Greene Shepherd

Cyanide Poisoning and Its Treatment

Cyanide is both widely available and easily accessible throughout the world. Although the compound is not frequently encountered, it has been used as a poison and contaminant in the past and is a potential terrorist agent. Cyanide has the ability to cause significant social disruption and demands special attention to public health preparedness. It can be obtained from a variety of sources, including industrial, medical, and even common household products. Another frequently encountered source of cyanide exposure is residential fires. Exposure to high concentrations of the chemical can result in death within seconds to minutes. Long‐term effects from cyanide exposure can cause significant morbidity. The only treatment for cyanide toxicity approved for use in the United States is a kit consisting of amyl nitrite, sodium nitrite, and sodium thiosulfate. Future research aims to find a faster‐acting, more effective, and better tolerated treatment for cyanide toxicity.

Role of Hydroxocobalamin in Acute Cyanide Poisoning

Objective: To review the recently approved cyanide antidote, hydroxocobalamin, and describe its role in therapy. Data Sources: Relevant publications were identified through a systematic search of PubMed using the MeSH terms and key words hydroxocobalamin and cyanide. This search was then limited to human studies published since 2000. Systematic searches were conducted through January 2008. References from identified articles were reviewed for additional pertinent human studies. Study Selection and Data Extraction: The literature search retrieved 7 studies on the safety and/or efficacy of hydroxocobalamin in humans. Four new studies were identified by the search and 3 studies were identified from the references. Data Synthesis: Studies of antidote efficacy in humans are ethically and logistically difficult. A preclinical study demonstrated that intravenous doses of hydroxocobalamin 5 g are well tolerated by volunteer subjects. Hydroxocobalamin has been shown to reduce cyanide concentrations in controlled studies of nitroprusside therapy and in heavy smokers. A retrospective study of 14 acute cyanide poisonings also demonstrated hydroxocobalamins safety and efficacy. Two studies examining hydroxocobalamin for smoke inhalation-associated cyanide poisoning indicated a possible benefit, but they are insufficient to establish definitive criteria for use in this setting. Randomized controlled trials of hydroxocobalamin and traditional cyanide antidotes (nitrites/thiosulfate) are lacking. Conclusions: Cyanide poisoning can rapidly cause death. Having an effective antidote readily available is essential for facilities that provide emergency care. In cases of cyanide ingestion, both the nitrite/thiosulfate combination and hydroxocobalamin are effective antidotes. Hydroxocobalamin offers an improved safety profile lor children and pregnant women. Hydroxocobalamin also appears to have a better safety profile in the setting of cyanide poisoning in conjunction with smoke inhalation. However, current data are insufficient to recommend the empiric administration of hydroxocobalamin to all victims of smoke inhalation.

High-Dose Insulin Therapy for Calcium-Channel Blocker Overdose

OBJECTIVE: To evaluate the evidence for using high-dose insulin therapy with supplemental dextrose and potassium in calcium-channel blocker (CCB) overdose. DATA SOURCES: Evidence of efficacy for high-dose insulin therapy with supplemental dextrose and potassium was sought by performing a search of MEDLINE and Toxline between 1966 and July 2004 using combinations of the terms calcium-channel blocker, overdose, poisoning, antidote, and insulin. Abstracts from the North American Congress of Clinical Toxicology for the years 1996–2003 were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Identified articles, including animal studies, case reports, and case series, were evaluated for this review. No clinical trials were available. DATA SYNTHESIS: Animal models of CCB overdose demonstrate that high-dose insulin with supplemental dextrose and potassium was a more effective therapy than calcium, glucagon, or catecholamines. High-dose insulin appears to enhance cardiac carbohydrate metabolism and has direct inotropic effects. Published clinical experience is limited to 13 case reports where insulin was used after other therapies were failing; 12 of these patients survived. High-dose insulin therapy was beneficial for CCB-induced hypotension, hyperglycemia, and metabolic acidosis. Bradycardia and heart block resolved in some patients, but persisted in others. CONCLUSIONS: Based on animal data and limited human experience, as well as the inadequacies of available alternatives for patients with significant poisoning, high-dose insulin therapy warrants further study and judicious use in patients with life-threatening CCB poisoning.

Pharmacokinetics and safety of lidocaine and monoethylglycinexylidide in liposuction: a microdialysis study.

High doses of lidocaine are administered to patients undergoing liposuction. Monoethylglycinexylidide, the active metabolite of lidocaine, is 80 to 90 percent as potent as lidocaine, and its relative toxicity is approximately that of lidocaine. Monoethylglycinexylidide has not previously been measured in studies on lidocaine in liposuction. The aims of this study were to characterize systemic exposure to lidocaine and monoethylglycinexylidide and to measure lidocaine and monoethylglycinexylidide levels within the tissues. Five female volunteers between the ages of 29 and 40 years underwent liposuction. Lidocaine (1577 to 2143 mg, corresponding to 19.9 to 27.6 mg/kg) was infiltrated during the procedure. Levels of lidocaine and monoethylglycinexylidide in blood and lipoaspirate were assessed perioperatively. Tissue lidocaine and monoethylglycinexylidide levels were measured postoperatively using a microdialysis technique in vivo. The peak (maximal) concentration of lidocaine plus monoethylglycinexylidide was 2.2 to 2.7 microg/ml. Time to peak lidocaine plus monoethylglycinexylidide was 8 to 28 hours after infiltration began. Absorbed lidocaine was estimated to be 911 to 1596 mg; therefore, 45 to 93 percent (mean, 64 percent) of the infiltrated dose was ultimately absorbed. Lipoaspirate analysis showed that 9.1 to 10.8 percent (mean, 9.7 percent) of the infiltrated dose was removed during the procedure. Tissue lidocaine levels below 5 microg/ml were demonstrated from 4 to 8 hours postoperatively. The peak lidocaine plus monoethylglycinexylidide concentration was within safe limits in this group of subjects. Time to peak lidocaine plus monoethylglycinexylidide signifies a delayed peak and therefore a longer period of potential lidocaine toxicity than was originally thought. Microdialysis results demonstrated that tissue lidocaine levels may be subtherapeutic within 4 to 8 hours of the procedure. Investigation into factors controlling the resorption of lidocaine during liposuction is warranted in an effort to improve the duration of effect. Furthermore, considering the active metabolite monoethylglycinexylidide, longitudinal studies are necessary to determine whether improving the side effect profile of lidocaine by reducing the dose administered during liposuction may be possible without decreasing the perioperative analgesic effect.

Adverse Effects Associated with Extra Doses of Bupropion

Study Objective. To determine the frequency of adverse effects, clinical outcomes, and possible dose‐response relationships associated with inadvertent extra doses of bupropion.

Pharmacokinetics and safety of epinephrine use in liposuction

Patients are routinely exposed to high-dose epinephrine infiltration during large-volume liposuction. Because of the serious cardiovascular side-effect profile of catecholamine overdose, the authors examined the safety of larger-volume liposuction by assessing epinephrine pharmacokinetics. Five female volunteers with American Society of Anesthesiologists physical status of I or II, aged 29 to 40 years and weighing 75.9 to 95 kg, underwent liposuction. The wetting solution contained 7.3 mg (SEM, 0.7 mg) of epinephrine, corresponding to 0.09 mg/kg (0.04 mg/kg). Total plasma epinephrine and norepinephrine concentrations were assessed by high-performance liquid chromatography. Approximate exogenous epinephrine absorption was calculated after correction for estimated endogenous epinephrine production. Pharmacokinetic assessments were performed using standard equations. The total plasma epinephrine peak occurred at the final intraoperative reading (5 hours after induction) and was 323 pg/ml (24.8 pg/ml), three to four times maximum baseline resting levels. The norepinephrine level was slightly elevated throughout the study period, with a reversal of the normal epinephrine/norepinephrine ratio (<0.5:1) demonstrated intraoperatively (>5:1). Estimated time to peak exogenous epinephrine level ranged from 1 to 4 hours from the start of infiltration. Area under the plasma concentration versus time curve was approximately 2089 to 2610 pg·hour/ml. Peak exogenous epinephrine concentration was estimated to be 286 to 335 pg/ml. Clearance was 764,508 ml/hour and volume of distribution was 0.4 liter/kg (0.006 liter/kg). Total absorbed epinephrine was estimated, 1.8 mg to 2.2 mg, equivalent to 25 to 32 percent of the infiltrated dose. The reversal of the normal epinephrine/norepinephrine ratio and the fact that norepinephrine levels were within normal range implied that the majority of plasma epinephrine measured was exogenously infiltrated and not endogenously synthesized. On the basis of these observations, pharmacokinetic analyses were performed. Although unequivocal toxic epinephrine levels were not demonstrated, epinephrine peaks were three to four times the maximum observed in normal resting patients. Peak levels were comparable to those observed during major physiologic stresses, such as exercising to exhaustion, open abdominal surgery, or cross-clamping the aorta during surgical repair. Furthermore, epinephrine has been associated with myocardial infarction, arrhythmias, and fatal asystole in susceptible patients at these levels. Patients should be carefully screened for clinical evidence of hemodynamic and cardiac pathology before larger-volume liposuction is undertaken, as it may result in unnecessary high risk for patients who have preexisting cardiovascular disorders. Healthy American Society of Anesthesiologists physical status I or II patients should have sufficient cardiac reserve to tolerate these catecholamine levels.

Serotonin Syndrome with Elevated Paroxetine Concentrations

OBJECTIVE To describe a case of serotonin syndrome due to paroxetine and ethanol. CASE SUMMARY A 57-year-old white man was brought to the emergency department one day after ingesting paroxetine 3600 mg and a pint of hard liquor. He denied the use of any other drug or herbal products and regular use of alcohol. Upon arrival to the hospital, vital signs were blood pressure 188/103 mm Hg, heart rate 114 beats/min, respiratory rate 28 breaths/min, temperature 36.8 °C, and O2 saturation 96% on room air. Findings on physical examination included dilated pupils, facial flushing, diaphoresis, shivering, myoclonic jerks, tremors, and hyperreflexia. A tentative diagnosis of serotonin syndrome was made. Initially, cyproheptadine 8 mg was administered orally with no observable effect. An additional 12 mg was given in 3 doses over 24 hours. Symptoms abated slowly over the next 6 days, during which a thorough evaluation failed to reveal any other potential causes for the patients condition. Serum paroxetine concentrations at 27.5 and 40 hours after ingestion were 1800 and 1600 ng/mL, respectively (normal 20–200 ng/mL). DISCUSSION Serotonin syndrome is rarely reported in patients taking only one serotonergic medication. Although serum paroxetine concentrations have not been shown to correlate with efficacy or toxicity, our patients serum paroxetine concentration was 9 times the upper end of the therapeutic range. Cyproheptadine, which has been suggested as a therapy, did not appear beneficial in this patient. Use of the Naranjo probability scale indicated a probable relationship between the serotonin syndrome and the overdose of paroxetine taken by this patient. CONCLUSIONS More studies are needed to better assess the role of cyproheptadine and other serotonin antagonists in the management of the serotonin syndrome. Regardless of the use of cyproheptadine or other agents, attention should be paid to fluid status, decontamination, and management of hyperthermia, agitation, and seizures.

Efficacy of the Cation Exchange Resin, Sodium Polystyrene Sulfonate, to Decrease Iron Absorption

Background: Iron is not bound by charcoal; therefore, a method of binding iron in the gastrointestinal tract to prevent absorption in iron overdose is needed. This study investigated the efficacy and safety of sodium polystyrene sulfonate to prevent absorption of iron in human volunteers. Methods: Six adult volunteers completed this prospective crossover trial. Following an oral dose of elemental iron 10 mg/kg, each subject received sodium polystyrene sulfonate 30 g or water as control. Baseline and serial serum iron samples were drawn to determine pharmacokinetic parameters. Results: A trend toward increased time to peak following sodium polystyrene sulfonate compared to the control arm (5.7 vs 3.6 hours) was observed but was not statistically significant (p = 0.517). A trend toward smaller area-under-the-curve for the sodium polystyrene sulfonate was evident but was not statistically significant (p = 0.77). Iron concentration increased on average 298 mcg/dL and 370 mcg/dL above baseline in the treatment and control arms (p = 0.44). Sodium polystyrene sulfonate is not an effective method of decontamination for iron overdose.

Homicidal poisoning deaths in the United States 1999―2005

Objectives. Homicidal poisoning is an intriguing but poorly described phenomenon. This study describes homicidal poisoning deaths in the United States during 1999–2005. Methods. A trend analysis of homicidal poisoning death was performed using Vital Statistics data. The National Mortality Statistics database was queried using “homicide” as injury intent and “poisoning” as mechanism for the years 1999–2005. Counts and rates were obtained for subgrouping by using demographic data and ICD-10 codes. Chi-square analysis calculated subgroup odds ratios (OR) and 95% confidence intervals (CI). Results. A total of 523 homicidal poisoning deaths were identified. The overall rate for the period was 0.26/million/year. Males were significantly (OR 1.34, CI 1.13–1.59) more likely to victims than females. Death was more likely at extremes of age. Rates were 2.05/million (OR 8.72, CI 6.63–11.49) in children <1 year and 0.56/million (OR 2.20, CI 1.38–3.52) at ages ≥85 years. Rates also varied by race and were more common among Blacks (0.43/million; OR 1.83, CI 1.47–2.26). The greatest rate was observed in Black infants (5.3/million; OR 21.34, CI 14.17–32.15). ICD-10 codes indicated that medications were the most common poison. Rates were significantly higher in the West and lower in the Northeast. Conclusion. The overall homicidal poisoning death rate was low between 1999 and 2005. The most common type of poison used was medications. Substantially higher rates were observed in vulnerable populations at extremes of age, particularly infants, and among Blacks. This challenges common notions of the victims of homicidal poisoning and the underlying motivation of their poisoners.

Iron Bezoar Retained in Colon Despite 3 Days of Whole Bowel Irrigation

Concretion formation is a documented complication of large iron ingestions. The generally accepted treatment is supportive care, whole bowel irrigation, and intravenous deferoxamine for systemic toxicity. Laparotomy and gastrotomy have also been used in patients with a high iron burden and bezoar formation. Though experiments suggest that iron is poorly absorbed in the colon, there are no case reports of iron overdose without systemic toxicity, despite a retained colonic bezoar. We report the case of a 16‐month‐old who presented to an Emergency Department 19 h after an iron ingestion. Initial laboratory studies revealed an anion gap of 14 mEq/L, and a 20 h serum iron concentration of 429 mcg/dL. An abdominal radiograph revealed multiple pills throughout the stomach and small bowel; whole bowel irrigation was initiated. Deferoxamine was administered at 10 mg/kg/h and then stopped when the serum iron level reached 27 mcg/dL, 36 h later. At this time, the abdominal radiograph showed an iron bezoar remaining in the ascending colon despite a clear rectal effluent from whole bowel irrigation. Despite whole bowel irrigation over the next 36 h, the iron bezoar was not removed and actually migrated proximally in the colon. Treatment was stopped on the third day and a normal diet was instituted with prompt passage of the bezoar.