic RYR1 sequence variants on BMI as a single factor. Due to the heterogeneity of genetic variants predisposing to malignant hyperthermia, and to incomplete information about their regional distribution, we describe the prevalence of RYR1 variants in our population. DESIGN: A retrospective cohort study. SETTING: A single University hospital. PATIENTS: Patients from malignant hyperthermia families with pathogenic RYR1 sequence variants were selected if BMI was available. OUTCOME MEASURES: BMI values were compared amongst malignant hyperthermia susceptible (MHS) and malignant hyperthermia-negative individuals using hierarchical multivariable analyses adjusted for age and sex and considering family clustering. Variant prevalence was calculated. RESULTS: The study included 281 individuals from 42 unrelated malignant hyperthermia families, 109 of whom were MHS and carriers of the familial RYR1 sequence variants. Median [IQR] BMI in MHS individuals with pathogenic RYR1 variants was 22.5 kg m-2 [21.3 to 25.6 kg m-2]. In malignant hyperthermia-negative individuals without variants, median BMI was 23.4 kg m-2 [21.0 to 26.3 kg m-2]. Using multivariable regression adjusted for age and sex, the mean difference was -0.73 (95% CI -1.51 to 0.05). No carrier of a pathogenic RYR1 sequence variant was found to have BMI higher than 30 kg m-2. Only 10 RYR1 variants from the list of the European MH Group were found in our cohort, the most common being p.Val2168Met (39% of families), p.Arg2336His (24%) and p.Arg614Cys (12%). CONCLUSION: The observed tendency towards lower BMI values in carriers of malignant hyperthermia-pathogenic RYR1 sequence variants points to a possible protective effect on obesity. This study confirms regional differences of the prevalence of malignant hyperthermia-pathogenic RYR1 sequence variants, with just three variants covering 75% of Swiss MHS families. TRIAL REGISTRATION: This manuscript is based on a retrospective analysis.

Impact of statin intake on malignant hyperthermia: an in vitro and in vivo swine study.

BACKGROUND: Statin intake is associated with muscular side effects, among which the unmasking of latent myopathies and of malignant hyperthermia (MH) susceptibility have been reported. These findings, together with experimental data in small animals, prompt speculation that statin therapy may compromise the performance of skeletal muscle during diagnostic in vitro contracture tests (IVCT). In addition, statins might reduce triggering thresholds in susceptible individuals (MHS), or exacerbate MH progression. We sought to obtain empirical data to address these questions. METHODS: We compared the responses of 3 different muscles from untreated or simvastatin treated MHS and non-susceptible (MHN) pigs. MHS animals were also invasively monitored for signs of impending MH during sevoflurane anesthesia. RESULTS: Muscles from statin treated MHS pigs responded with enhanced in vitro contractures to halothane, while responses to caffeine were unaltered by the treatment. Neither agent elicited contractures in muscles from statin treated MHN pigs. In vivo, end- tide pCO2, hemodynamic evolution, plasma pH, potassium and lactate concentrations consistently pointed to mild acceleration of MH development in statin-treated pigs, whereas masseter spasm and rigor faded compared to untreated MHS animals. CONCLUSIONS: The diagnostic sensitivity and specificity of the IVCT remains unchanged by a short-term simvastatin treatment in MHS swine. Evidence of modest enhancement in cardiovascular and metabolic signs of MH, as well as masked pathognomonic muscle rigor observed under simvastatin therapy suggest a potentially misleading influence on the clinical presentation of MH. The findings deserve further study to include other statins and therapeutic regimes.

Pain Response to Open Label Placebo in Induced Acute Pain in Healthy Adult Males.

BACKGROUND: Open label placebos with patient education are effective in reducing chronic pain, and recent studies on their effect on pain have established interest in this field. Nevertheless, data on their effect on acute pain are scarce, and on hyperalgesia and allodynia, absent. This study assessed the effect of open label placebos on acute pain in healthy adult males and the influence of placebo education. METHODS: Thirty-two healthy males were included in this prospective, randomized, assessor-blinded crossover, single-center study assessing pain intensities (via numeric rating scale), area of hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a pain model utilizing intracutaneous electrical stimulation. The authors compared the effect of intravenous open label placebo on pain compared to no treatment. The authors further examined the effect of placebo on hyperalgesia and allodynia, and the influence of education (short vs. detailed) before placebo application. Saliva cortisol concentrations were also measured. RESULTS: Pain ratings (median, first to third quartile) were 21% lower during placebo treatment compared to no treatment, 4.0 (3.2 to 4.9) versus 5.1 (4.7 to 5.4), respectively (P = 0.001). The areas of hyperalgesia and allodynia were lower during placebo treatment compared to no treatment (hyperalgesia, 30 cm [17 to 47] vs. 55 cm [42 to 68], P = 0.003; allodynia, 24 cm [11 to 39] vs. 45 cm [31 to 62], P = 0.007). This corresponds to reductions of 47%. The extent of placebo education had no effect on pain. Saliva cortisol decreased significantly over time and was under the limit of detectability in the majority of participants in postbaseline measurements in both treatment branches. Baseline cortisol was not associated with the placebo effect or strength applied of current to reach defined pain ratings. CONCLUSIONS: Open label placebos might play a role in multimodal analgesic concepts.

Association between intra-operative fentanyl dosing and postoperative nausea/vomiting and pain: A prospective cohort study.

BACKGROUND: Postoperative nausea and/or vomiting (PONV) is one of the anaesthesia-related effects most dreaded by patients and may delay hospital discharge. Although scores and risk factors are established, many were developed before contemporary anaesthesia regimens and without focussing on modifiable anaesthesia-related variables. OBJECTIVE: To examine whether, in association with a contemporary anaesthesia regimen, there is an association between intra-operative fentanyl dose and PONV, and, second, postoperative pain within the first 24 h. DESIGN: Prospective, observational cohort. SETTING: Single-centre university hospital. PATIENTS: Inclusion criteria were opioid-naive patients without chronic pain and with a simplified Apfel score at least 2 undergoing abdominal, gynaecological or otorhinolaryngological inpatient surgery. INTERVENTION: None. MAIN OUTCOME MEASURE: With logistic regression, we examined three models of increasing complexity exploring the relationship between PONV and fentanyl dosing: Model 1, simplified Apfel score + intra-operative fentanyl; Model 2, Model 1 + pre-emptive antiemetic prophylaxis; Model 3, Model 2 + postoperative morphine. Model 1 was the primary analysis. Second, we explored whether or not postoperative pain scores were associated with intra-operative fentanyl dosing. RESULTS: From the 363 patients, 163 (45%) experienced PONV, despite the use of total intravenous anaesthesia with propofol in more than 80% of the cohort, and some 66% of patients receiving additional antiemetic agents. After adjusting for the simplified Apfel score, higher intra-operative fentanyl dose was associated with PONV: odds ratio per µg h, 1.006 [95% confidence interval (CI) 1.002 to 1.010]. Including intra-operative fentanyl in the simplified Apfel score also increased the area under the receiver operator characteristics curve [0.601 (95% CI 0.555 to 0.662) vs. 0.651 (95% CI 0.594 to 0.707); P = 0.016]. Finally, a higher intra-operative fentanyl dose was associated with higher 24 h pain scores (P = 0.001) and a trend towards higher 24 h morphine requirements (P = 0.055). CONCLUSION: Even when using propofol and antiemetic agents, PONV within the first 24 h remained higher than expected. Intra-operative fentanyl, a modifiable risk factor, is associated with the incidence of PONV and postoperative pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03201315.

[Malignant Hyperthermia - Diagnosis in Practice]. / Maligne Hyperthermie: Diagnostik konkret.

Testing for malignant hyperthermia (MH) susceptibility is usually performed either in relatives of MH susceptible persons or in patients with an MH suspicious clinical event. There are two diagnostic options: muscle biopsy with in-vitro contracture testing and molecular genetic diagnosis. Patients with familial MH mutations are usually tested genetically. A genetic screening can be performed in clinical events with a high pretest probability. MH susceptibility can be confirmed by presence of a diagnostic MH mutation. Absence of MH mutations cannot exclude MH. The only option to exclude MH susceptibility is contracture testing.

Post-dural puncture headache.

Neuraxial analgesia and anesthesia are widely used in obstetric anesthesia. The most frequent complication after neuraxial blocks is post-dural puncture headache. It can occur after unintentional dural puncture during epidural procedures or after spinal anesthesia. Unintentional dural puncture occurs in 0.15-1.5% of labor epidural analgesia and 50-80% of these women develop post-dural puncture headache. The headache is typically orthostatic in nature and can be so incapacitating that the mother becomes bedbound and is no longer able to care for herself and her newborn child. A wide variety of prophylactic and therapeutic measures have been tried. So far, the therapeutic epidural blood patch is the only treatment for which there is enough evidence to recommend its routine use for severe cases of post-dural puncture headache. Larger multicenter trials are needed to back up alternative treatment strategies.

Time course of copeptin during a model of experimental pain and hyperalgesia: A randomised volunteer crossover trial.

BACKGROUND: A reliable biomarker for quantifying pain or hyperalgesia has yet to be found. A surrogate marker of arginine vasopressin, copeptin, is elevated in a number of states of physiological and psychological stress and may have a role in quantifying pain and/or hyperalgesia. OBJECTIVES: To evaluate copeptin as a biomarker for pain or hyperalgesia developing after 120 min of sustained electrical stimulation. DESIGN: Secondary analysis of a randomised, double-blinded, crossover trial. SETTING: Single, tertiary university hospital from September 2014 to January 2015. PARTICIPANTS: A total of 16 healthy, opioid-naïve white men with no confounding medication or history of pain. INTERVENTIONS: Copeptin and cortisol were measured five times during an established model of transdermal electrical stimulation designed to assess pain and hyperalgesia. MAIN OUTCOME MEASURES: The primary outcome was the change in copeptin concentration after 120 min of sustained electrical stimulation. Secondary outcomes were copeptin and cortisol concentrations after a subsequent period of rest and analyses of copeptin and cortisol concentrations were made in high-dose and low-dose fentanyl groups separately. RESULTS: Total copeptin concentrations were not significantly elevated after 120 min [9.15 pmol l (interquartile ranges (IQR), 3.45 to 35.45 pmol l); P = 0.150] compared with baseline [6.15 pmol l (IQR, 3.60 to 10.62 pmol l)]. In the high-dose fentanyl group, there was a significant increase in copeptin within individuals [P = 0.001; median, 37.9 pmol l (IQR, 8.1 to 62 pmol l)] after 120 min, and in the low-dose fentanyl group a significant decrease in copeptin concentrations within individuals [P = 0.006; median, 4.7 pmol l (IQR, 3.13 to 9.35 pmol l)]. No correlation between copeptin concentration and either the area under the pain curve or area under the hyperalgesia curve could be found, indicating that the observed differences may be due to other fentanyl-mediated effects. CONCLUSION: Copeptin concentrations do not appear to be associated directly with pain and hyperalgesia. Instead, some fentanyl-mediated effect or effects appear to have greatly increased copeptin concentrations from baseline to 120 min. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02252458.

Different protocols used today to achieve total opioid-free general anesthesia without locoregional blocks.

With increasing awareness of both short- and long-term problems associated with liberal perioperative opioid administration, the need for routinely and clinically feasible alternatives is greater than ever. Opioid-free anesthesia-previously reserved for bariatric surgery-is receiving increasing attention in mainstream anesthesia. In this review, we present the truly multimodal concept of opioid-free anesthesia, which circumvents a number of opioid-related problems. For a concrete clinical perspective, we present in depth our opioid-free protocol for bariatric surgery. However, clinicians must be aware of potential problems related to opioid-free anesthesia.

Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy Volunteers?: A Double-blind, Randomized, Crossover Trial.

BACKGROUND: Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of fentanyl dosing on pain perception and central sensitization in healthy volunteers using established pain models. METHODS: Twenty-one healthy, male volunteers were included in this randomized, double-blind, crossover study and received either intravenous low-dose (1 µg/kg) or high-dose (10 µg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration. RESULTS: A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower [95% CI, 0.63 to 1.02]; P < 0.001) but increased areas of hyperalgesia (+30.5% [95% CI, 16.6 to 44.4%]; P < 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% [95% CI, -15.4 to 23.5%]; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% [95% CI, 29.7 to 56.3%]; P < 0.001) and tolerance (+32.5% [95% CI, 21.7 to 43.4%]; P < 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea. CONCLUSIONS: A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores.

Intra- and postoperative intravenous ketamine does not prevent chronic pain: A systematic review and meta-analysis.

Background and aims The development of postoperative chronic pain (POCP) after surgery is a major problem with a considerable socioeconomic impact. It is defined as pain lasting more than the usual healing, often more than 2-6 months. Recent systematic reviews and meta-analyses demonstrate that the N-methyl-D-aspartate-receptor antagonist ketamine given peri- and intraoperatively can reduce immediate postoperative pain, especially if severe postoperative pain is expected and regional anaesthesia techniques are impossible. However, the results concerning the role of ketamine in preventing chronic postoperative pain are conflicting. The aim of this study was to perform a systematic review and a pooled analysis to determine if peri- and intraoperative ketamine can reduce the incidence of chronic postoperative pain. Methods Electronic searches of PubMed, EMBASE and Cochrane including data until September 2013 were conducted. Subsequently, the titles and abstracts were read, and reference lists of reviews and retrieved studies were reviewed for additional studies. Where necessary, authors were contacted to obtain raw data for statistical analysis. Papers reporting on ketamine used in the intra- and postoperative setting with pain measured at least 4 weeks after surgery were identified. For meta-analysis of pain after 1, 3, 6 and 12 months, the results were summarised in a forest plot, indicating the number of patients with and without pain in the ketamine and the control groups. The cut-off value used for the VAS/NRS scales was 3 (range 0-10), which is a generally well-accepted value with clinical impact in view of quality of life. Results Our analysis identified ten papers for the comprehensive meta-analysis, including a total of 784 patients. Three papers, which included a total of 303 patients, reported a positive outcome concerning persistent postsurgical pain. In the analysis, only one of nine pooled estimates of postoperative pain at rest or in motion after 1, 3, 6 or 12 months, defined as a value ≥3 on a visual analogue scale of 0-10, indicated a marginally significant pain reduction. Conclusions Based on the currently available data, there is currently not sufficient evidence to support a reduction in chronic pain due to perioperative administration of ketamine. Only the analysis of postoperative pain at rest after 1 month resulted in a marginally significant reduction of chronic postoperative pain using ketamine in the perioperative setting. Implications It can be hypothesised, that regional anaesthesia in addition to the administration of perioperative ketamine might have a preventive effect on the development of persistent postsurgical pain. An additional high-quality pain relief intra- and postoperatively as well after discharge could be more effective than any particular analgesic method per se. It is an assumption that a low dose infusion ketamine has to be administered for more than 72 h to reduce the risk of chronic postoperative pain.

Severe anaphylactic shock due to ethylene oxide in a patient with myelomeningocele: successful exposure prevention and pretreatment with omalizumab.

Ethylene oxide (EO) is a highly reactive gas widely used for sterilization of medical devices, for example, plastic materials and ventriculoperitoneal shunts. Allergic reactions to EO are rare and have been observed mainly in patients during hemodialysis and myelomeningocele patients. We describe severe anaphylaxis to EO in a patient with myelomeningocele during general anesthesia. A detailed description is provided about the prevention measures aimed at reducing exposure to EO including a novel approach by resterilization with plasma. Also, pretreatment with omalizumab was implemented for the first time in such a case. With these measures, further surgeries in our patient were uneventful.

Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic paralyses.

Myotonia congenita and periodic paralyses are hereditary skeletal muscle channelopathies. In these disorders, various channel defects in the sarcolemma lead to a severely disturbed membrane excitability of the affected skeletal muscles. The clinical picture can range from severe myotonic reactions (e.g., masseter spasm, opisthotonus) to attacks of weakness and paralysis. Provided here is a short overview of the pathomechanisms behind such wide-ranging phenotypic presentations in these patients, followed by recommendations concerning the management of anesthesia in such populations.

Malignant hyperthermia.

Malignant hyperthermia (MH) is a subclinical myopathy, usually triggered by volatile anaesthetics and depolarising muscle relaxants. Clinical symptoms are variable, and the condition is sometimes difficult to identify. Nevertheless, rapid recognition and specific as well as symptomatic treatment are crucial to avoid a lethal outcome. Molecular genetic investigations have confirmed the skeletal muscle type ryanodine receptor to be the major MH locus with more than 70% of MH families carrying a mutation in this gene. There is no screening method to test for MH, as current tests are invasive (open muscle biopsy) or restricted to MH families with known MH-associated mutations (molecular genetic testing). The prevalence of the MH trait is unknown, because the clinical penetrance after contact with triggering agents is very variable. More recently, MH mutations have been associated with rhabdomyolysis following statin therapy or with non-pharmacological triggering, such as exertional heat stroke.

Lactic acid restores skeletal muscle force in an in vitro fatigue model: are voltage-gated chloride channels involved?

High interstitial K(+) concentration ([K(+)]) has been reported to impede normal propagation of electrical impulses along the muscle cell membrane (sarcolemma) and then also into the transverse tubule system; this is one considered underlying mechanism associated with the development of muscle fatigue. Interestingly, the extracellular buildup of lactic acid, once considered an additional cause for muscle fatigue, was recently shown to have force-restoring effects in such conditions. Specifically, it was proposed that elevated lactic acid (and intracellular acidosis) may lead to inhibition of voltage-gated chloride channels, thereby reestablishing better excitability of the muscle cell sarcolemma. In the present study, using an in vitro muscle contractile experimental setup to study functionally viable rectus abdominis muscle preparations obtained from normal swine, we examined the effects of 20 mM lactic acid and 512 µM 9-anthracenecarboxylic acid (9-AC; a voltage-gated chloride channel blocker) on the force recovery of K(+)-depressed (10 mM K(+)) twitch forces. We observed a similar muscle contractile restoration after both treatments. Interestingly, at elevated [K(+)], myotonia (i.e., hyperexcitability or afterdepolarizations), usually present in skeletal muscle with inherent or induced chloride channel dysfunctions, was not observed in the presence of either lactic acid or 9-AC. In part, these data confirm previous studies showing a force-restoring effect of lactic acid in high-[K(+)] conditions. In addition, we observed similar restorative effects of lactic acid and 9-AC, implicating a beneficial mechanism via voltage-gated chloride channel modulation.

Tropisetron blocks analgesic action of acetaminophen: a human pain model study.

Because the mechanism underlying the analgesic action of acetaminophen remains unclear, we investigated the possible interaction of acetaminophen with central serotonergic pathways. The effects of acetaminophen, tropisetron, the combination of both drugs, and saline on pain perception and central sensitization in healthy volunteers were compared. Sixteen healthy volunteers were included in this randomized, double-blind, placebo-controlled crossover study. Intracutaneous electrical stimulation (46.1 ± 19.1 mA) induced acute pain (numeric rating scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia and allodynia were regularly assessed before, during, and after a 15-min infusion of acetaminophen, tropisetron, the combination of both drugs, and saline. Acetaminophen concentrations were measured to rule out any pharmacokinetic interaction. Both acetaminophen and tropisetron led to decreased pain ratings as compared to saline. However, when acetaminophen and tropisetron were administered simultaneously, the pain ratings were not affected. There was no significant difference in the evolution of the hyperalgesic and allodynic areas during the study period between the study groups (P = .06 and P = .33, respectively). Acetaminophen serum levels were not significantly different when associated with tropisetron (P = .063), although we observed a trend toward lower acetaminophen concentrations when both drugs were concurrently administered. In summary, while the combination of acetaminophen and tropisetron showed no analgesic action, each drug administered alone led to decreased pain ratings as compared to saline. In an electrically evoked human pain model, the combination of acetaminophen with tropisetron was free of any analgesic potential. However, when administered on its own, both acetaminophen and tropisetron were mildly analgesic.

Induction of therapeutic hypothermia requires modulation of thermoregulatory defenses.

Hypothermia has been linked to beneficial neurologic outcomes in different clinical situations and its therapeutic value is considered important. For example, in asphyctic neonates and in patients with out-of-hospital cardiac arrest (with ventricular fibrillation as the initial cardiac rhythm), rapid installation of hypothermia has been reported to add substantial therapeutic benefits over nonthermal standard treatments. Yet, in other groups of patients in which the application of therapeutic hypothermia may be applied with clinical benefits, the optimization of therapy remains less straightforward, as the body possesses vigorous defense mechanisms to protect it from inducing hypothermia, that is, especially in conscious patients and/or in those in which the hypothalamus remains intact, such as stroke patients or patients who suffer a myocardial infarction or spinal cord injury. This overview summarizes the body's primary reactions to hypothermia and the defense mechanisms available or evoked. Then, clinically applicable ways to overcome these forceful cold defenses of the body are described to ensure both an optimal induction process for therapeutic hypothermia and maximal subjective comfort for these conscious patients.

Induction of mild hypothermia by noninvasive body cooling in healthy, unanesthetized subjects.

The induction of mild hypothermia has been considered as an important means to provide protection against cerebral ischemia. Yet, to date, the relative clinical efficacies of different noninvasive methods for reducing core body temperature have not been thoroughly studied. The aim of the current investigation was to compare the relative effectiveness of several noninvasive cooling techniques for reducing core temperatures in healthy volunteers. Cooling methods included convective/conductive and evaporative/conductive combinations, as well as evaporative cooling alone. Additionally, focal facial warming was employed as a means to suppress involuntary motor activity and thus better enable noninvasive cooling. Core temperatures were measured so to monitor the relative efficiencies of these induced cooling methodologies. With each employed methodology, rectal temperature reductions were induced, with combined evaporative/conductive (n=4, 1.44°C±0.99°C) and convective/conductive (n=4, 1.51°C±0.89°C) approaches yielding the largest decreases: note, that evaporative cooling alone was not as efficient in lowering core body temperature (n=10, 0.56°C±0.20°C; n=16, 0.58°C±0.27°C). In this study on healthy volunteers, the evaporative/conductive and convective/conductive combination methods were more effective in reducing core temperatures as compared with an evaporative approach alone. These therapeutic approaches for the induction of mild hypothermia (including the use of facial warming) could be employed in warranted clinical cases, importantly without the need for administration of anesthetics or paralytics.

Analgesic and antihyperalgesic properties of propofol in a human pain model.

BACKGROUND: Propofol (Disoprivan, AstraZeneca AG, Zug, Switzerland) has long been considered to be nonanalgesic. However, accumulating evidence shows that propofol possesses modulatory action on pain processing and perception. In this study, the authors investigated the modulatory effects of propofol and a formulation similar to the solvent of propofol (10% Intralipid; Fresenius Kabi, Stans, Switzerland) on pain perception and central sensitization in healthy volunteers. METHODS: Fourteen healthy volunteers were included in this randomized, double-blind, placebo-controlled, crossover study. Intracutaneous electrical stimulation (48.8 +/- 25.8 mA) induced spontaneous acute pain (Numeric Rating Scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia were assessed regularly before, during, and after a 45-min target-controlled infusion (2 microg/ml) of propofol, the solvent 10% Intralipid, and saline. RESULTS: During administration, propofol significantly decreased pain scores and areas of hyperalgesia and allodynia compared with both 10% Intralipid and saline (placebo-corrected mean Numerical Rating Scale score reduction by propofol: 38 +/- 28%). This difference disappeared shortly after cessation of the infusion. Thereafter, no significant group differences were observed in the Numerical Rating Scale score and the areas of hyperalgesia or allodynia. However, there was a trend to reduced hyperalgesia and allodynia after propofol treatment. Pharmacodynamic modeling regarding the analgesic effect of propofol showed an EC50 (half-maximum effect site concentration) of 3.19 +/- 0.37 microg/ml. Ten percent Intralipid was free of pain-modulatory effects in the authors' experiments. CONCLUSIONS: Propofol showed short-lasting analgesic properties during its administration, whereas the solvent-like formulation 10% Intralipid had no effect on pain perception.