Antidote removal during haemodialysis for massive acetaminophen overdose.

CONTEXT: Haemodialysis is sometimes used for patients with massive acetaminophen overdose when signs of "mitochondrial paralysis" (lactic acidosis, altered mental status, hypothermia and hyperglycaemia) are present. The role of haemodialysis is debated, in part because the evidence base is weak and the endogenous clearance of acetaminophen is high. There is also concern because the antidote acetylcysteine is also dialyzable. We prospectively measured serum acetylcysteine concentrations during haemodialysis in three such cases. CASE DETAILS: Three adults each presented comatose and acidemic 10 to ~18 h after ingesting > 1000mg/kg of acetaminophen. Two were hypothermic and hyperglycaemic. Serum lactate concentrations ranged from 7 mM to 12.5 mM. All three were intubated, and initial acetaminophen concentrations were as high as 5980 µM (900 µg/mL). An intravenous loading dose of 150 mg/kg acetylcysteine was initiated between 10.8 and ~18 h post ingestion, and additional doses were empirically administered during haemodialysis to compensate for possible antidote removal. A single run of 3-4 h of haemodialysis removed 10-20 g of acetaminophen (48-80% of remaining body burden), reduced serum acetaminophen concentrations by 56-84% (total clearance 3.4-7.8 mL/kg/min), accelerated native acetaminophen clearance (mean elimination half-life 580 min pre-dialysis, 120 min during and 340 min post-dialysis) and corrected acidemia. Extraction ratios of acetylcysteine across the dialysis circuit ranged from 73% to 87% (dialysance 3.0 to 5.3 mL/kg/min). All three patients recovered fully, and none developed coagulopathy or other signs of liver failure. DISCUSSION: When massive acetaminophen ingestion is accompanied by coma and lactic acidosis, emergency haemodialysis can result in rapid biochemical improvement. As expected, haemodialysis more than doubles the clearance of both acetaminophen and acetylcysteine. Because acetylcysteine dosing is largely empirical, we recommend doubling the dose during haemodialysis, with an additional half-load when dialysis exceeds 6 h.

Pentobarbital for severe gamma-butyrolactone withdrawal.

STUDY OBJECTIVE: Gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL) have become popular drugs of abuse. Acute overdose with either agent results in a well-recognized syndrome of central nervous system and respiratory depression. Recently, a withdrawal syndrome has been described for GHB. We report a severe form of GBL withdrawal, characterized by delirium, psychosis, autonomic instability, and resistance to benzodiazepine therapy. METHODS: We performed a chart review of consecutive admissions for GBL withdrawal in a regional toxicology treatment center. RESULTS: During a 6-month period, 5 patients presented with severe withdrawal attributed to abrupt GBL discontinuation. Patients manifested tachycardia, hypertension, paranoid delusions, hallucinations, and rapid fluctuations in sensorium. Test results for ethanol and routine drugs of abuse were negative. Initial treatment with high doses of lorazepam proved ineffective. Pentobarbital was then administered, resulting in excellent control of behavioral, autonomic, and psychiatric symptoms and in rapid reduction or avoidance of benzodiazepines. Median hospital stay was 5 days. No patient had respiratory depression or required mechanical ventilation. Patients were discharged on tapering doses of benzodiazepines or pentobarbital and were free of psychotic symptoms at follow-up. CONCLUSION: GBL discontinuation can result in severe withdrawal, necessitating ICU admission. Pentobarbital may be more effective than benzodiazepines at controlling delirium in patients with abnormal vital signs, paranoid delusions, and hallucinations as a result of GBL withdrawal.

Phentolamine reduces myocardial injury and mortality in a rat model of phenylpropanolamine poisoning.

BACKGROUND: Phenylpropanolamine produces dose-related, life-threatening cardiovascular, and central nervous toxicity from alpha-adrenergic overstimulation. Although some recommend the alpha-adrenergic antagonist, phentolamine, as treatment for such toxicity, its therapeutic efficacy has not been previously studied. We sought to determine if pretreatment with phentolamine could reduce acute myocardial injury and mortality in rats administered an overdose of phenylpropanolamine. METHODS: In the mortality arm of the study, 28 unanesthetized, male Wistar rats (14 animals per group) were randomized to receive an intraperitoneal injection of phentolamine (3 mg/kg) or an equal volume of normal saline diluent (control group). Twenty-five minutes later, all rats received an intraperitoneal injection of phenylpropanolamine (150 mg/kg). Mortality was compared at 24 hours. In the myocardial injury arm of the study, 20 unanesthetized rats (10 per group) were randomized to receive an intraperitoneal injection of phentolamine (3 mg/kg) or normal saline (control group). Twenty-five minutes later, all rats received an intraperitoneal injection of phenylpropanolamine (75 mg/kg). Seventy-two hours after phenylpropanolamine administration, all surviving animals were sacrificed and transverse sections of their hearts were graded histologically for injury by a blinded cardiac pathologist. RESULTS: Twelve rats died within 6 hours of phenylpropanolamine administration. Mortality was significantly lower in the phentolamine-pretreated rats (2/14; 14%) as compared to the control group (10/14; 71%; p = 0.006). The degree of myocardial injury was significantly lower in the phentolamine-pretreated rats (0) as compared to the control group (1.4 +/- 1.6; p = 0.012). CONCLUSION: In this rat model, phentolamine pretreatment prevented acute myocardial injury and significantly reduced lethality from an intraperitoneal phenylpropanolamine overdose.

Core rewarming via warm lavage liquid ventilation in a swine model of hypothermia-associated ventricular fibrillation.

OBJECTIVES: To determine whether warm lavage liquid ventilation (LV) would provide rapid cardiopulmonary rewarming in swine with severe hypothermia and ventricular fibrillation. METHODS: Intubated common swine (n = 3; mean +/- SEM weight 26+/-1.2 kg) were cooled to a mean aortic temperature of 26.4+/-0.9 degrees C. Ventricular fibrillation was induced by transthoracic electrical shock. Rewarming was initiated by continuous endotracheal instillation of warm (44 degrees C) pre-oxygenated, perfluorocarbon liquid at 5 mL/kg/min. Endotracheal instillation of perfluorocarbon occurred while standard gas ventilation continued. Manual chest compressions were performed throughout the 30-minute rewarming process. Outcome measures were the absolute and relative rates of change of all temperatures. RESULTS: After 30 minutes of warm lavage LV, the mean aortic and pulmonary artery temperatures increased by 6.6+/-0.6 degrees C, respectively. Esophageal, nasal, and rectal temperatures did not change significantly. In one animal, normal sinus rhythm spontaneously returned after 16 minutes of rewarming. CONCLUSIONS: During cardiac arrest, warm lavage liquid ventilation may produce rapid cardiopulmonary rewarming.

Reversal of severe methanol-induced visual impairment: no evidence of retinal toxicity due to fomepizole.

CASE REPORT: We report a case of methanol poisoning exhibiting complete recovery from severe visual impairment following treatment with ethanol, fomepizole, and hemodialysis. An adult male presented with central blindness after ingesting methanol. Initial visual acuity was <20/800 (finger counting at 1-2 feet) with retinal edema on fundoscopy, arterial pH 7.19, methanol 97 mg/dL (30 mmol/L), formate 14.3 mmol/L, and ethanol undetectable. The patient was treated with ethanol, then fomepizole intravenously (15, 10, then 5 mg/kg), and hemodialysis. Methanol metabolism was effectively blocked by fomepizole even after ethanol had been eliminated, and the patient recovered 20/20 vision by day 14 with normal fundoscopy. This case report confirms highly efficient inhibition of alcohol dehydrogenase by fomepizole, as well as demonstrate the safety of fomepizole in a patient already exhibiting end-organ retinal toxicity. The potential for fomepizole to inhibit retinol dehydrogenase, an isoenzyme of alcohol dehydrogenase essential to vision, did not appear to be clinically significant in this symptomatic methanol-poisoned patient.

Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. For the Methylpyrazole for Toxic Alcohols Study Group.

STUDY OBJECTIVE: The elimination kinetics of ethylene glycol (EG) in human subjects treated with fomepizole (4-methylpyrazole) were analyzed to establish the efficacy of alcohol dehydrogenase (ADH) inhibition and to characterize elimination pathways. METHODS: Drug concentration data from patients enrolled in the EG arm of the Methylpyrazole for Toxic Alcohols trial, a prospective, multicenter, open-label trial of fomepizole, were analyzed and compared with published estimates. RESULTS: In 19 patients analyzed (EG concentrations of 3.5 to 211 mg/dL), elimination was first order during fomepizole monotherapy (half-life of 19.7+/-1.3 hours) and was not affected by the presence of ethanol. The elimination rate was significantly faster (half-life of <8.6+/-1.1 hours, P <.001) in the absence of fomepizole and ethanol. EG elimination by the kidneys was directly proportional to remaining renal function as estimated by creatinine clearance, with a fractional excretion of 25.5%+/-9.4%. Renal elimination and hemodialysis were the only significant routes of EG elimination as long as fomepizole concentrations were maintained well above 10 micromol/L (EG/fomepizole molar ratio, <100:1). All patients with normal serum creatinine concentrations at the initiation of fomepizole treatment had rapid rates of renal elimination (half-life of 16.8+/-0.8 hours). CONCLUSION: At doses used, fomepizole effectively inhibits ADH-mediated metabolism of EG. Serum creatinine concentration at presentation and creatinine clearance can be used to predict EG elimination during fomepizole therapy and can help determine which patients will require hemodialysis to expedite EG elimination. An absolute EG concentration above 50 mg/dL should no longer be used as an independent criterion for hemodialysis in patients treated with fomepizole.

Enhanced mortality from perfluorocarbon administration in a rat model of kerosene aspiration.

BACKGROUND: Aspiration of low-viscosity hydrocarbons may lead to fulminant pneumonitis and acute respiratory distress syndrome. Animal and human studies suggest that partial liquid ventilation with perfluorocarbon improves gas exchange and pulmonary function in acute respiratory failure. The objective of this investigation was to determine the effect of intratracheal perfluorocarbon administration and a brief period of partial liquid ventilation on survival in a rat model of severe hydrocarbon aspiration. METHODS: Two randomized, non-blinded, controlled experiments were performed. First, male Wistar rats (n = 12) were given 0.3 mL/kg kerosene via direct intratracheal instillation and after 5 minutes were randomized to partial liquid ventilation or standard gas ventilation (control) groups. Partial liquid ventilation rats (n = 6) received 20 mL/kg of pre-oxygenated FC-77 intratracheally and positive-pressure gas ventilation (FiO2 = 1.0), and control rats (n = 6) received positive-pressure gas ventilation alone. Animals were observed for survival and 7-day mortality was compared using the Fisher Exact test. The study was then repeated in 12 additional animals using a 15-minute interval between kerosene instillation and treatment (PLV vs control). RESULTS: Mortality was significantly greater in the partial liquid ventilation group (5 of 6; 83%) as compared to the control group (1 of 6; 17% [p = 0.039]). Results were identical in the repeat study. All animals that died succumbed from acute respiratory failure within 24 hours of kerosene instillation. CONCLUSION: In this rat model of severe kerosene aspiration, intratracheal perfluorocarbon administration and a brief period of partial liquid ventilation proved detrimental and significantly increased mortality.

Randomized, double-blind study on sedatives and hemodynamics during rapid-sequence intubation in the emergency department: The SHRED Study.

STUDY OBJECTIVE: To compare thiopental, fentanyl, and midazolam for rapid-sequence induction and intubation (RSI). METHODS: Eighty-six patients undergoing RSI in the emergency department were randomly assigned in a double-blind fashion to receive either thiopental (5 mg/kg), fentanyl (5 microg/kg), or midazolam (.1 mg/kg) before paralysis was induced. Outcome measures were mortality, speed and ease of intubation, and hemodynamics. RESULTS: Of the patients who received thiopental, 93% were intubated within 2 minutes of paralysis (P=.037), but systolic blood pressure fell an average of 38 mm Hg in this group (P=.045). The midazolam group had a greater number of delayed intubations (31%) and an average heart rate increase of 17 beats/minute (P=.008). Mortality (24% inhospital) was unaffected by drug assignment. In all three groups, patients with pulmonary edema had the greatest decrease in blood pressure during RSI, and patients exposed to multiple attempts at intubation manifested pronounced hypertension. CONCLUSION: Fentanyl provided the most neutral hemodynamic profile during RSI, although factors other than choice of sedative can play a more significant role in determining hemodynamic response. Depth of sedation may influence the speed of RSI.

Implementation of the Ottawa Knee Rule for the use of radiography in acute knee injuries.

CONTEXT: The Ottawa Knee Rule is a previously validated clinical decision rule that was developed to allow physicians to be more selective and efficient in their use of plain radiography for patients with acute knee injuries. OBJECTIVE: To assess the impact on clinical practice of implementing the Ottawa Knee Rule. DESIGN: Controlled clinical trial with before-after and concurrent controls. SETTING: Emergency departments of 2 teaching and 2 community hospitals. PATIENTS: All 3907 consecutive eligible adults seen with acute knee injuries during two 12-month periods before and after the intervention. INTERVENTION: During the after period in the 2 intervention hospitals, the Ottawa Knee Rule was taught to all house staff and attending physicians who were encouraged to order knee radiography according to the rule. MAIN OUTCOME MEASURES: Referral for knee radiography, accuracy and reliability of the rule, mean time in emergency department, and mean charges. RESULTS: There was a relative reduction of 26.4% in the proportion of patients referred for knee radiography in the intervention group (77.6% vs 57.1 %; P<.001), but a relative reduction of only 1.3% in the control group (76.9% vs 75.9%; P=.60). These changes over time were significant when the intervention and control groups were compared (P<.001). The rule was found to have a sensitivity of 1.0 (95% confidence interval [CI], 0.94-1.0) for detecting 58 knee fractures. The K coefficient for interpretation of the rule was 0.91 (95% CI, 0.82-1.0). Compared with nonfracture patients who underwent radiography during the after-intervention period, those discharged without radiography spent less time in the emergency department (85.7 minutes vs 118.8 minutes) and incurred lower estimated total medical charges for physician visits and radiography (US $80 vs US $183). CONCLUSIONS: Implementation of the Ottawa Knee Rule led to a decrease in use of knee radiography without patient dissatisfaction or missed fractures and was associated with reduced waiting times and costs. Widespread use of the rule could lead to important health care savings without jeopardizing patient care.

Prospective validation of a decision rule for the use of radiography in acute knee injuries.

OBJECTIVE: To validate a previously derived decision rule for the use of radiography in patients with acute knee injury. DESIGN: Prospectively administered survey. SETTING: Emergency departments of two university hospitals serving adults. PATIENTS: Convenience sample of 1096 of 1251 eligible adults with acute knee injuries; 124 patients were examined by two physicians. MAIN OUTCOME MEASURES: Attending emergency physicians assessed each patient for standardized clinical variables and determined the need for radiography according to the decision rule. Patients who did not have radiography underwent a structured telephone interview at day 14 to determine the possibility of a fracture. The rule was assessed for ability to correctly identify the criterion standard, fracture of the knee. An attempt was made to refine the rule by means of univariate and recursive partitioning analyses. RESULTS: The decision rule had a sensitivity of 1.0 (95% confidence interval [CI], 0.94 to 1.0) for identifying 63 clinically important fractures. Physicians correctly interpreted the rule in 96% of cases, and the k value for interpretation was 0.77 (95% CI, 0.65 to 0.89). The potential relative reduction in use of radiography was estimated to be 28%. The probability of fracture, if the decision rule were "negative," is estimated to be 0% (95% CI, 0% to 0.4%). Attempts to refine the rule led to a model with improved specificity but with an unacceptable loss of sensitivity. CONCLUSION: Prospective validation has shown this decision rule to be 100% sensitive for identifying fractures of the knee, to be reliable and acceptable, and to have the potential to allow physicians to reduce the use of radiography in patients with acute knee injury.