Steven E. Aks

Colchicine poisoning: the dark side of an ancient drug

Introduction. Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. Methods. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included “colchicine” and “poisoning” or “overdose” or “toxicity” or “intoxication.” Toxicokinetics. Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. Therapeutic and toxic doses. The usual adult oral doses for FMF is 1.2–2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5–0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7–26 mg. Drug interactions. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Mechanisms of toxicity. Colchicines toxicity is an extension of its mechanism of action – binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. Reproductive toxicology and lactation. Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Clinical features. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10–24 h after ingestion – gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion – multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. Diagnosis. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Management. Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Conclusion. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.

The Price of Gold: Mercury Exposure in the Amazonian Rain Forest

Concern has surfaced over the recent discovery of human mercury exposure throughout the tropical rain forest of South Americas Amazon River Basin. The probable source of mercury has been traced to gold mines located within the interior. The mining process involves the extraction of gold from ore by burning off a mercury additive, resulting in vaporization of elemental mercury into the surrounding environment. The purpose of this case series is to document mercury levels in miners and local villagers presenting with a history of exposure, or signs and symptoms consistent with mercury toxicity. Over a five year period (1986-91), the whole blood and urine mercury levels of 55 Brazilian patients demonstrating signs and symptoms consistent with mercury exposure were collected. Thirty-three (60%) of the subjects had direct occupational exposure to mercury via gold mining and refining. Whole blood mercury levels ranged from 0.4-13.0 micrograms/dL (mean 3.05 micrograms/dL). Spot urine levels ranged 0-151 micrograms/L (mean = 32.7 micrograms/L). Occupational mercury exposure is occurring in the Amazon River Basin. Interventions aimed at altering the gold mining process while protecting the workers and surrounding villagers from the source of exposure are essential. The impact of the gold mining industry on general environmental contamination has not been investigated.

The toxic patient as a potential organ donor

The use of organs from poisoned victims for the purpose of transplantation has been poorly studied; criteria for organ donation is virtually non-existent in such cases. To further elucidate these indications, a retrospective review of all organ transplantation donated by poisoned victims in Northern and Central Illinois was undertaken. From January 1988 to December 1993, 17 poisoned victims were identified as having donated organs to 41 recipients. Eleven of the donors died as a direct result of drug toxicity, whereas six donors had drug-related deaths. The cases were reviewed for toxin involved, organ preoperative function and postoperative function (up to 1 year after transplant). Kidney transplants postoperative function was rated as good if creatinine was less than 1.9, fair if creatinine was 2 to 2.9, and poor if creatinine was 3. Donor age ranged from 2 years to 54 years. Toxins involved in donation included ethanol (n = 8), cocaine (n = 5), carbon monoxide (5), barbiturates (2) and lead (1), six patients had multiple drugs. Two of the nine recipients of livers died intraoperatively, both unrelated to organ function. Thirty-two kidneys were transplanted with 28 having good 10-day postoperative function, three having fair postoperative function, and one (cocaine donor) having poor postoperative function. One kidney transplanted from a cocaine donor had a thrombosed graft 5 days postoperatively. Deaths involving toxins in general does not seem to be a contraindication to donation of liver and kidney for transplantation.

Drug use patterns at major rock concert events

STUDY OBJECTIVE To describe alcohol and drug use patterns in patients presenting to first aid stations at major rock concerts. METHODS We retrospectively reviewed all charts generated at the first aid stations of five major rock concerts featuring the rock groups Pink Floyd, the Grateful Dead, and the Rolling Stones. The first aid stations, located at a sports stadium, were staffed by paramedics, emergency medicine nurses, and physicians. We recorded the following data: patient demographics, history of drug or ethanol use, time spent by patient in first aid station, treatment rendered, diagnosis, and patient disposition. RESULTS A total of 253, 286 spectators attended the five concert events. The rate of use of the first aid station was 1.2 per 1,000 patrons. The average age of the patrons was 26.3 +/- 7.9 years (range, 3 to 56 years). The most common diagnoses were minor trauma 130 (42%) and ethanol or illicit drug intoxication 98 (32%). Of the patients treated, 147 (48%) admitted to using illicit drugs or ethanol while attending the concerts. The median time spent in the first aid station was 15 +/- 22.5 minutes (range, 5 to 150 minutes). One hundred patients (32.5%) were treated and released, 98 (32%) were transported to emergency departments, and 110 (35.5%) signed out against medical advice. CONCLUSION Minor trauma and the use of illicit drugs and ethanol were common in spectators presenting to first aid stations at these concert events. Physicians and paramedical personnel working at rock concerts should be aware of the current drug use patterns and should be trained in treating such drug use.

Can Nebulized Naloxone Be Used Safely and Effectively by Emergency Medical Services for Suspected Opioid Overdose

Abstract Background. Emergency medical services (EMS) traditionally administer naloxone using a needle. Needleless naloxone may be easier when intravenous (IV) access is difficult and may decrease occupational blood-borne exposure in this high-risk population. Several studies have examined intranasal naloxone, but nebulized naloxone as an alternative needleless route has not been examined in the prehospital setting. Objective. We sought to determine whether nebulized naloxone can be used safely and effectively by prehospital providers for patients with suspected opioid overdose. Methods. We performed a retrospective analysis of all consecutive cases administered nebulized naloxone from January 1 to June 30, 2010, by the Chicago Fire Department. All clinical data were entered in real time into a structured EMS database and data abstraction was performed in a systematic manner. Included were cases of suspected opioid overdose, altered mental status, and respiratory depression; excluded were cases where nebulized naloxone was given for opioid-triggered asthma and cases with incomplete outcome data. The primary outcome was patient response to nebulized naloxone. Secondary outcomes included need for rescue naloxone (IV or intramuscular), need for assisted ventilation, and adverse antidote events. Kappa interrater reliability was calculated and study data were analyzed using descriptive statistics. Results. Out of 129 cases, 105 met the inclusion criteria. Of these, 23 (22%) had complete response, 62 (59%) had partial response, and 20 (19%) had no response. Eleven cases (10%) received rescue naloxone, no case required assisted ventilation, and no adverse events occurred. The kappa score was 0.993. Conclusion. Nebulized naloxone is a safe and effective needleless alternative for prehospital treatment of suspected opioid overdose in patients with spontaneous respirations.

Fractional mercury levels in Brazilian gold refiners and miners

A field study survey of individuals residing in the region of Para, Brazil, was conducted to determine fractional mercury levels in individuals at risk for exposure in the Brazilian Amazon region. Subjects with a history of exposure to mercury either in the gold mining or refining industry, or exposure to these processes through proximity were included. Three groups were identified as either having recent (less than 2 d since last exposure), intermediate (less than 60 d), or remote (greater than 60 d) exposure to mercury vapors. Fractional blood and urinary mercury levels were assessed for these groups. Group I (recent) had the highest geometric mean blood 24.8 (SD 44.1, range 7.6-158.8) micrograms/L and urine 75.6 (SD 213.4, range 6.5-735.9) micrograms/g-cr (microgram mercury per gram of creatinine) mercury; intermediate (group II) geometric mean blood 7.6 (SD 5.5, range 2.2-19.4) micrograms/L and urine levels 23.8 (SD 84.0, range 7.8-297.0) micrograms/g-cr; the lowest levels in remote exposure (group III): geometric mean blood 5.6 (SD 3.3, range 3.1-14.3) micrograms/L and urine 7.0 (SD 9.8, range 3.1 to 32.9) micrograms/g-cr. The fraction of organic was lowest in group I (32.4%), higher in group II (65.7%), and highest in group III (72.2%). While the frequency of symptoms was comparable in the recent and intermediate groups (2.6 mean, SD 2.3, range 0-8, and 3.1 mean, SD 1.9, range 0-7, symptoms per patient), those with remote exposure demonstrated the highest rate of reporting (6.4 mean, SD 4.1, range 0-11, symptoms per patient). There is significant exposure to mercury for those working in or living near the mining and refining industry. Blood and urine levels are a better marker of recent than remote exposure. The fraction of organic mercury increases with time since exposure. Symptoms may be persistent and low levels of blood and urine mercury do not exclude remote or cumulative toxicity.

Acute accidental lindane ingestion in toddlers

Lindane toxicity has been reported to occur mostly by way of dermal exposure. Cases of ingestion in which blood levels have been determined are rare. We present three such cases, along with a comparison of cases in the literature with respect to blood level half-lives and correlation with signs of toxicity. Emergency physicians can prevent acute ingestion by educating patients on the proper use of lindane and by selecting less toxic scabicidal agents.

Emerging drugs of abuse.

Keeping up with emerging drugs of abuse will always be a challenge for physicians. As law enforcement agencies classify certain drugs as illegal, “street pharmacists” rapidly adapt and develop new congeners of old drugs for distribution and use. It is essential that physicians have a solid foundation in the general classes of drugs of abuse. Many of the newer drugs have similar effects and respond well to meticulous and aggressive supportive management. Sources of current information and surveillance should be available to physicians in order to stay on top of current trends. Poison Centers along with local public health officials should be important sources of current information on these agents. Internet sites, social media, and search engines can be additional tools to stay on top of drug of abuse trends. A major problem is tracking these novel psychoactive substances often referred to as “legal highs.” These products are sold in head shops, the Internet, and other sources. Synthetic cathinones (commonly referred to as bath salts) and synthetic cannabinoids are 2 very good illustrations of the problem of these “legal highs” and will be discussed later. These substances tend to be slightly altered chemicals derived from other known drugs of abuse. They were easily obtained on the Internet and in tobacco head shops and were finally banned once public health and law enforcement officials identified these compounds and adapted laws. Recent legislation shows that authorities can act quickly to implement important public health laws. In 2012, Senate Bill 3190 included synthetic cannabinoids in the Schedule I category, which subsequently dropped their availability considerably. A recent New York Times article nicely summarizes the cycle of one drug of abuse. Ecstasy [3,4-methylenedioxy-N-methylamphetamine (MDMA)] has been abused for several decades. Its street use was complicated by adulteration and substitution. However, there has been a resurgence of this drug as “Molly,” which is touted to be a “pure” form of ecstasy. Much of this street information is unreliable, but the fact that Molly appeared in the Fashion Section of the New York Times is notable. Also, many substances marketed as “Molly” are not MDMA.

Whole Bowel Irrigation and the Hemodynamically Unstable Calcium Channel Blocker Overdose: Primum Non Nocere

Sustained-release calcium channel blocker (CCB SR) overdoses are potentially life-threatening ingestions. These patients may not become hemodynamically unstable until many hours after ingestion. On theoretical grounds, some have suggested that whole bowel irrigation (WBI) with polyethylene glycol electrolyte lavage solution may be of value in the management of these cases. We report two cases with poor outcome (including one fatality) that were complicated by the use of WBI. Both cases were treated with WBI beginning before and continuing after developing hypotension. WBI should be avoided in the setting of the hemodynamically unstable CCB SR overdose.

Melanotan II injection resulting in systemic toxicity and rhabdomyolysis

Introduction. Melanotan products are currently purchased over the Internet and are designed to induce melanogenesis to create sunless tanning as well are used as sexual stimulants. We report a novel case of systemic toxicity with sympathomimetic excess and rhabdomyolysis after use of Melanotan II. Case report. A 39 year-old Caucasian male injected subcutaneously 6 mg of Melanotan II purchased over the Internet in an attempt to darken his skin during wintertime. This dose was six times the recommended starting dose per the patient. In the emergency department two hours post injection, he complained of diffuse body aches, sweating, and a sensation of anxiety. Vital signs included BP 151/85 mmHg, HR 130 bpm that peaked at 146 bpm, and temperature of 97.8°F. Physical exam demonstrated a restless and anxious appearing male with mydriasis, diaphoresis, tachycardia, and diffuse muscle tremors. Pertinent laboratory values were creatinine 2.25 mg/dL, CPK 1760 IU/L, troponin 0.23 ng/mL, WBC 19.1 k/μL. Urinalysis demonstrated 3 + blood with red cell casts but 0–2 RBC/hpf. Qualitative urine drug screen was negative for metabolites of cocaine and amphetamines but positive for opiates. The patient received benzodiazepines for agitation and anxiety and had improvement in his symptoms. He was admitted to the ICU and during hospitalization his CPK elevated to 17773 IU/L 12 hours later. He continued to receive intravenous fluids with sodium bicarbonate for rhabdomyolysis and his CPK decreased to 2622 IU/L with improvement of creatinine to 1.23 mg/dL upon discharge from the ICU after 3 days. The substance, which he injected, was analyzed via mass spectrometry and was confirmed to be Melanotan II when compared with an industry purchased standard sample. Discussion. Melanotan products are purchased via the Internet and have three main formulations (Melanotan I, Melanotan II, and bremelanotide). Melanotan I increases melanogenesis and eumelanin content to produce sunless tanning. Melanotan II also increases skin pigmentation but also produces spontaneous penile erections and sexual stimulation. Bremelanotide is a variation of Melanotan II that is specifically designed for sexual stimulation. This unique case highlights the potential of systemic toxicity with sympathomimetic excess, rhabdomyolysis, and renal dysfunction from Melanotan II use. Conclusion. Melanotan II use resulted in systemic toxicity including apparent sympathomimetic symptoms, rhabdomyolysis, and renal dysfunction.