Comparison of air and ground transport of cardiac patients.

PURPOSE: To investigate the outcome of cardiac patients transported by helicopter versus ground ambulance SETTING: A hospital-based helicopter program in southeastern Minnesota METHODS: Retrospective chart review assessing an 18-month period (January 1998 to June 1999). Charts were reviewed for type of cardiac diagnosis, level of pain, treatments en route, time to intervention, and length of stay (LOS). Two-hundred-sixty-six cardiac patients came by helicopter. Of the 86 turndowns, 50 came by ground ambulance; 28 records were recovered in this group. These patients composed the comparison ground group. RESULTS: Prehospital time was less for patients transported by air than ground transports (P <.001). The amount of time from the call for transport until arrival at our hospital was less for helicopter transports (P =.002). Air transports had more patients with reduced chest pain on arrival. Difference in CCU LOS was not significant (P =.94). Air patients spent an average of 2 fewer days in the hospital than did ground patients (P =.036). DISCUSSION: Helicopter transport benefits the cardiac patient with decreased chest pain as a result of more treatments en route; decreased time from the call until arrival, resulting in decreased time to intervention; and shorter prehospital time and hospital stays. CONCLUSION: All of these improved variables relate to salvaged cardiac muscle.

Patient outcomes following defibrillation with a low energy biphasic truncated exponential waveform in out-of-hospital cardiac arrest.

PRIMARY OBJECTIVE: To determine the outcome of patients with out-of-hospital cardiac arrest and ventricular fibrillation as the presenting rhythm while using automated external defibrillators (AEDs) that delivered non-escalating, impedance-compensated low-energy (150 J) shocks. MATERIALS AND METHODS: AEDs delivering low-energy biphasic truncated exponential (BTE) shocks were employed in an emergency medical services (EMS) system in which first-arriving personnel - police, firefighters or paramedics - delivered the initial shocks. Patients were classified according to their response to shocks: restoration of sustained spontaneous circulation (ROSC) without need for epinephrine and other advanced life support (ALS) interventions; and ALS, those requiring epinephrine in all instances. The primary end-point was neurologically-intact discharge survival. Secondary end-points were ROSC with shocks only and the call-to-shock time interval. RESULTS: Of 42 patients with VF arrest treated with BTE shocks, 35 were bystander-witnessed. Of these 35, 14 (38%) regained a sustained ROSC on-scene with shocks only, needing no epinephrine for ROSC. All 14 survived to discharge home. Of the remaining 21 patients needing ALS intervention, only two (9.5%) survived to discharge. Overall, 16/35 patients (46%) survived to discharge home, an outcome comparable to our experience with patients treated with escalating high-energy monophasic waveform shocks. CONCLUSIONS: Low-energy (150 J) non-escalating biphasic truncated exponential waveform shocks terminate VF in out-of-hospital cardiac arrest with high efficacy; patient outcome is comparable with that observed with escalating high-energy monophasic shocks. Low-energy shocks, in addition to high efficacy, may confer the advantage of less shock-induced myocardial dysfunction, though this will be difficult to define in the clinical circumstance of long-duration VF provoked by a pre-existing diseased myocardial substrate.

Spinal immobilization in the field: clinical clearance criteria and implementation.

Awareness of the health and financial repercussions of unnecessary immobilization has made cervical spinal immobilization controversial in out-of-hospital care. Clinical criteria for clearance of the cervical spine in the hospital based on mechanism of injury have been supported by many trauma centers. However, implementation of clinical criteria for cervical spinal clearance in out-of-hospital settings is not as well validated by multicenter studies or accepted by many emergency departments. This consensus group recommends that clinical criteria to determine "low-risk" patients be available for use by emergency medical services providers in out-of-hospital settings; however, training, audits, quality management, integration into the medical community, and extent of program implementation should be decided based on individual emergency medical services systems.

Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4.

OBJECTIVE: Halothane undergoes both oxidative and reductive metabolism by cytochrome P450 (CYP), respectively causing rare immune-mediated hepatic necrosis and common, mild subclinical hepatic toxicity. Halothane also causes lipid peroxidation in rodents in vitro and in vivo, but in vivo effects in humans are unknown. In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mechanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidation in vivo. This investigation tested the hypotheses that halothane causes lipid peroxidation in humans in vivo, and that CYP2A6 or CYP3A4 inhibition can diminish halothane metabolism. METHODS: Patients (n = 9 each group) received single doses of the mechanism-based inhibitors troleandomycin (CYP3A4), methoxsalen (CYP2A6) or nothing (controls) before a standard halothane anaesthetic. Reductive halothane metabolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath, fluoride in urine, and oxidative metabolites trifluoroacetic acid and bromide in urine were measured for 48 h postoperatively. Lipid peroxidation was assessed by plasma F2-isoprostane concentrations. RESULTS: The halothane dose was similar in all groups. Methoxsalen decreased 0- to 8-h trifluoroacetic acid (23 +/- 20 micromol vs 116 +/- 78 micromol) and bromide (17 +/- 11 micromol vs 53 +/- 49 micromol) excretion (P < 0.05), but not thereafter. Plasma F2-isoprostanes in controls were increased from 8.5 +/- 4.5 pg/ml to 12.5 +/- 5.0 pg/ml postoperatively (P < 0.05). Neither methoxsalen nor troleandomycin diminished reductive halothane metabolite or F2-isoprostane concentrations. CONCLUSIONS: These results provide the first evidence for halothane-dependent lipid peroxidation in humans. Methoxsalen effects on halothane oxidation confirm in vitro results and suggest limited CYP2A6 participation in vivo. CYP2A6-mediated, like CYP2E1-mediated human halothane oxidation, can be inhibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical halothane reduction and lipid peroxidation were not amenable to suppression by CYP inhibitors.

Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity.

Methoxsalen (8-methoxypsoralen) is an effective and selective mechanism-based inhibitor of human hepatic cytochrome P-450 (CYP)2A6 in vitro, and may have utility as a clinical probe for CYP2A6-catalyzed xenobiotic metabolism in humans in vivo. This investigation explored single-dose oral methoxsalen effects on human CYP2A6 activity in vivo, assessed by coumarin 7-hydroxylation. Eleven volunteers received 50 mg of oral coumarin on two occasions in a randomized crossover, 90 min after oral methoxsalen or nothing (controls). Plasma and urine 7-hydroxycoumarin and plasma methoxsalen concentrations were determined by HPLC. Methoxsalen pretreatment diminished area under the curve of plasma 7-hydroxycoumarin versus time by 24% (2.40 +/- 0.48 versus 3.20 +/- 0.55 microg. h. ml(-1); P <.001), and also decreased plasma 7-hydroxycoumarin C(max) (0.80 +/- 0.26 versus 1.4 +/- 0.5 microg/ml; P <.05); however, 7-hydroxycoumarin concentrations were only diminished 0.75 to 2 h after coumarin administration, but not thereafter. Methoxsalen diminished urine 7-hydroxycoumarin excretion in 0- to 1- and 1- to 2-h samples, but not thereafter, and total excretion was unchanged. Considerable individual variability in methoxsalen plasma concentrations was observed. There were significant correlations between the decrease in plasma 7-hydroxycoumarin C(max) and plasma methoxsalen C(max), but not between the decrease in plasma 7-hydroxycoumarin area under the curve and methoxsalen disposition. These results show that single-dose oral methoxsalen, in conventional doses, was a moderately effective inhibitor of human CYP2A6 activity in vivo, however, the duration of inhibition was limited. Interindividual variability in the extent of CYP2A6 inhibition appeared attributable to variability in the absorption and first-pass clearance of methoxsalen. Alternative doses, timing, and/or routes of methoxsalen administration are required for greater, longer, and more reproducible CYP2A6 inhibition than that provided by single-dose methoxsalen.

Public-access defibrillation.

This paper provides a general overview of the current status of public-access defibrillation (PAD). The objectives are to describe the rationale for PAD, to define different levels of PAD as enumerated by the American Heart Association AED Task Force, to review the development of PAD over the past decade, and to discuss the cost-benefit of PAD, mainly from models and a few small implementations throughout the country. A prospective, randomized, controlled clinical trial (the Public Access Defibrillation Phase I Trial) has been designed to compare nontraditional targeted bystander CPR using AEDs with that not using AEDs. It is expected that the trial will resolve many of the uncertainties about the benefits of PAD.

Lack of single-dose disulfiram effects on cytochrome P-450 2C9, 2C19, 2D6, and 3A4 activities: evidence for specificity toward P-450 2E1.

Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of cytochrome P-450 2E1 (CYP2E1)1 in vitro. Single-dose disulfiram diminishes CYP2E1 activity in vivo and has been used to identify CYP2E1 participation in human drug metabolism and prevent CYP2E1-mediated toxification. Specificity of single-dose disulfiram toward CYP2E1 in vivo, however, remains unknown. This investigation determined single-dose disulfiram effects on human CYP 2C9, 2C19, 2D6, and 3A4 activities in vivo. In four randomized crossover experiments, volunteers received isoform-selective probes (oral tolbutamide, mephenytoin, dextromethorphan, or i.v. midazolam) on two occasions, 10 h after oral disulfiram or after no pretreatment (controls). Plasma and/or urine parent and/or metabolite concentrations were measured by HPLC or gas chromatography-mass spectrometry. CYP2C9, 2C19, 2D6, and 3A4 activities were determined from the tolbutamide metabolic ratio, 4'-hydroxymephenytoin excretion, and dextromethorphan/dextrorphan ratios in urine and midazolam systemic clearance, respectively. Midazolam clearance (670 +/- 190 versus 700 +/- 240 ml/min, disulfiram versus controls), dextromethorphan/dextrorphan metabolic ratio (0.013 +/- 0.033 versus 0.015 +/- 0.035), 4'-hydroxymephenytoin excretion (122 +/- 22 versus 128 +/- 25 micromol), and tolbutamide metabolite excretion (577 +/- 157 versus 610 +/- 208 micromol) were not significantly altered by disulfiram pretreatment, although the tolbutamide metabolic ratio was slightly diminished after disulfiram (60 +/- 17 versus 81 +/- 40, p <.05). Results show that single-dose disulfiram does not cause clinically significant inhibition of human CYP2C9, 2C19, 2D6, and 3A4 activities in vivo. When single-dose disulfiram is used as an in vivo probe for P-450, inhibition of drug metabolism suggests selective involvement of CYP2E1. Single-dose disulfiram should not cause untoward drug interactions from inhibition of other P-450 isoforms.

Clinical isoflurane metabolism by cytochrome P450 2E1.

BACKGROUND: Some evidence suggests that isoflurane metabolism to trifluoroacetic acid and inorganic fluoride by human liver microsomes in vitro is catalyzed by cytochrome P450 2E1 (CYP2E1). This investigation tested the hypothesis that P450 2E1 predominantly catalyzes human isoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. METHODS: Twenty-two elective surgery patients who provided institutionally-approved written informed consent were randomized to receive disulfiram (500 mg orally, N = 12) or nothing (controls, N = 10) the evening before surgery. All patients received a standard isoflurane anesthetic (1.5% end-tidal in oxygen) for 8 hr. Urine and plasma trifluoroacetic acid and fluoride concentrations were quantitated in samples obtained for 4 days postoperatively. RESULTS: Patient groups were similar with respect to age, weight, gender, duration of surgery, blood loss, and delivered isoflurane dose, measured by cumulative end-tidal isoflurane concentrations (9.7-10.2 MAC-hr). Postoperative urine excretion of trifluoroacetic acid (days 1-4) and fluoride (days 1-3) was significantly (P<0.05) diminished in disulfiram-treated patients. Cumulative 0-96 hr excretion of trifluoroacetic acid and fluoride in disulfiram-treated patients was 34+/-72 and 270+/-70 micromoles (mean +/- SD), respectively, compared to 440+/-360 and 1500+/-800 micromoles in controls (P<0.05 for both). Disulfiram also abolished the rise in plasma metabolite concentrations. CONCLUSIONS: Disulfiram, a selective inhibitor of human hepatic P450 2E1, prevented 80-90% of isoflurane metabolism. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical isoflurane metabolism in vivo.

Single-dose disulfiram does not inhibit CYP2A6 activity.

BACKGROUND: Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of human liver cytochrome P450 2E1 (CYP2E1) in vitro. A single dose of disulfiram, which significantly diminishes human P450 2E1 activity in vivo, has been used to investigate the role of CYP2E1 in human drug metabolism and to prevent CYP2E1-mediated biotransformation. Nevertheless, the specificity of single-dose disulfiram toward human CYP2E1 in vivo is unknown. Because diethyldithiocarbamate also inhibits human liver CYP2A6 in vitro, this investigation explored the effect of single-dose disulfiram on human CYP2A6 activity in vivo. METHODS: CYP2A6 activity was assessed by the 7-hydroxylation of coumarin, which is catalyzed selectively by CYP2A6. Ten healthy volunteers received 50 mg oral coumarin on two occasions in a randomized crossover design, approximately 10 hours after 500 mg oral disulfiram was administered or after no pretreatment (control group). Plasma and urine 7-hydroxycoumarin and plasma coumarin concentrations were determined by HPLC. RESULTS: The area under the plasma 7-hydroxycoumarin versus time curve (2.69 +/- 0.90 micrograms.hr/ml) was not decreased after disulfiram pretreatment (3.33 +/- 0.93 micrograms.hr/ml). Furthermore, maximum plasma concentration (Cmax) of 7-hydroxycoumarin (1.4 +/- 0.5 versus 1.8 +/- 0.6 micrograms/ml) and time to reach Cmax (1.0 +/- 0.2 and 1.0 +/- 0.4 hour) were unchanged by disulfiram pretreatment. Urinary 7-hydroxycoumarin excretion over a 24-hour period (38.9 +/- 10.8 mg) was also undiminished by disulfiram pretreatment (45.2 +/- 6.6 mg). CONCLUSIONS: Single-dose disulfiram does not inhibit human CYP2A6 activity in vivo. When single-dose disulfiram is used as an in vivo probe for P450, inhibition of drug metabolism suggests involvement of CYP2E1 but not CYP2A6.

Role of the renal cysteine conjugate beta-lyase pathway in inhaled compound A nephrotoxicity in rats.

BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats and undergoes metabolism to glutathione and cysteine S-conjugates, with further metabolism by renal cysteine conjugate beta-lyase to reactive intermediates. Evidence suggests that toxicity is mediated by renal uptake of compound A S-conjugates and metabolism by beta-lyase. Previously, inhibitors of the beta-lyase pathway (aminooxyacetic acid and probenecid) diminished the nephrotoxicity of intraperitoneal compound A. This investigation determined inhibitor effects on the toxicity of inhaled compound A. METHODS: Fischer 344 rats underwent 3 h of nose-only exposure to compound A (0-220 ppm in initial dose-response experiments and 100-109 ppm in subsequent inhibitor experiments). The inhibitors (and targets) were probenecid (renal organic anion transport mediating S-conjugate uptake), acivicin (gamma-glutamyl transferase), aminooxyacetic acid (renal beta-lyase), and aminobenzotriazole (cytochrome P450). Urine was collected for 24 h, and the animals were killed. Nephrotoxicity was assessed by histology and biochemical markers (serum BUN and creatinine; urine volume; and excretion of protein, glucose, and alpha-glutathione-S-transferase, a predominantly proximal tubular cell protein). RESULTS: Compound A caused dose-related proximal tubular cell necrosis, diuresis, proteinuria, glucosuria, and increased alpha-glutathione-S-transferase excretion. The threshold for toxicity was 98-109 ppm (294-327 ppm-h). Probenecid diminished (P < 0.05) compound A-induced glucosuria and excretion of alpha-glutathione-S-transferase and completely prevented necrosis. Aminooxyacetic acid diminished compound A-dependent proteinuria and glucosuria but did not decrease necrosis. Acivicin increased nephrotoxicity of compound A, and aminobenzotriazole had no consistent effect on nephrotoxicity of compound A. CONCLUSIONS: Nephrotoxicity of inhaled compound A in rats was associated with renal uptake of compound A S-conjugates and cysteine conjugates metabolism by renal beta-lyase. Manipulation of the beta-lyase pathway elicited similar results, whether compound A was administered by inhalation or intraperitoneal injection. Route of administration does not apparently influence nephrotoxicity of compound A in rats.

Seven years' experience with early defibrillation by police and paramedics in an emergency medical services system.

PRIMARY OBJECTIVE: To assess the outcome of patients with out-of-hospital cardiac arrest with ventricular fibrillation as the presenting rhythm in an emergency medical services system utilizing a combined police/paramedic response to provide early defibrillation. MATERIALS AND METHODS: Police and paramedics were dispatched from law enforcement and ambulance communications centers, respectively. First-arriving personnel delivered initial shocks, all using automated external defibrillators. Patients were classified according to response to initial shocks: restoration of pulses with shocks only or in need of advanced life support, including epinephrine. Discharge survival was defined as return to home without disabling neurologic injury. RESULTS: Over the 7-year period of study 131 patients presented with ventricular fibrillation: 58 were first treated by police and 73 by paramedics. Restoration of pulses with shocks only and discharge survival were not different in police and paramedic groups, with overall survival of 40% (53 of 131 patients). Among the survivors, 19% (18/95 patients) obtained a spontaneous circulation only after administration of epinephrine and other ALS interventions. CONCLUSION: Both restoration of a functional circulation, without need for advanced life support interventions, and discharge survival without neurologic disability are very dependent upon the rapidity with which defibrillation is accomplished, regardless of who delivers the shocks. In addition, a smaller but significant number of patients who require ALS interventions, including epinephrine, for restoration of a spontaneous circulation survive to discharge. Short time differences, on the order of 1 min, are significant determinants of both immediate response to shocks and discharge survival.

Determination of the halothane metabolites trifluoroacetic acid and bromide in plasma and urine by ion chromatography.

Halothane (CF3CHClBr), a widely used volatile anesthetic, undergoes extensive biotransformation in humans. Oxidative halothane metabolism yields the stable metabolites trifluoroacetic acid and bromide which can be detected in plasma and urine. To date, analytical methodologies have either required extensive sample preparation, or two separate analytical procedures to determine plasma and urine concentrations of these analytes. A rapid and sensitive method utilizing high-performance liquid chromatography-ion chromatography (HPLC-IC) with suppressed conductivity detection was developed for the simultaneous detection of both trifluoroacetic acid and bromide in plasma and urine. Sample preparation required only ultrafiltration. Standard curves were linear (r2> or =0.99) from 10 to 250 microM trifluoroacetic acid and 2 to 5000 microM bromide in plasma and 10 to 250 microM trifluoroacetic acid and 2 to 50 microM bromide in urine. The assay was applied to quantification of trifluoroacetic acid and bromide in plasma and urine of a patient undergoing halothane anesthesia.

Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro.

The volatile anesthetic halothane undergoes substantial biotransformation generating metabolites that mediate hepatotoxicity. Aerobically, halothane undergoes cytochrome P450-catalyzed oxidation to trifluoroacetic acid (TFA), bromide and a reactive intermediate that can acetylate liver proteins. These protein neo-antigens stimulate an immune reaction that mediates severe hepatic necrosis ("halothane hepatitis"). This investigation identified the human P450 isoform(s) that catalyze oxidative halothane metabolism. Halothane oxidation by human liver microsomes was assessed by TFA and bromide formation. Eadie-Hofstee plots of TFA and bromide formation were both nonlinear, suggesting the participation of multiple P450s. Microsomal TFA and bromide formation were inhibited 45 to 66% and 21 to 26%, respectively, by the P450 2A6 inhibitors 8-methoxypsoralen and coumarin, 84 to 90% by the P450 2E1 inhibitor 4-methylpyrazole and 55% by diethyldithiocarbamate, an inhibitor of both P450 2A6 and 2E1. Selective inhibitors of P450s 1A, 2B6, 2C9/10, 2D6 and 3A4 did not affect halothane oxidation. At saturating halothane concentrations (2.4 vol%) only cDNA-expressed P450 2A6 and 2B6 catalyzed significant rates of TFA and bromide formation, and P450 2E1 catalyzed comparatively minimal oxidation. Conversely, at subsaturating halothane concentrations (0.30 vol%), metabolism by P450 2E1 exceeded that by P450 2A6. Among a panel of human liver microsomes, there were significant linear correlations between halothane oxidation and P450 2A6 activity and protein content at saturating halothane concentrations (2.4 vol%), and a significant correlation between metabolite formation and P450 2E1 activity (but not P450 2A6 activity) at subsaturating concentrations (0.12 vol%). These experiments suggested P450 2A6 and 2E1 as the predominant catalysts at saturating and subsaturating halothane concentrations, respectively. Further kinetic analysis using cDNA-expressed P450 and liver microsomes clearly demonstrated that P450 2E1 is the high affinity/low capacity isoform (Km = 0.030-0.053 vol%) and P450 2A6 is the low affinity/high capacity isoform (Km = 0.77-1.2 vol%). Evidence was also obtained for substrate inhibition of P450 2E1. The in vitro clearance estimates (Vmax/Km) for microsomal P450 2E1 (4.3-5.7 ml/min/g) were substantially greater than those for microsomal P450 2A6 (0.12-0.21). These clearances, as well as rates of apparent halothane oxidation predicted from kinetic parameters in conjunction with plasma halothane concentrations measured during clinical anesthesia in humans, demonstrated that both P450 2E1 and P450 2A6 participate in human halothane metabolism, and that P450 2E1 is the predominant catalytic isoform.

Identification and isolation of CD1a positive putative tumour infiltrating dendritic cells in human breast cancer.

Identification of dendritic cells (DC) in human tissues has been technically problematic due to the lack of truly specific immunohistochemical markers for DC's. Human dendritic cells express CD1a glycoprotein at certain points in their life cycle. CD1a positive cells are present in many human tumours and have been associated with improved survival. However, little information exists concerning the separation of DC from human tumours. The current study reports that human breast carcinomas have low densities of CD1a positive cells with dendritic morphology, and details are shown of a technique for successful separation of these cells from tumour tissues.

Role of renal cysteine conjugate beta-lyase in the mechanism of compound A nephrotoxicity in rats.

BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats, in which it undergoes extensive metabolism to glutathione and cysteine S-conjugates. The mechanism of compound A nephrotoxicity in rats is unknown. Compound A nephrotoxicity has not been observed in humans. The authors tested the hypothesis that renal uptake of compound A S-conjugates and metabolism by renal cysteine conjugate beta-lyase mediate compound A nephrotoxicity in rats. METHODS: Compound A (0-0.3 mmol/kg in initial dose-response experiments and 0.2 mmol/kg in subsequent inhibitor experiments) was administered to Fischer 344 rats by intraperitoneal injection. Inhibitor experiments consisted of three groups: inhibitor (control), compound A, or inhibitor plus compound A. The inhibitors were probenecid (0.5 mmol/kg, repeated 10 h later), an inhibitor of renal organic anion transport and S-conjugate uptake; acivicin (10 mg/kg and 5 mg/kg 10 h later), an inhibitor of gamma-glutamyl transferase, an enzyme that cleaves glutathione conjugates to cysteine conjugates; and aminooxyacetic acid (0.5 mmol/kg and 0.25 mmol/kg 10 h later), an inhibitor of renal cysteine conjugate beta-lyase. Urine was collected for 24 h and then the animals were killed. Nephrotoxicity was assessed by light microscopic examination and biochemical markers (serum urea nitrogen and creatinine concentration, urine volume and urine excretion of protein, glucose, and alpha-glutathione-S-transferase [alpha GST], a marker of tubular necrosis). RESULTS: Compound A caused dose-related nephrotoxicity, as shown by selective proximal tubular cell necrosis at the corticomedullary junction, diuresis, proteinuria, glucosuria, and increased alpha GST excretion. Probenecid pretreatment significantly (P < 0.05) diminished compound A-induced increases (mean +/- SE) in urine excretion of protein (45.5 +/- 3.8 mg/24 h vs. 25.9 +/- 1.7 mg/24 h), glucose (28.8 +/- 6.2 mg/24 h vs. 10.9 +/- 3.2 mg/24 h), and alpha GST (6.3 +/- 0.8 micrograms/24 h vs. 1.0 +/- 0.2 microgram/24 h) and completely prevented proximal tubular cell necrosis. Aminooxyacetic acid pretreatment significantly diminished compound A-induced increases in urine volume (19.7 +/- 3.5 ml/24 h vs. 9.8 +/- 0.8 ml/24 h), protein excretion (37.2 +/- 2.7 mg/24 h vs. 22.2 +/- 1.8 mg/24 h), and alpha GST excretion (5.8 +/- 1.5 vs. 2.3 micrograms/24 h +/- 0.8 microgram/24 h) but did not significantly alter the histologic pattern of injury. In contrast, acivicin pretreatment increased the compound A-induced histologic and biochemical markers of injury. Compound A-related increases in urine fluoride excretion, reflecting compound A metabolism, were not substantially altered by any of the inhibitor treatments. CONCLUSIONS: Intraperitoneal compound A administration provides a satisfactory model of nephrotoxicity. Aminooxyacetic acid and probenecid significantly diminished histologic and biochemical evidence of compound A nephrotoxicity, whereas acivicin potentiated toxicity. These results suggest that renal uptake of compound A-glutathione or compound A-cysteine conjugates and cysteine conjugates metabolism by renal beta-lyase mediate, in part, compound A nephrotoxicity in rats.

High discharge survival rate after out-of-hospital ventricular fibrillation with rapid defibrillation by police and paramedics.

STUDY OBJECTIVE: To assess outcome in patients with ventricular fibrillation (VF) treated by defibrillator-equipped police and emergency medical technician-paramedics in an advanced life support (ALS) emergency medical services (EMS) system. METHODS: We carried out a retrospective observational outcome study of all consecutive adult patients with atraumatic cardiac arrest treated from November 1990 through July 1995. The study was carried out in a city with a population of 76,865 in an area of 32.6 square miles. Central 911 dispatched police and an ALS ambulance simultaneously. Accurate intervals were obtained with the synchronization of all defibrillator clocks with the 911 dispatch clock. The personnel who arrived first delivered the initial shock. After shocks delivered by police, paramedics provided additional treatment if needed. Main outcome measures were time elapsed before delivery of the first shock, restoration of spontaneous circulation (ROSC), and survival to discharge home. RESULTS: Of 84 patients, 31 (37%) were first shocked by police. Thirteen of the 31 demonstrated ROSC, without need for ALS treatment. All 13 survived to discharge. The other 18 patients required ALS; 5 (27.7%) survived. Among the 53 patients first shocked by paramedics, 15 had ROSC after shocks only, and 14 survived. The other 38 needed ALS treatment; 9 survived. Call-to-shock time for all patients was less in the police group than in the paramedic group (5.6 versus 6.3 minutes, P = .038). For all patients, call-to-shock time was less in those with ROSC after shocks only than in those who needed ALS (5.4 versus 6.3 minutes, P = .011). Survival to discharge was 49% (41 of 84), with 18 of 31 (58%) in the police group and 23 of 53 (43%) in the paramedic group. Call-to-shock time for survivors was 5.8 minutes; it was 6.4 minutes for the nonsurvivors (P = .020). Neither ROSC nor discharge survival was significantly different between police and paramedic-shocked patients. ROSC after initial shock and call-to-shock time were major determinants of survival, whether the first shocks were administered by police or by paramedics. With ROSC after shocks only, 27 of 28 (96%) survived, whereas 14 of 56 (25%) needing ALS survived (P < .001). CONCLUSION: A high discharge-to-home survival rate was obtained with early defibrillation by both police and paramedics. When shocks resulted in ROSC, the overwhelming majority of patients survived (96%). Even brief time decreases (eg. 1 minute) in call-to-shock time increase the likelihood of ROSC from shocks only, with a consequent decrease in the need for ALS intervention. Short call-to-shock time and ROSC response to shocks only are major determinants of a high rate of survival after VF.

P450-dependent and nonenzymatic human liver microsomal defluorination of fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product.

The volatile anesthetic sevoflurane is degraded by strong bases in the carbon dioxide absorbent in clinical anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, also called "Compound A"). FDVE is nephrotoxic in rats, where it is extensively biotransformed. Patients undergoing sevoflurane anesthesia have been exposed to low inhaled concentrations of FDVE. Although sevoflurane renal toxicity under conditions of FDVE formation has not been reported, there is still considerable concern about FDVE metabolism in humans and the potential for FDVE nephrotoxicity. Sevoflurane undergoes P450-catalyzed liver microsomal defluorination. We tested the hypothesis that FDVE also undergoes human liver microsomal defluorination. Defluorination occurred both in the absence and presence of NADPH; rates of total and NADPH-dependent fluoride formation were 1.6 +/- 0.1 and 1 +/- 0.1 nmol.min-1.mg-1 protein (mean +/- SD), respectively, in four human livers. Enzymatic defluorination was linear with respect to time, protein concentration, and was saturable with respect to substrate concentration. NADPH-dependent, but not NADPH-independent, FDVE defluorination was partially inhibited by coumarin, orphenadrine, diethyldithlocarbamate, and 4-methypyrazole. Microsomes containing cDNA-expressed human P4502E1 exhibited substantial catalytic activity toward FDVE defluorination. Microsomal FDVE defluorination was significantly diminished in the presence of the parent anesthetic, sevoflurane, from 1.3 to 0.6 nmol.min-1.mg-1. These results show that FDVE undergoes both P450-catalyzed and nonenzymatic defluorination by human liver microsomes. P4502E1 is implicated in the enzymatic defluorination. Nonenzymatic defluorination may result from FDVE addition to protein thiols. Enzymatic and/or nonenzymatic defluorination may be etiologic factors in FDVE nephrotoxicity in rats. In contrast, P450-dependent FDVE defluorination may be of less clinical consequence in humans, because it is inhibited by the parent anesthetic, sevoflurane.