Patil Armenian

Role of liquid chromatography–high-resolution mass spectrometry (LC-HR/MS) in clinical toxicology

Background. Gas chromatography (GC) and liquid chromatography (LC) coupled with mass spectrometry (MS) are widely used to confirm drug screening results and for urine screening in presumed intoxicated patients. These techniques are better suited to targeted analysis than to general unknown screening and, due to the complexity of testing, results are seldom available rapidly enough to contribute to the immediate care of the patient. High resolution (HR)/MS with time-of-flight (TOF) or orbitrap instruments offer potential advantages in clinical toxicology. Comparison of GC-MS, LC-MS/MS and LC-HR/MS. For unknown analyses, GC-MS and LC-MS/MS require comparison of full-scan spectra against preestablished libraries. Operation in full-scan mode greatly reduces sensitivity and some drugs present in low but significant concentrations may be missed. Selected ion monitoring (SIM) in GC/MS and selected reaction monitoring (SRM) in LC-MS/MS, where only targeted ions are monitored, increase sensitivity but require prior knowledge of what compound is to be measured. LC-HR/MS offers mass assignment with an accuracy of 0.001 atomic mass units (amu) compared with 1 amu in conventional MS. Tentative identification is thus directed to a very limited set of compounds (or even one unique compound) based on the exact molecular formula rather than a fragmentation pattern, since HR/MS can discriminate between compounds with the same nominal molecular mass. LC-MS/MS has clear advantages over GC/MS in ease and speed of sample preparation and the opportunities for its automation. LC-HR/MS is more suitable to clinical toxicology because the drugs present in a sample are rarely known a priori, and tentative identifications of unknowns can be made without the availability of a reference standard or a library spectrum. Blood can be used in preference to urine which is more relevant to the patients current clinical situation. Methods. A literature search was conducted using PUBMED for clinical toxicology, adulterants in illicit drugs and herbal supplements, and case reports using LC-TOF/MS and LC-HR/MS. Only 42 papers in English were identified in these searches. LC-HR/MS in clinical toxicology. LC-HR/MS has been used to detect designer drugs, doping agents, (neurosteroids) and adulterants such as levamisole, a veterinary antihelmitic found in street cocaine, and pharmaceuticals in herbal medications marketed to contain only natural ingredients. LC-HR/MS has proved useful for cases where existing tests were unable to identify the cause of the intoxication. One patient suffered a drug-induced seizure which was originally thought to be caused by an herbal medication, but diphenhydramine was determined to be the culprit. In another, 5-oxoproline was identified as the cause of metabolic acidosis seen in chronic acetaminophen (paracetamol) use. LC-HR/MS has successfully identified medications that were mislabeled or misrepresented street drugs. In one case, medications sold as diazepam were determined to be glyburide instead. The identification of novel designer amines, stimulants found in “bath salts”, and synthetic cannabinoids are well suited to LC-HR/MS. Dozens or even hundreds of possible compounds cannot realistically be tested on an individual basis by targeted LC-MS/MS or GC/MS analysis. Conclusions. LC-HR/MS offers unique opportunities for time-sensitive clinical analysis of blood samples from intoxicated patients and for comprehensive screening in a wide range of situations and materials. While the identification is not as definitive as that obtained by conventional fragmentation MS, the presumptive identification can be confirmed later with standards and spectral library matches. Optimum utilization of the presumptive diagnosis requires close collaboration between the laboratory analysts and their clinical counterparts.

Serum verapamil concentrations before and after Intralipid® therapy during treatment of an overdose

Context. Intralipid® infusion is useful in reversing cardiac and central nervous system toxicity of local anesthetic drugs, and recent reports suggest utility in other drug overdoses. Case details. A 47-year-old man presented to the emergency department with hypotension and complete heart block 3 h after a sustained-release verapamil overdose. He was given supportive care including calcium and hyperinsulinemia/euglycemia therapy. Nineteen and 29 h post-ingestion, Intralipid® was administered as a bolus, followed by an infusion. Objective. The objective of this study was to determine the serum verapamil concentrations before and after Intralipid® administration and to ascertain its clinical effects. Discussion. It was found that administration of Intralipid® was followed by a decrease in verapamil concentration once the lipid had been removed from the sample, demonstrating that Intralipid® was effective in sequestering verapamil, effectively removing it from the serum, and supporting its use in the treatment of verapamil overdose. Intralipid® administration was associated with an increase in the patient’s blood pressure, but because other vasoactive drugs were given at the same time, it was difficult to determine its relative contribution to clinical improvement.

Multiple MDMA (Ecstasy) Overdoses at a Rave Event: A Case Series

Twelve patients with 3,4-methylenedioxymethamphetamine (MDMA) toxicity from a single rave event presented to multiple San Francisco Bay area hospitals with various life-threatening complications including seizures and hyperthermia. Eight required emergent endotracheal intubation and six had hypotension. Hyperkalemia, acute kidney injury, and rhabdomyolysis were present in most of the patients. In all, 2 patients died, 4 survived with permanent neurologic, musculoskeletal, and/or renal sequelae, and 6 survived without any apparent lasting deficits. Hyperthermia was present in 10 patients and was severe (40.9-43° C) in 7. Using multiple cooling methods, the average time to achieve cooling was 2.7 hours. Serum drug analysis was performed on 3 patients, demonstrating toxic MDMA concentrations without the presence of other xenobiotics. Two capsules confiscated by police at the event contained 82% and 98% MDMA, respectively, without other pharmacologically active compounds. Capsule #2 contained 270 mg MDMA, which is more than twice the amount of MDMA usually contained in 1 dose. The MDMA-induced hyperthermia significantly contributed to the morbidity and mortality in this case series. Factors contributing to the severity of the hyperthermia include ingestion of large doses of MDMA, a warm ambient environment, and physical exertion.

Ketamine as a first-line treatment for severely agitated emergency department patients

Objective Emergency physicians often need to control agitated patients who present a danger to themselves and hospital personnel. Commonly used medications have limitations. Our primary objective was to compare the time to a defined reduction in agitation scores for ketamine versus benzodiazepines and haloperidol, alone or in combination. Our secondary objectives were to compare rates of medication redosing, vital sign changes, and adverse events in the different treatment groups. Methods We conducted a single‐center, prospective, observational study examining agitation levels in acutely agitated emergency department patients between the ages of 18 and 65 who required sedation medication for acute agitation. Providers measured agitation levels on a previously validated 6‐point sedation scale at 0‐, 5‐, 10‐, and 15‐min after receiving sedation. We also assessed the incidence of adverse events, repeat or rescue medication dosing, and changes in vital signs. Results 106 patients were enrolled and 98 met eligibility criteria. There was no significant difference between groups in initial agitation scores. Based on agitation scores, more patients in the ketamine group were no longer agitated than the other medication groups at 5‐, 10‐, and 15‐min after receiving medication. Patients receiving ketamine had similar rates of redosing, changes in vital signs, and adverse events to the other groups. Conclusion In highly agitated and violent emergency department patients, significantly fewer patients receiving ketamine as a first line sedating agent were agitated at 5‐, 10‐, and 15‐min. Ketamine appears to be faster at controlling agitation than standard emergency department medications.

The electric Kool-Aid NBOMe test: LC-TOF/MS confirmed 2C-C-NBOMe (25C) intoxication at Burning Man

Designer drugs are constantly evolving, with the NBOMe derivatives of the 2C class of phenethylamines recently emerging in the US market. Cases of 2C-I-NBOMe toxicity have recently been reported in the literature. No reports to date describe the clinical effects 2C-C-NBOMe toxicity.

Pediatric ergot alkaloid exposures reported to the California Poison Control System: 1997–2008

Abstract Context. The risk of toxicity from exposure to ergot alkaloid-containing medications in children is uncertain. Due to the alarming historical experience with severe toxicity and the syndrome of ergotism from natural and synthetic ergot alkaloids, triage recommendations for pediatric exposures to medicinal agents containing ergot alkaloids may be inappropriate and inconsistent. Objectives. The goal of this study was to describe the clinical effects of unintentional ergot alkaloid exposures in children and to identify the need for hospitalization in these cases. Methods. This was a retrospective cohort study of all pediatric (< 7 years old) ergot alkaloid exposures reported to the California Poison Control System (CPCS) from 1997 to 2008. Case narratives were reviewed and assessed for patient demographics, ergot alkaloid agent and dose, route of and reason for exposure, symptoms, therapy, hospitalization period, and final outcome. Results. Of the 374 cases, 353 met the inclusion criteria. The median age was 24 months (Range: 7–72 months) with more than 99% oral route of exposure. The most frequent clinical effect was gastrointestinal distress (16%), followed by lethargy (5%). Two cases with significant vascular and CNS symptoms were identified, both with complete recovery. For symptomatic patients, all symptoms were there at time of initial presentation. The majority, 62%, of all patients were treated in the hospital setting. The median length of hospital stay was 4 h (Range: 1–36 h). Ergot exposures had a similar number of serious outcomes (moderate or worse effects) compared to all other pediatric poisonings reported to the CPCS during the study period (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.25–3.95), but were associated with a disproportionately higher number of hospitalizations (OR, 13.8; 95% CI, 11.1–17.1). Conclusions. Pediatric ergot exposures were associated with few transient adverse effects but multiple hospitalizations. Rare cases of significant toxicity associated with methylergonovine exposures were found. Current poison control send-in protocols and emergency department (ED) guidelines should consider home management and short ED stays as opposed to lengthy critical care bed admissions.

Catecholaminergic polymorphic ventricular tachycardia found in an adolescent after a methylenedioxymethamphetamine and marijuana-induced cardiac arrest.

Objective:To illustrate the challenges of managing patients with acute, undiagnosed arrhythmias through a case that demonstrates a possible association between catecholaminergic polymorphic ventricular tachycardia, a genetically determined severe arrhythmia disorder that often presents as either syncope or sudden death, and 3,4-Methylenedioxymethamphetamine (“Ecstasy”) combined with marijuana, which are often considered safe drugs by users. Design:Case report. Setting:Pediatric intensive care unit. Patient:A 15-yr-old male collapsed suddenly after ingesting an unknown substance and smoking marijuana. He was successfully resuscitated by first-responder chest compressions and rescue breaths along with a single 100-J shock by paramedics. He was intubated and transferred to a pediatric intensive care unit. Initial cardiac workup was negative but severe instability on vasopressors and a family history of intermittent palpitations and syncope in his brother raised suspicion for catecholaminergic polymorphic ventricular tachycardia. Identification of the unknown substance required coordination with a toxicology laboratory. Interventions:The patient had extremely labile cardiovascular responses to vasopressors. On day 5, his blood pressure was stable and he was extubated. A full cardiac workup, including a catheterization (preadmission to pediatric intensive care unit), electrocardiogram, cardiac magnetic resonance imaging were done to screen out most structural arrythmogenic diseases. A specific genetic test for catecholaminergic polymorphic ventricular tachycardia was sent. Measurements and Main Results:The patient’s methylenedioxymethamphetamine blood level was 87 ng/mL approximately 12 hrs after ingestion. Given the 3–8 hr half-life of methylenedioxymethamphetamine, it is likely that levels were toxic at the time of ingestion (>110 ng/mL). Marijuana may have provided a synergistic critical catecholamine release to trigger an arrhythmia. Genetic testing showed a ryanodine receptor-2 mutation that was consistent with catecholaminergic polymorphic ventricular tachycardia. Conclusions:While an initial cardiac workup for an acute, undiagnosed arrhythmia may be negative, family history may be a simple, essential component of patient management and disease diagnosis. This case demonstrates a possible association between methylenedioxymethamphetamine, marijuana, and catecholaminergic polymorphic ventricular tachycardia. All genetic and structural arrythmogenic disorders should be considered when working up a patient with presumed toxin-induced arrhythmias.

Hot and Cold Drugs: National Park Service Medication Stability at the Extremes of Temperature

Abstract Study Objective: National Park Service (NPS) Parkmedics provide medical care in austere environments. The objective of this study was to evaluate the stability of specific medications used by Parkmedics at extremes of temperatures likely to be faced in the field. Methods: This is a bench research study conducted in the laboratory setting over a 4-week period. Parenteral medications were separated into 4 temperature exposure groups: A) 45°C (hot); B) −20°C (cold); C) hot then cold temperatures alternating weekly; and D) cold then hot temperatures alternating weekly. At study start and the end of each week, three aliquots from each group were sampled to determine the remaining drug concentration through liquid chromatography-quadrupole time-of-flight mass spectrometry (Agilent LC 1260- QTOF/MS 6550). Quantitative analysis was done using Agilent MassHunter Quantitative Analysis software. The mean drug concentration from triplicate aliquots was expressed as percentage of its baseline concentration to monitor the drugs stability during storage. Results: Eight medications were analyzed (atropine, diphenhydramine, fentanyl, hydromorphone, midazolam, morphine, naloxone, ondansetron). Hydromorphone, morphine, and ondansetron showed the greatest stability, at above 90% of original concentration in all study arms. Diphenhydramine, fentanyl and midazolam showed heat independent degradation, degrading the same way regardless of heat exposure. By the end of the study period, 51–56% midazolam remained in all groups. Atropine and naloxone showed heat dependent degradation, degrading more when exposed to heat. Atropine had the most degradation, being undetectable after 4 weeks of heat exposure. Conclusions: We recommend that EMS providers replace atropine, naloxone, diphenhydramine, fentanyl, and midazolam frequently if they are practicing in low call volume or high-temperature environments. Further studies will be needed to determine if re-dosing midazolam, naloxone, and atropine is the appropriate clinical strategy in this setting if adequate clinical effect is not reached with a single dose.

Illicit Distribution of Prescription Drugs Report of Inadvertent Chloroquine Toxicity and a Market Survey of Businesses Serving Ethnic Minority Populations

Objective: To report a case of life-threatening cinchonism from illicit purchase of chloroquine and survey local ethnic markets to determine what medications are sold without a prescription. Case Report: A 44-year-old Hmong woman presented with abdominal pain and vomiting 30 minutes after ingesting 20 presumed acetaminophen pills in a self-harm gesture. Initial vital signs were normal, and an electrocardiogram (ECG) showed normal sinus rhythm, QRS = 130 ms, and QTc = 455 ms. Her systolic blood pressure dropped to 84 mm Hg, which was unchanged after 3 L normal saline, but improved after 150 mEq NaHCO3. A repeat ECG showed QRS = 114 ms and QTc = 588 ms. Serum labs were significant for K 2.8 mmol/L and Mg 1.8 mg/dL; 2.5 hours later, the family brought in the medication, which was 250 mg tablets of chloroquine phosphate. K and Mg were repleted, and she was admitted to the intensive care unit with complete recovery. Serum chloroquine level 9 hours after ingestion was 530 ng/mL (therapeutic = 20-400 ng/mL). Methods: We identified local ethnic markets through patient and hospital employee referrals and Internet searches. Results: In our survey, 3 of 4 ethnic markets sold prescription medications: 35 were identified, of which 5 are discontinued by the FDA (diphenidol, phenacetin, metamizole, phenylbutazone, and sibutramine). Conclusions: A variety of prescription medications, including 5 discontinued by the FDA, were available in markets serving our community’s ethnic minorities. Health care workers should be aware of this public health risk, which can result in serious toxicity, as described in this case of chloroquine overdose.

Narcan or Nar-can’t: Tips and Tricks to Safely Reversing Opioid Toxicity

ANNALS CASE Your next patient is a 34-year-old man with a history of intravenous drugusewhowasbrought inby emergencymedical services. In the field, he had a respiratory rate of 5 breaths/min, decreased mental status, and pinpoint pupils, all of which significantly improved with out-of-hospital naloxone. He now has normal mental status and normal vital signs, and admits to intravenous fentanyl (or so he was told) use. After downing 3 hospital tuna salad sandwiches, he requests discharge. Sound familiar? Well, it should. Drug overdose is now the leading cause of injury death in the United States, with frequency tripling from 1999 to 2014. Illicit opioids contribute to the significant increase in opioid-associated deaths. The result: you have probably administered naloxone recently once, twice, or even dozens of times to reverse acute opioid overdoses. But what is the “standard” dose again? And how long do patients need to be observed? For somethingwe do frequently, the lack of evidence-based dosing and observation times is troubling. Lucky for us, the recent publication by Scheuermeyer et al examines the safety of an empiric emergency department (ED) protocol for the management of patients with presumed fentanyl intoxication. After primarily intravenous fentanyl use, the majority of patients were safely discharged after a 2-hour observation period.