Airway management research: a systematic review.

Recent controversy regarding the ethics of conducting airway research in patients led to disagreements concerning the value and frequency of manikin-based investigation. However, no formal examination of the methodology of airway research has been undertaken. We, therefore, performed a systematic bibliometric review of airway management research to describe the conduct, quantify the subjects (patient vs. manikin vs. other), assess the reported outcomes and map global trends. We retrieved 1505 relevant studies published between 2006 and 2017, together recruiting 359,648 subjects, of which 341,233 were patients, the remaining being volunteers or subjects managing manikins, human cadavers, animals or bench models. There were 701 randomised controlled clinical trials (46.6%), 83 non-randomised experimental clinical trials (5.5%), 298 observational studies (19.8%) and 423 non-patient studies (28.1%). A total of 1082 studies (71.9%) were patient studies and 322 were manikin studies (21.4%). The total annual number of airway management studies increased over time, as did the annual number of patient studies, but there was no significant increase in the annual number of manikin studies over time. Of the patient studies, subject baseline characteristics were most likely to be ASA status 1-2 (n = 531, 49.1%), populations were most often elective surgical patients (n = 918, 84.8%) and the most common interventions studied were tracheal intubation (n = 820, 54.4%) or supraglottic airway device insertion (n = 257, 17.1%). There was a total of 77 different primary outcomes used in the included studies, the most commonly reported being success rate and procedure time. By understanding how and what has been previously studied these data can be used to form the basis for future priority setting exercises, core outcome set development, and could inform strategy on the future directions of airway management research.

A pilot randomised trial of community-based care following discharge from hospital with a recent spinal cord injury in Bangladesh.

OBJECTIVES: To explore the feasibility of conducting a full trial designed to determine the effectiveness of a model of community-based care for people with spinal cord injury in Bangladesh. STUDY DESIGN: A pilot randomised trial. SETTING: Community, Bangladesh. SUBJECTS: Participants were 30 people with recent spinal cord injury who were wheelchair-dependent and soon to be discharged from hospital. INTERVENTION: Participants randomised to the intervention group received a package of care involving regular telephone contact and three home visits over two years. Participants randomised to the control group received usual care consisting of a telephone call and an optional home visit. MAIN MEASURES: Participants were assessed at baseline and two years after randomization. The primary outcome was mortality and secondary outcomes were measures of complications, depression, participation and quality of life. RESULTS: A total of 24 participants had a complete spinal cord injury and six participants had an incomplete spinal cord injury. Median (interquartile) age and time since injury at baseline were 31 years (24 to 36) and 7 months (4 to 13), respectively. Two participants, one in each group, died. Five participants had pressure ulcers at two years. There were no notable impediments to the conduct of the trial and no significant protocol violations. The phone calls and home visits were delivered according to the protocol 87% and 100% of the time, respectively. Follow-up data were 99% complete. CONCLUSION: This pilot trial demonstrates the feasibility of a full clinical trial of 410 participants, which has recently commenced. SPONSORSHIP: University of Sydney, Australia.

www.elearnSCI.org: a global educational initiative of ISCoS.

OBJECTIVE: To develop a web-based educational resource for health professionals responsible for the management of spinal cord injury (SCI). The resource:www.elearnSCI.org is comprised of seven learning modules, each subdivided into various submodules. Six of the seven modules address the educational needs of all disciplines involved in comprehensive SCI management. The seventh module addresses prevention of SCI. Each submodule includes an overview, activities, self-assessment questions and references. DEVELOPMENT OF THE RESOURCE: Three hundred and thirty-two experts from The International Spinal Cord Society (ISCoS) and various affiliated societies from 36 countries were involved in developing the resource through 28 subcommittees. The content of each submodule was reviewed and approved by the Education and Scientific Committees of ISCoS and finally by an Editorial Committee of 23 experts. KEY FEATURES: The content of the learning modules is relevant to students and to new as well as experienced SCI healthcare professionals. The content is applicable globally, has received consumer input and is available at no cost. The material is presented on a website underpinned by a sophisticated content-management system, which allows easy maintenance and ready update of all the content. The resource conforms to key principles of e-learning, including appropriateness of curriculum, engagement of learners, innovative approaches, effective learning, ease of use, inclusion, assessment, coherence, consistency, transparency, cost effectiveness and feedback. CONCLUSION: www.elearnSCI.org provides a cost effective way of training healthcare professionals that goes beyond the textbook and traditional face-to-face teaching.

The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility.

It has been suggested that exertional rhabdomyolysis (ER) and malignant hyperthermia (MH) are related syndromes. We hypothesize that patients with unexplained ER harbor mutations in the ryanodine receptor gene type 1 (RYR1), a primary gene implicated in MH, and therefore ER patients are at increased risk for MH. Although there are reported cases of MH in individuals of African descent, there are no data available on molecular characterization of these patients. We analyzed RYR1 in six, unrelated African American men with unexplained ER, who were subsequently diagnosed as MH susceptible (MHS) by the Caffeine Halothane Contracture Test. Three novel and two variants, previously reported in Caucasian MHS subjects, were found in five studied patients. The novel variants were highly conserved amino acids and were absent among 230 control subjects of various ethnic backgrounds. These results emphasize the importance of performing muscle contracture testing and RYR1 mutation screening in patients with unexplained ER. The MHS-associated variant Ala1352Gly was identified as a polymorphism predominant in individuals of African descent. Our data underscore the need for investigating RYR1 across different ethnic groups and will contribute to interpretation of genetic screening results of individuals at risk for MH.

Effects of ryanodine on skeletal muscle lactate and pyruvate in malignant hyperthermia-susceptible and normal swine as assessed by microdialysis.

BACKGROUND: The caffeine/halothane contracture test in North America and the in vitro contracture test in Europe are currently the only validated bioassays for diagnosing malignant hyperthermia susceptibility and phenotyping families. Both tests are invasive requiring surgical muscle biopsy. Here, we report first use of the selective ryanodine receptor type I agonist ryanodine in a percutaneous microdialysis protocol designed to test whether microdialysis-induced local metabolic responses of skeletal muscle due to ryanodine receptor activation can differentiate between malignant hyperthermia-sensitive and normal pigs. METHODS: Six microdialysis catheters were implanted percutaneously into the adductor muscles of the right and left thighs of malignant hyperthermia-susceptible (n = 9) and normal (n = 8) anaesthetized (ketamine/propofol) and mechanically ventilated swine. Systemic blood gases, haemodynamic parameters and creatine kinase levels were measured before, during and after microdialysis perfusion of ryanodine. After a post-implantation equilibration period of 30 min, one catheter perfused (2 micro min-1) with 0.9% NaCl (control) and was compared with the remaining five catheters perfused with increasing concentrations of ryanodine (0.2-100 micromol). Lactate and pyruvate levels were measured enzymatically. RESULTS: Continuous perfusion with ryanodine revealed dose-dependent sigmoidal increases in the dialysate lactate and lactate-pyruvate ratio parameters; these effects were greatly augmented in malignant hyperthermia-susceptible pigs compared to normal pigs (two- to threefold): estimated EC50 greatly decreased (>19-fold) while the maximum effect increased (>twofold) in the malignant hyperthermia-susceptible group. CONCLUSION: The in vivo percutaneous microdialysis protocol for skeletal muscle, using ryanodine as the ryanodine receptor type I agonist and dialysed lactate-pyruvate parameters as metabolic index, can reproducibly differentiate between malignant hyperthermia-susceptible and normal swine.

Effects of bufalin on norepinephrine turnover in canine saphenous vein.

Abundant experimental data suggest that an endogenous digitalislike factor is responsible for some essential hypertension. Some forms of hypertension have also been associated with increased levels of catecholamines. We therefore designed experiments to investigate the role of digitalislike factors in the regulation of norepinephrine turnover in the neurovascular junction. We chose bufalin, an amphibian-derived compound that shares many of the physiological properties postulated as characteristic of digitalislike compounds, as a model of the mammalian compound. In vitro experiments in canine saphenous veins showed that, in addition to inhibiting norepinephrine uptake, bufalin increased norepinephrine overflow by an amount larger than could be explained solely by uptake inhibition. The effect of bufalin on norepinephrine overflow is inhibited by tetrodotoxin, which suggests a dependence of this response on Na+ influx through the neuronal membranes. We propose that Na+,K(+)-ATPase inhibition resulting in neuronal depolarization is responsible for the augmented norepinephrine turnover caused by bufalin and that these indirect effects of norepinephrine on the cardiovascular system may play a role in the etiology of hypertension.

Effect of prolonged dietary administration of vanadate on blood pressure in the rat.

Vanadate, a potent naturally occurring Na+,K+-ATPase inhibitor thought to have a role in regulating Na+-K+ pump activity, was fed to uninephrectomized rats drinking tap water or a 1% solution of sodium chloride for as long as 56 weeks. Feeding was achieved by adding sodium orthovanadate to normal rat chow equivalent to 100 or 200 ppm vanadium by weight. In the rats drinking tap water, systolic pressure gradually increased over a period of several weeks and then was sustained in a dose-related manner for the duration of the treatment. The increased pressure was not associated with changes in water intake, urine output, or urinary sodium excretion but correlated positively with plasma vanadium levels ranging from 0.04 to 0.27 microgram/ml. Increased pressure was associated with increased heart-to-body-weight ratio but did not appear to occur in a small group of animals drinking the 1% solution of sodium chloride. These findings, considered in the light of others, indicate that vanadate deserves continued study in relation to hypertension.

Neurovascular effects of reactive oxygen intermediates produced by photoradiation.

These experiments examined the effect of reactive oxygen intermediates, produced by laser illumination of the photosensitizer hematoporphyrin derivative, on the accumulation and release of norepinephrine from sympathetic nerve terminals. Using an isolated, spirally cut, superfused caudal artery of the rat, basal overflow of norepinephrine (NE) was significantly increased both during and after generation of reactive oxygen intermediates. Generation of reactive oxygen intermediates increased overflow of NE in vascular preparations in which release of NE had previously been elevated by the continuous superfusion of Krebs' solution, containing high concentrations of potassium (40 mM). Calcium free solutions did not block the overflow of norepinephrine augmented by reactive oxygen intermediates. This increase in overflow was due both to an increase in release of NE and an inhibition of accumulation of NE.

Further isolation of endogenous factors in canine and human plasma that inhibit [(3)H]norepinephrine accumulation.

We have previously shown that both homologous canine plasma and a crude extract of this plasma contain substances that inhibit accumulation of [(3)H]norepinephrine ([(3)H]NE) by the canine saphenous vein. The purpose of this study was to further purify these substances and to determine if similar factors were present in human plasma. Crude extracts of plasma were purified with a Folch extraction in which most of the biological activity was recovered in the bottom or organic phase. This phase significantly inhibited [(3)H]NE uptake by the canine saphenous vein (23.5 +/- 7.6% by concentrate from 9.1 ml of original plasma/ml incubate solution) and increased development of tension following transmural electrical stimulation by 91.5 +/- 23.3% (extract from 1 ml of plasma/ml bath solution). The Folch extracts obtained from 100ml of plasma were purified by column and thin layer (TLC) chromatography. Samples were applied to a silicic acid column and eluted with chloroform, acetone, and methanol. The [(3)H]NE uptake inhibitory activity was primarily recovered in the methanol fraction. TLC of the methanol fraction of canine plasma on silica gel G plates (with pre-absorbent) resulted in five zones which were then assayed for their ability to inhibit [(3)H]NE accumulation by the saphenous vein. In the first zone (concentrate from 27.5 ml plasma/ml bath solution) there was significantly greater inhibitory activity (55.4 +/- 8.3%), than in the corresponding zone obtained from solvent blanks (20.7 +/- 4.1%). These results indicate that there is a factor or possibly factors in canine and human plasma that have thin layer chromatographic properties of a polar lipid, which inhibit [(3)H]NE accumulation and enhance the contractile response of vascular smooth muscle to transmural electrical stimulation.

In vitro responses of cat skeletal muscle to halothane and caffeine.

Strips of soleus (100% type I) and gracilis (90% type II) muscle were obtained from anesthetized cats and mounted in organ baths filled with aerated Krebs-Ringer solution (37 degrees C). The contractile patterns in response to electrical stimulation (0.1 Hz, 25 V, 5 ms), caffeine, halothane, and caffeine in the presence of halothane were examined in the two fiber types. The ability of 25 microM dantrolene to alter the contractile patterns was also evaluated. In vitro contractile properties in response to electrical stimulation were similar to properties observed in situ, except that twitch tension in soleus muscle was significantly less in vitro than in situ. In the presence of halothane, type I soleus muscle developed a rapid contracture. The contracture was blocked by pretreatment with dantrolene and was reversed by addition of dantrolene at the peak of the response. Halothane-induced contractures were not observed at any time in type II gracilis. Type I soleus was also significantly more sensitive both to caffeine alone and to caffeine in the presence of halothane than was type II gracilis. In both fiber types, halothane increased the sensitivity of the muscles to caffeine. Dantrolene attenuated caffeine-induced contractures in both fiber types, but the attenuating effect was less in the presence of halothane. The findings of a halothane-induced contracture in the cat soleus and differential sensitivities of the two muscle fiber types to caffeine indicate that further studies in these two muscles may be useful for delineating the mechanisms inducing contracture in muscle from individuals susceptible to malignant hyperthermia.

Verapamil and zero Ca2+ alter responses of cat muscle to halothane and caffeine.

Strips of soleus (slow twitch, oxidative) and gracilis (fast-twitch, glycolytic) muscle were obtained from 27 anesthetized cats and mounted in organ baths filled with oxygenated Krebs-Ringer solution (37 degrees C). The responses to caffeine, halothane (1%), caffeine in the presence of halothane, and electrical stimulation in the presence of halothane were examined in the two fiber types. These responses were compared with those observed in paired strips of muscle that had been treated with verapamil (10 or 28 microM), a slow calcium (Ca2+) channel blocker, with zero Ca2+, or with zero Ca2+ where magnesium (3.7 mM Ca2+) was added to replace the Ca2+. Halothane-induced contractures in the soleus were blocked by verapamil and zero Ca2+. Caffeine-induced contractures and tetanic contractions were attenuated in zero Ca2+ and by verapamil in both fiber types. Halothane overcame verapamil-induced reductions of caffeine contractures and tetanic contractions in both fiber types. In contrast, halothane did not overcome zero Ca2+-induced reductions in caffeine contractures or tetanic contractions in either fiber type. Furthermore, the addition of Mg2+ to the zero Ca2+ did not restore the responses. The findings with verapamil indicate that in cat muscle, both halothane- and caffeine-induced contractures and tetanic contractions are dependent on the influx of extracellular Ca2+. This extracellular Ca2+ may enter through the slow Ca2+ channels. However, because halothane in combination with caffeine or electrical stimulation overcame the effects of verapamil, there may be other sites involved.

Analytic performance and contamination control methods of a ligase chain reaction DNA amplification assay for detection of Chlamydia trachomatis in urogenital specimens.

A ligase chain reaction (LCR) DNA amplification assay that targeted the cryptic plasmid of Chlamydia trachomatis was developed to detect C. trachomatis urogenital tract infection. The objectives of this study were to determine the cutoff and analytic performance of the LCR assay and to characterize the effectiveness of its postdetection contamination control method. The assay's cutoff was determined after receiver-operator characteristic (ROC) analysis of 4660 clinical data points. The assay detected one infectious unit per reaction of each of the 15 C. trachomatis serovars and did not cross-react with 13 Chlamydia pneumoniae strains, 13 Chlamydia psittaci strains, and 87 other bacteria, fungi, parasites, or viruses. In addition, the assay did not detect 77 processed urine specimens collected from patients with urinary tract infections caused by yeast or bacteria other than C. trachomatis. The assay was sufficiently precise to detect consistently two infectious units of C. trachomatis per reaction. False-positive assay results attributable to contamination with amplified product were minimized by the use of standard procedures as well as by a postdetection chemical inactivation method that could reduce the amount of amplified LCR product by a factor of > or = 10(7).

Inhibition of inositol phospholipid hydrolysis in endothelial cells by pentobarbital.

Barbiturates alter cardiovascular function, in part by an effect on vascular cells. However, a biochemical mechanism for the effect is unknown. We have, therefore, studied the effect of barbiturates on inositol phospholipid hydrolysis in cultured rat aortic endothelial cells. Hydrolysis was stimulated by angiotensin II, norepinephrine and phenylephrine. Pentobarbital, and other barbiturates, inhibited hydrolysis at pharmacological and clinical concentrations (0.1-0.5 mM). The inhibition by pentobarbital was concentration-dependent, reversed by washing, and was decreased by high concentrations of angiotensin II. Kinetic studies gave an apparent Km of hydrolysis by angiotensin II of 1.2 nM, which showed mixed inhibition by pentobarbital (Ki = 0.45 mM). Schild analysis of data obtained from pentobarbital inhibition curves also showed a deviation from a competitive type inhibition. [125I]Angiotensin II was bound to a high-affinity receptor (Kd = 1.2 nM), which showed a competitive type inhibition of binding by pentobarbital (0.5 mM). Although inhibition of [125I]angiotensin II binding appeared to be competitively inhibited by pentobarbital, the data, taken together, point to a deviation from a simple competitive type inhibition.

Factors contributing to differences in the regulation of cGMP in isolated porcine pulmonary vessels.

Guanosine 3',5'-cyclic monophosphate (cGMP) is an important second messenger in many biological systems including vascular smooth muscle where it mediates relaxation. Cellular levels of cGMP are regulated primarily by three enzymes; nitric oxide (NO) synthase, soluble guanylate cyclase, and cGMP-phosphodiesterase. Basal cGMP levels of isolated endothelium intact porcine pulmonary vein are five fold higher than in pulmonary artery. The objective of this study was to investigate possible reasons for this difference. Therefore, we compared NO synthase activity of pulmonary vein with artery and used pharmacologic approaches to compare soluble guanylate cyclase and phosphodiesterase activities in these vessels. NO synthase activities of pulmonary vein and artery were measured by monitoring the conversion of exogenous L-[14C]arginine to L-[14C]citrulline and by quantifying NO formation from endogenous L-arginine. Rates (pM/min per mg protein) of basal L-citrulline and NO formation from endothelium intact pulmonary vein (29.0 +/- 4.8 and 44 +/- 7.1, respectively) were significantly higher than from artery (8.3 +/- 2.2 and 17.1 +/- 3.3). Western blot analysis indicated higher constitutive NO synthase protein in the vein than in artery. N-nitro-L-arginine (0-100 microM), a potent inhibitor of NO synthase, induced contractions of the pulmonary vein which were significantly higher than those of the artery. N-nitro-L-arginine (5 and 20 microM) in the presence of phosphodiesterase inhibitors, decreased basal cGMP levels of endothelium intact blood vessels. In endothelium denuded pulmonary vein and artery, basal cGMP levels were not different from each other, but increased significantly following stimulation of soluble guanylate cyclase with exogenous NO. In the presence of both non-specific and specific cGMP phosphodiesterase inhibitors, exogenous NO-induced cGMP levels of endothelium denuded tissues were not significantly different from each other. However, in the absence of the phosphodiesterase inhibitors, exogenous NO-induced cGMP was significantly less in the artery than in the vein. These results suggest that (I) the intact porcine pulmonary vein contains higher levels of NO synthase activity than pulmonary artery, and that (II) the soluble guanylate cyclase activities in pulmonary vein and artery are equally responsive to NO, and finally (III) pulmonary artery expresses greater phosphodiesterase activity than vein. Higher NO synthase and lower phosphodiesterase activity may explain the greater accumulation of cGMP in the pulmonary vein compared to the artery.

Halothane attenuates nitric oxide relaxation of rat aortas by competition for the nitric oxide receptor site on soluble guanylyl cyclase.

Endothelial cells play an important role in the regulation of vascular activity through the release of endothelium derived relaxing factor (EDRF) now believed to be nitric oxide (NO). NO and the NO donor drug nitroglycerin relax vascular smooth muscle by stimulating soluble guanylyl cyclase leading to elevation of intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP). Halothane has been shown to inhibit the action of NO on blood vessels. This study was designed to further investigate the mechanisms by which halothane attenuates NO-induced vascular relaxations. This was done by examining the effects of halothane on nitroglycerin and NO-induced relaxations in the presence and absence of the inhibitors of soluble guanylyl cyclase, methylene blue and 6-anilino-5,8-quinolinedione (LY 83583). Thoracic aortas from anesthetized male Sprague-Dawley rats were excised and cut into rings and the endothelium was removed. The aortic rings were suspended in organ baths containing Krebs solution and equilibrated at their optimal passive tension. When a stable plateau of contraction was produced by EC60 concentrations of norepinephrine, increasing concentrations of nitroglycerin or NO were added to the baths to relax the rings. This contraction-relaxation procedure was repeated three or four times. In some baths halothane was administered by a calibrated vaporizer 10 min before beginning the second procedure. Either methylene blue or LY 83583 was added to the baths 20 min before the third procedure. The combination of halothane, methylene blue or LY 83583 was added before the fourth procedure. Halothane, methylene blue or LY 83583 significantly inhibited nitroglycerin-induced relaxation individually. Halothane and LY 83583 also significantly inhibited NO-induced relaxations (5 x 10(-9)-3 x 10(-8) M and 5 x 10(-9)-3 x 10(-5) M, respectively) individually. The combination of halothane and methylene blue or halothane and LY 83583 significantly inhibited nitroglycerin-induced relaxation, also, the combination of halothane and LY 83583 significantly inhibited NO-induced relaxations. Halothane, methylene blue and LY 83583 treatment led to rightward shift in the concentration-effect curves. Halothane, in combination with methylene blue or LY 83583, produced inhibition equivalent to the sum of their individual effects. The present study demonstrates that the halothane, methylene blue and LY 83583 attenuate nitroglycerin and NO-induced relaxations of endothelium-denuded rat aortic rings. This suggests that halothane, methylene blue and LY 83583 may act through competitive antagonism at a common site of action on soluble guanylyl cyclase in the EDRF/NO relaxation pathway.

Comparative effects of exogenous nitrovasodilators on cGMP levels in different canine blood vessels.

Nitrovasodilators, by releasing nitric oxide (NO) in vascular smooth muscle, activate soluble guanylate cyclase (sGC) in vascular smooth muscle. However, there is little information on their relative effectiveness, concentration ranges, or on the incubation times required to produce maximum sGC stimulation. To determine the optimal concentrations and incubation times we measured 3', 5'-cyclic guanosine monophosphate (cGMP) levels in response to different concentrations of NO, S-nitroso-L-cysteine (SNC), and S-nitroso-N-acetylpenicillamine (SNAP), in canine aorta, femoral, and carotid arteries incubated in Krebs. Production of cGMP following incubation of endothelium denuded tissues with NO, SNC, and SNAP peaked close to 20 +/- 5, 90 +/- 20, and 120 +/- 60 seconds respectively. Results indicate that cGMP levels vary with concentration of nitrovasodilators and time of incubation. SNAP was the least effective in increasing cGMP levels among the three nitrovasodilators used. In different vascular beds, the production of cGMP in the presence of nitrovasodilators may depend on variations in the levels of guanylate triphosphate (GTP) and/or sGC.

Reversal of the antinociceptive effects of centrally-administered morphine by the benzodiazepine receptor antagonist Ro 15-1788.

The effects of the benzodiazepine receptor antagonist, Ro 15-1788, were examined on analgesia induced by morphine after central (intracerebroventricular, i.c.v., or intrathecal, i.t.) and systemic administration. Analgesia was assessed in squirrel monkeys trained to respond under an electric shock titration procedure and in mice using the radiant heat tail-flick test. Central and systemic administration of morphine produced antinociceptive effects that were antagonized by 0.1 mg/kg of naloxone in both species. Ro 15-1788 antagonized the effects of morphine after central (i.c.v. or i.t.) administration but did not alter the effects of morphine given by the systemic route. This novel interaction suggests that Ro 15-1788 may be useful in pharmacologically separating neural substrates subserving opiate analgesia.

Vascular effects of halothane and isoflurane: cGMP dependent and independent actions.

This study investigated the effects of halothane and isoflurane on cGMP-dependent and independent regulation of vascular contraction of the isolated rat aorta and on NO-stimulated soluble guanylate cyclase (sGC) isolated from the perfused rat liver. For the studies of the aorta, isometric tension of isolated rings, with and without, endothelium was recorded and cGMP content measured. ACh was used to initiate endothelial-dependent relaxation of norepinephrine (NE)-contracted rings while NO was used to directly stimulate isolated aortic ring sGC which catalyzes the isolated aortic ring formation of cGMP. Both halothane and isoflurane interfered with ACh and NO relaxations and with NO-stimulated increases in cGMP. Halothane was more potent, having significant attenuating effects at 0.34 mM (1 MAC) and 0.72 mM (2 MAC) while isoflurane had effects only at 0.53 mM (2 MAC). For the isolated sGC studies, a soluble liver fraction was prepared from perfused rat livers. In the absence of NO stimulation, neither halothane nor isoflurane modified the activity of the sGC. However, during NO-stimulation halothane produced significant, concentration-dependent, inhibition of sGC activity over a wide range of NO concentrations. Isoflurane also inhibited sGC activity, but to a lesser extent than halothane. The mechanism whereby the anesthetics could interfere with sGC from liver and blood vessels is unknown. It could result from anesthetic interaction at hydrophobic sites that may exist in GC. However, the results of both the aorta and liver sGC enzyme studies support the suggestion that these anesthetics can compete with NO for its binding site on the ferrous heme of sGC, with chemical structural differences accounting for the potency variations. Both anesthetics also had cGMP independent effects, causing concentration dependent relaxations of NE-contracted vessels without endothelium. Isoflurane was about 5 times more effective at 1 MAC than halothane. Therefore, the net effects of these anesthetics involve the sum of two opposite effects on tension of vessels with intact endothelium: 1) interference with NO-stimulated cGMP relaxation and 2) direct stimulation of relaxation (not dependent on changes in cGMP).

Request for medical evaluation: an approach for on-site occupational health professionals.

The role of the occupational health professional in determining fitness for duty is expanding. Proper determination of fitness for duty diffuses acute situations in the workplace. The occupational health professional's role is nonjudgmental and objective. This protocol protects the occupational health service from punitive actions.