Samuel J. Stellpflug

Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin.

Introduction. Nebivolol, a beta blocker with 3–10 times more β1 cardioselectivity than metoprolol, has caused hypotension and bradycardia in overdose. We report a nebivolol-induced cardiac arrest in the setting of a polydrug ingestion, successfully resuscitated with intravenous fat emulsion (IFE) and high-dose insulin (HDI). Case report. A 48-year-old man was brought to the emergency department after ingesting nebivolol and ethanol, along with possibly diazepam and cocaine. He had a heart rate of 71/min and a blood pressure of 98/61 mmHg. The initial ECG showed sinus rhythm with a QTc of 483 ms and a QRS of 112 ms. Over the subsequent 4 h, he became bradycardic and hypotensive and developed bradyasystolic cardiac arrest. Standard resuscitation including epinephrine had no effect. Spontaneous circulation returned 30 s after a 100 mL bolus of 20% IFE, and the patient then became briefly hypertensive and tachycardic with heart rate and blood pressure measured as high as 123/min and 251/162 mmHg, respectively. His care included IFE infusion along with HDI bolus and infusion with doses as high as 21.8 units/kg/h. With subsequent hypotension, vasopressors were withheld in favor of HDI and supportive care. He was discharged with baseline neurologic function. Discussion. We hypothesize that after the administration of IFE the epinephrine was able to exert its effect on receptors previously occupied with the nebivolol. This would be congruent with the lipid sink theory of IFE mechanism. Conclusion. We report an overdose involving nebivolol in a polydrug ingestion resulting in cardiac arrest, successfully treated with IFE and a very HDI infusion.

2C or Not 2C: Phenethylamine Designer Drug Review

New groups of synthetic “designer drugs” have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as “legal” highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.

High-dose insulin: A consecutive case series in toxin-induced cardiogenic shock

Context. Cardiovascular medication overdoses can be difficult to treat. Various treatment modalities are currently recommended. Objective. To describe patient outcomes and adverse events of high-dose insulin therapy in consecutive overdose patients in cardiogenic shock after implementation of a high-dose insulin protocol (1–10 U/kg/h, while avoiding or tapering off vasopressors). Methods. This is an observational consecutive case series of patients identified from a registry. Data were collected by retrospective chart review of patients treated by our toxicology service with this protocol from February 2007 until March 2010. Results. Twelve patients were treated with high-dose insulin. The mean age was 36.5 years (SD 11.7). Seven patients had pre-existing vasopressor therapy, and all were tapered off vasopressors while on insulin. Two patients experienced pulseless electrical activity cardiac arrest prior to high-dose insulin therapy. Intravenous fat emulsion was given to two patients. The mean maximum insulin infusion rate was 8.35 U/kg/h (mean = 8.35, SD 6.34). The mean duration of insulin infusion was 23.5 h (SD 19.7). The mean duration of glucose infusion post-insulin was 25.2 h (SD 17.7). The primary toxins were β-blocker in five, calcium channel blocker in two, combined β-blocker/calcium channel blocker in two, tricyclic antidepressant in one, and polydrug in 2. Clinical outcomes. Eleven of 12 patients survived. One patient expired 9 h into insulin therapy from cardiac arrest shortly after the insulin was stopped and a vasopressor re-initiated (protocol deviation). Adverse events. Six patients experienced a total of 19 hypoglycemic events. Hypokalemia (defined as < 3.0 mEq/L) developed in eight patients. Adverse sequelae. Necrotic digits occurred in one patient with known clotting disorder after receiving high-dose norepinephrine and INR reversal with fresh frozen plasma prior to insulin therapy. One patient was discharged with mild anoxic injury thought due to pulseless electrical activity arrest prior to insulin therapy. Three of these 12 patients have been previously described in published case reports. Conclusion. High-dose insulin therapy based on a 1–10 U/kg/h dosing guideline and recommending avoidance of vasopressors appears to be effective in the treatment of toxin-induced cardiogenic shock. Hypoglycemia was the most frequent adverse event, followed by hypokalemia. Adverse events did not lead to adverse sequelae.

A prospective study of ketamine versus haloperidol for severe prehospital agitation

Abstract Context: Ketamine is an emerging drug for the treatment of acute undifferentiated agitation in the prehospital environment, however no prospective comparative studies have evaluated its effectiveness or safety in this clinical setting. Objective: We hypothesized 5 mg/kg of intramuscular ketamine would be superior to 10 mg of intramuscular haloperidol for severe prehospital agitation, with time to adequate sedation as the primary outcome measure. Methods: This was a prospective open label study of all patients in an urban EMS system requiring chemical sedation for severe acute undifferentiated agitation that were subsequently transported to the EMS system’s primary Emergency Department. All paramedics were trained in the Altered Mental Status Scale and prospectively recorded agitation scores on all patients. Two 6-month periods where either ketamine or haloperidol was the first-line therapy for severe agitation were prospectively compared primarily for time to adequate sedation. Secondary outcomes included laboratory data and adverse medication events. Results: 146 subjects were enrolled; 64 received ketamine, 82 received haloperidol. Median time to adequate sedation for the ketamine group was 5 minutes (range 0.4–23) vs. 17 minutes (range 2–84) in the haloperidol group (difference 12 minutes, 95% CI 9–15). Complications occurred in 49% (27/55) of patients receiving ketamine vs. 5% (4/82) in the haloperidol group. Complications specific to the ketamine group included hypersalivation (21/56, 38%), emergence reaction (5/52, 10%), vomiting (5/57, 9%), and laryngospasm (3/55, 5%). Intubation was also significantly higher in the ketamine group; 39% of patients receiving ketamine were intubated vs. 4% of patients receiving haloperidol. Conclusions: Ketamine is superior to haloperidol in terms of time to adequate sedation for severe prehospital acute undifferentiated agitation, but is associated with more complications and a higher intubation rate.

A case of U-47700 overdose with laboratory confirmation and metabolite identification.

Abstract Context: The opioid epidemic has included use of traditional drugs and recently newer synthetics. It is critically important to recognize and identify these new drugs both clinically and through appropriately designed toxicology testing. There is little available information on a synthetic gaining popularity, U-47700. Case details: A 23-year-old female presented after using “U4” by nasal insufflation and injection. She was cyanotic with respiratory depression and responded to naloxone in the field. She was found to have non cardiogenic pulmonary edema and hemoptysis which improved with BiPAP. Urine and serum samples were analyzed using mass spectrometry, confirming 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide or U-47700. The sample was further analyzed elucidating metabolism specifics. Drug and metabolite concentrations were subsequently measured in both serum and urine. The parent compound of U-47700 was detected at 394 ng/mL and 228 ng/mL in serum and urine, respectively. Metabolites detected in appreciable amounts included the desmethyl (1964 ng/mL in urine), bisdesmethyl (618 ng/mL), desmethyl hydroxy (447 ng/mL), and bisdesmethyl hydroxy forms (247 ng/mL) of U-47700. Discussion: U-47700 is a potent μ-opioid receptor agonist and has recently been used recreationally, contributing to hospitalizations and likely deaths in the community. This is a case report describing an exposure to U-47700 with subsequent laboratory analysis. Based upon this one case, parent U-47700 appear to be an appropriate marker of use in a serum sample. However, demethylated metabolites appear dominant as urinary markers of U-47700 use.

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning*

Abstract Background: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. Methods: Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. Results: For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid® 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence. Conclusion: Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.

Bath Salts: The Ivory Wave of Trouble

Mephedrone and MDPV are both β-ketophenethylamine derivatives of cathinone, a compound isolated from the East African plant Catha edulis (khat, qat). Mephedrone is commonly referred to as plant food, MCAT, 4-MMC, meow meow, meph, and drone; MDPV is commonly called MTV, MDPK, Magic, and Super Coke. Both are structurally similar to amphetamines, with mephedrone sharing close similarities with methamphetamine and MDPV with ecstasy (3,4-methylenedioxymethamphetamine; MDMA). Bath salts pose an increasing public health risk in the United States, with reports of toxicity and mortality increasing along with calls to poison centers throughout the United States. Packages labeled with innocuous monikers such as White Ice, Ivory Wave, Ocean Snow, Lunar Wave, and Vanilla Sky intentionally belie the dangerous substances within, which are by no means intended to replace legitimate bath products. The white or tan crystalline powder commonly is administered by nasal insufflation or oral ingestion; however, rectal suppository and less commonly, intramuscular or intravenous injection, are also reported.1,2 A movement to ban these substances is growing in the United States, following similar actions in Europe.3 Although successfully outlawed in some locales, this movement has not eliminated the public health hazards posed by mephedrone or MDPV. Emergency physicians (EP) should thus be knowledgeable in the epidemiology of bath salt abuse, the clinical toxidrome with which bath salt toxicity presents, and appropriate treatment strategies to reduce morbidity and mortality in patients presenting with bath salt toxicity.

Cardiotoxic Overdose Treated with Intravenous Fat Emulsion and High-Dose Insulin in the Setting of Hypertrophic Cardiomyopathy

High-dose insulin (HDI) and intravenous fat emulsion (IFE) are used in overdoses, although rarely combined. To our knowledge, IFE therapy has not been reported in overdoses of diltiazem, metoprolol and amiodarone. We report a severe overdose of these drugs treated with HDI and IFE in a patient with hypertrophic cardiomyopathy (HCM). We also discuss the potential clinical implications of the inotropic effects of HDI in the setting of HCM and the use and efficacy of IFE in this overdose.

A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock

Background. High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. Methods. This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. Results. 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. Conclusion. HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.

The association between ketamine given for prehospital chemical restraint with intubation and hospital admission

INTRODUCTION Intramuscular ketamine has become increasingly popular for prehospital chemical restraint of severely agitated or violent patients because of its favorable adverse effect profile, rapid onset, and wide therapeutic window. However, there is currently no literature quantifying the need for intubation or hospital admission for these patients once they reach the emergency department. METHODS Medical records for patients receiving prehospital ketamine who were transported to a single level 1 trauma center were abstracted. Ketamine dose, patient weight, final disposition, and presence of intubation were recorded. Exclusion criteria were missing dose or weight and ketamine given for an indication other than chemical restraint. Statistical analysis was preformed with unadjusted Student t test. Statistical significance was defined as P < .05. RESULTS A convenience sample of 51 consecutive patients was identified with 2 excluded because of missing data, leaving 49 for analysis. Ketamine dosing ranged from 2.25 to 9.42 mg/kg (mean, 5.26 ± 1.65 mg/kg). Significant differences were noted between those who required intubation (n = 14) and those who did not (n = 35) (6.16 ± 1.62 mg/kg vs 4.90 ± 1.54 mg/kg, P = .02). No patients were intubated prehospital. There was an increased dose in patients admitted to a medical ward (57%, 28/49) that approached statistical significance (5.62 ± 1.80 vs 4.78 ± 1.31, P = .06). CONCLUSION Intubation was observed in our emergency department in 29% of patients administered intramuscular ketamine for prehospital chemical restraint. There was a positive association between higher ketamine doses and both endotracheal intubation and hospital admission. Future research should aim to define the minimum effective ketamine dose for successful chemical restraint.