Updates In Toxicology
Authors: Aaron Skolnik, MD, FAAEM, Clinical Fellow, Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix Children’s Hospital, Center for Pharmacology and Toxicology Education and Research, University of Arizona College of Medicine, Phoenix.
Frank LoVecchio, DO, MPH, FACEP, Co-medical Director, Banner Good Samaritan Poison and Drug Information Center, Professor and Research Director, Maricopa Integrated Health System, University of Arizona College of Medicine, Phoenix.
Peer Reviewer: Timothy J. Wiegand, MD, Director of Medical Toxicology and Toxicology Consult Service, Associate Clinical Professor of Emergency Medicine, University of Rochester Medical Center and Strong Memorial Hospital, Rochester, NY.
The past few years have seen a number of emerging household toxins, novel antidotes, and new prescription drugs on which to overdose. The following article reviews the latest updates in medical toxicology, with a focus on accidental exposures and drug overdoses as they pertain to the practicing emergency physician.
Detergent Pod Ingestion
Case. Thirty minutes prior to arrival, a 22-month-old male was found at home vomiting profusely near an open container of laundry detergent pods. The child developed respiratory distress and drooling. During transport by EMS, the patient became extremely drowsy and arrived in the ED with an absent gag reflex. He is intubated and admitted to a pediatric intensive care unit (ICU). Laboratory studies are unremarkable, and chest radiography shows clear lung fields. The following morning, the patient is extubated without difficulty. He is able to tolerate an age-appropriate diet and is discharged to home later that day.
Introduction/Epidemiology. Exposures to household products are commonly reported to United States poison centers. Of those reported, approximately 5% are related to laundry detergents, with the vast majority occurring in children aged 5 years or younger.1 Liquid detergent pods (also referred to as liquitabs, sachets, or capsules) became available in the United Kingdom in 2001.2,3 Several abstracts were presented at national meetings in Europe and the United States between 2006 and 2009 describing metabolic acidosis, acute respiratory distress syndrome (ARDS), and central nervous system (CNS) depression following unintentional ingestion of these pods.4-6
Beginning in 2010, laundry detergent pods were introduced in the United States. These pods consist of a liquid or gel detergent preparation encapsulated in a dissolvable sachet. Frequently, products are brightly colored and attractively packaged, which may contribute to early childhood exposures.2,7 During the one-month period from May 17 to June 17, 2012, there were 485 exposures to liquid detergent pods reported to U.S. poison centers, of which 99% were unintentional. The mean age of children exposed to laundry pods was 3 years. Children younger than age 5 years were significantly more likely to be exposed to laundry pods than their older counterparts.7 In the United Kingdom, the National Poisons Information Service received 647 inquiries regarding laundry pod exposures between March 2008 and April 2009. Again, the vast majority (96.1%) occurred in children younger than age 5, and 99.7% of detergent pod exposures were unintentional.3
In both the United States and the United Kingdom, ingestion was the most common route of exposure, followed by ocular, skin, and inhalational exposures.3,7
Pathophysiology. The pathophysiology of systemic poisoning from laundry detergent pods is poorly understood. The capsules themselves consist of a dissolvable outer membrane (usually polyvinyl alcohol) containing a mixture of anionic detergents, non-ionic detergents, propylene glycol, ethanol, and cationic surfactants.8 The volume of each capsule is between 32-43 mL, and the pH of its contents varies.3,7,9,10
It has been suggested that the presence of ethanol and propylene glycol in the detergent mixture may be responsible for the CNS effects, but this has not been substantiated.3
The relationship between aspiration of exogenous surfactants and development of pulmonary injury/ARDS is well known. This is the likely culprit for acute pulmonary injury seen after detergent pod ingestions.11
Ocular toxicity also appears to be related to surfactants in the mixture, which is not strongly alkaline, although those mixtures with a higher pH may exacerbate ophthalmic injury. Unpublished data from one manufacturer suggest that detergent pods were “slightly to moderately irritating to the eye” and led to slight to moderate erosion of corneal epithelium in an ex vivo chicken eye study. Conjunctivitis, keratitis, corneal abrasion, and conjunctival and corneal epithelial burns have all been reported following ocular exposure to laundry pod contents.3,8,9,12,13
The potential for dermal injury and caustic injury to the gastrointestinal tract appears to be related to irritant effects of the detergent mixture, with the molecular mechanism still undefined. These products do not elaborate a strong alkaline solution, as powdered detergents containing “builders” do.3,9
Clinical Presentation. The typical presentation of laundry pod ingestion (including multiple routes of exposure) appears to include nausea, vomiting, coughing/choking, and rash. The key feature distinguishing pod ingestion from ingestion of other liquid detergent preparations is the possibility of significant CNS depression.3,7 Drowsiness or respiratory depression appears to occur much more commonly with pod ingestion than with liquid detergent ingestion. In the United Kingdom, drowsiness was reported in 11/573 (1.9%) cases, some requiring endotracheal intubation for low Glasgow Coma Scale (GCS).3 Symptomatic children may develop respiratory distress. Symptoms associated with pharyngeal and gastrointestinal caustic injury, including stridor, abdominal pain, drooling/sialorrhea, and stomatitis, are infrequently reported.3
Diagnosis. The diagnosis of laundry detergent pod ingestion should be made from the history. Whenever possible, the exact product should be identified. The regional poison control center (1-800-222-1222 in the United States) can help with product identification and ingredients.
Any child with altered mental status should have point-of-care glucose testing, urine drugs of abuse screening, and serum or blood ethanol level checked. Brain imaging by computed tomography or magnetic resonance imaging should be considered if the history is incomplete or if there is a history of trauma.
Children with hypoxia, history of choking or vomiting, or prominent respiratory symptoms should undergo chest radiography to evaluate for aspiration pneumonitis or ARDS.
There are no diagnostic studies with proven benefit in laundry pod poisoning. In ill-appearing children, it may be prudent to test electrolytes and acid-base status, as metabolic acidosis has been reported.3,7
Management. Early airway management and intensive supportive care are the mainstays of treatment for laundry pod ingestions. The local poison control center should be contacted to assist in management whenever possible.
Gastric decontamination and activated charcoal are not likely to be of any benefit.
Oxygen should be provided to children with respiratory symptoms or hypoxia, and intubation should be considered in those with persistent failure to oxygenate, failure to ventilate, loss of airway protective reflexes, or profound CNS depression.
Endoscopy may be indicated in some patients to evaluate caustic effects, but there are currently not enough data to firmly recommend for or against endoscopy. So far, most children with evidence of caustic injury have low-grade injuries that resolve with intensive supportive care.3,7 Fraser and colleagues reported a series of five children with glottic or periglottic edema, one of whom underwent surgery for subglottic stenosis, with normal endoscopy at two-month follow-up. Until there is more experience, gastroenterology and/or surgical consultation for endoscopic evaluation should be obtained when children have signs or symptoms suggestive of corrosive injury, hollow viscous perforation, glottic/periglottic edema, or peritonitis.
Children who present to the ED with a reported laundry pod ingestion and remain asymptomatic for six hours post-ingestion may be discharged home.
Kids and Buprenorphine
Case. A 30-month-old girl becomes unarousable at home. She was seen to be playing with her mother’s purse 40 minutes prior. Point-of-care blood glucose testing is normal. She is noted to have pinpoint pupils, orange residue on her lips, and a respiratory rate of 6 breaths per minute. She is given a weight-based dose of intravenous naloxone with normalization of her vitals. Her mother confirms that several buprenorphine/naloxone sublingual tablets are missing.
Introduction/Epidemiology. Buprenorphine is an opioid receptor agonist-antagonist that has been FDA approved for treatment of opioid addiction since 2002. The drug is available as sublingual tablets or rapidly dissolving sublingual films alone (Subutex®) or co-formulated with naloxone (Suboxone®) in 2 mg (0.5 mg naloxone) or 8 mg (2 mg naloxone) strengths.14
Unlike methadone therapy, buprenorphine treatment may be prescribed from an office-based practice, and patients fill and typically self-administer prescriptions for the drug. The number of physicians prescribing and patients using buprenorphine continues to steadily rise in the United States. With this increase, the number of pediatric buprenorphine exposures reported to U.S. poison centers has also increased. In 2002, there were only two cases reported in children younger than 6 years old. By 2011, that number had increased to 1,121.1,15 The manufacturer of Suboxone® introduced rapidly dissolving sublingual films in 2010 with individual child-resistant packaging. However, data on the company’s website indicate that one child in 50 was able to open two or more packages during testing.16 Buprenorphine ingestions were disproportionately responsible for ED visits and emergency hospitalizations for drug ingestions in children younger than age 6 years when compared to all other opioid prescriptions and all retail prescriptions combined.17
Accidental buprenorphine ingestions in young children have been associated with delayed and prolonged toxicity, with life-threatening and sometimes fatal outcomes.14,15,18-20
Pathophysiology. Buprenorphine is a synthetic opioid that has muopioid receptor agonist and kappa-opioid receptor antagonist effects. The drug has poor enteral bioavailability and, as such, is marketed as sublingual tablets and films. Buccal bioavailability is 27.8%, and sublingual bioavailability is 51%. Co-formulation with naloxone is to prevent intravenous abuse, as the naloxone is not absorbed when used as prescribed. Once absorbed, the drug is primarily metabolized in the liver to an active metabolite, norbuprenorphine. Norbuprenorphine also exhibits mu-opioid agonism and is capable of causing respiratory depression when administered alone.21 The elimination half-lives of buprenorphine and its metabolite norbuprenorphine are long (37 and 34 hours, respectively). It is believed that enterohepatic recirculation prolongs the duration of action of the drug.14,19
In adults, buprenorphine exhibits a “ceiling effect,” limiting respiratory depression as increasing doses are administered. In addition, most adults prescribed buprenorphine are not opioid-naïve and are somewhat desensitized to mu-opioid agonism. In children, this is not the case. Children exposed to even very small doses (0.07 mg/kg) of buprenorphine have experienced significant opioid intoxication.20 One study demonstrated that the ventilatory depressing effects of buprenorphine exceeded those of morphine in children.22
As part of natural exploratory behaviors, toddlers may suck on buprenorphine tablets or films, leading to significant medication absorption via the buccal or sublingual mucosa, even if the medication is retrieved from the child’s mouth.14,18
Diagnosis. In young children, buprenorphine intoxication is a clinical diagnosis. It presents with a classic opioid toxidrome consisting of respiratory depression, CNS depression, and miosis. Intoxicated children may also present with vomiting, diaphoresis, or pallor.14,19,20
Arterial or venous blood gases need not be obtained. However, if performed, they may show hypoventilatory respiratory acidosis and possible concomitant hypoxia.
Importantly, buprenorphine does not produce a positive opioid screen on most urine drugs of abuse panels. Drug-specific testing for buprenorphine and norbuprenorphine can be performed by a number of methods, including gas chromatography/mass spectroscopy, but these are “send-out” tests and do not result in time to influence clinical decision-making in the ED.14,23
Management. Management of pediatric buprenorphine exposures consists of airway management, reversal of respiratory depression with naloxone, and supportive care.
Most reported cases of buprenorphine exposure in pediatric patients present with symptoms within the first six hours.14,19,20 However, in one case, a child was found apneic 13 hours after reported exposure.24 Children with suspected or confirmed exposure to buprenorphine who are asymptomatic at the time of ED evaluation should be monitored for 12 hours. Those who remain asymptomatic with normal vital signs for age at 12 hours post-ingestion can be discharged to home if caregivers are reliable.
Children with respiratory depression should receive intravenous naloxone titrated to normalization of respiratory effort. Naloxone should be given as 0.1 mg/kg IV push per dose, and may be repeated every 2 minutes until the desired effect is achieved. Children who fail to respond to naloxone may require endotracheal intubation and mechanical ventilation. Those who initially respond to naloxone boluses but suffer recurrent respiratory depression may require a naloxone infusion at two-thirds of the reversal dose per hour (i.e., 0.067 mg/kg/hr), titrated to effect. Children who have CNS depression and/or require mechanical ventilation or multiple doses of naloxone should be admitted to a pediatric ICU until symptoms resolve. Figure 1 includes a flowchart for management of known or suspected pediatric buprenorphine exposure.14
Figure 1: Pediatric Buprenorphine
Intravenous Lipid Emulsion (ILE)
Background. In 1998, Weinberg and colleagues first demonstrated a cardioprotective effect of intravenous lipid emulsion (ILE) infusion using a rat model of bupivacaine toxicity.25 Subsequent experiments have demonstrated benefit to lipid emulsion therapy in multiple animal models of toxicity due to local anesthetics and other lipophilic drugs, including tricyclic antidepressants.26-33 Human case reports, beginning in 2006, suggest ILE has played a beneficial role in successful resuscitations from cardiac arrest or severe cardiotoxicity induced by local anesthetics, cardiovascular drugs, anticonvulsants, and psychotropic agents in overdose.34-44
ILE therapy has several proposed mechanisms of action.43 One theory suggests that it works as an intravascular “sink,” sequestering lipophilic drugs in a lipid phase and preventing free drug from exerting its toxic effects on target end organs. Subsequent bench work and some human case reports have further supported the “lipid sink” theory.26,43,45
Favoring other mechanisms of action, the volume of administered lipid in antidotal dosing is far less than that of typical total body fat stores in adults.44 In addition, a more recent review paper suggested that the apparent response to lipid emulsion rescue was the same for lipophilic versus non-lipophilic drugs.44
Another proposed mechanism of action is a direct inotropic effect of lipid emulsion, possibly by providing free fatty acids to energy-starved mitochondria. An inotropic effect of lipid infusion (at less than “lipid sink” concentrations) has been shown in one model.46 It has also been suggested that alterations in carnitine transport and free fatty acid metabolism may be partially responsible for the beneficial effects of lipid emulsion.47,48
New Potential Uses for Intravenous Lipid Emulsion
Cocaine. From the United Kingdom, the first report of ILE as an antidotal treatment in severe cocaine toxicity was published in 2011. Jakkala-Saibaba and colleagues describe a 28-year-old man who presented in status epilepticus, with severe metabolic acidosis and ventilator-dependent respiratory failure. The authors note an increasing norepinephrine requirement (although they also state that the patient’s lowest recorded systolic blood pressure was 90 mmHg) and cardiovascular instability as indication for ILE. Following ILE bolus and infusion, the patient’s rhythm returned to sinus, and norepinephrine was rapidly weaned. The patient had hypertriglyceridemia, mildly elevated amylase, and a lipemic blood sample noted, but recovered uneventfully.49
This case was followed by one from the United States, wherein a 26-year-old man presented unresponsive, in status epilepticus, following crack cocaine use. The patient had wide-complex tachycardia with QTc prolongation that did not respond to magnesium and sodium bicarbonate. He then became hemodynamically unstable, and a 100 mL of 20% ILE was given as an infusion. Within 10 minutes of the infusion commencement, the QRS narrowed to 82 ms and QTc normalized.50
Neither of the above cases is ideal. Flaws aside, the response to ILE described in the above case reports is compelling. In summary, the existing literature suggests cocaine can be added to the list of drugs for which ILE is likely to be useful in severe poisoning.
Propranolol. Propranolol has been a proposed drug target for ILE treatment since 2008, with demonstrated amelioration of propranolol-induced hypotension in an animal model.51 Since then, two human case reports have been published detailing the use of ILE for acute propranolol toxicity.
Jovic-Stosic et al reported on a 31-year-old woman with a reported ingestion of 3.6 g of propranolol in addition to ethanol. Ingestion was confirmed by propranolol level. She had coma, seizures, hypoglycemia, shock, and wide-complex tachycardias. She received 500 mL (a large dose) of 20% ILE, with some improvement in hemodynamics, then returned to sinus rhythm and normal blood pressure following the infusion of additional ILE.53
The pharmacologic characteristics of propranolol align well with the prevailing lipid sink theory of ILE mechanism. Propranolol is a highly lipophilic drug and, as such, may be the most likely of the commercially available beta-blockers to respond to ILE therapy.54,55 Ultimately, for patients as sick as those above, the risk-benefit of trying ILE therapy (failing conventional therapies including crystalloid, vasopressors, glucagon, benzodiazepines, and sodium bicarbonate) is highly favorable when it comes to propranolol overdoses.
Pediatric Patients. ILE has been used since its inception as an antidote in children as well as in adults. A literature review was recently published summarizing the available case reports and abstracts on ILE treatment in patients younger than 18 years old. The authors reviewed 14 cases in which ILE was used to treat intoxication by local anesthetics in seven cases and other agents in seven cases. Other intoxicants included bupropion, dosulepin, amitriptyline, diltiazem, quetiapine, lamotrigine, and verapamil.
In 13 of the 14 cases, there appeared to be a beneficial response to ILE treatment. In one case, reported as an abstract, there was no apparent hemodynamic response to ILE (at unclear dosing) and the patient was managed with multiple other therapies, including extracorporeal membrane oxygenation, and ultimately recovered. Of note, the dosing regimens employed in the pediatric cases varied significantly.56
Risks/Complications of ILE Therapy. Nearly all of the human data on use of ILE as an antidote comes from case reports and abstracts. The patient population addressed in these reports is often critically ill, with multiple confounding comorbidities. Therefore, the risks and complications attributed to ILE are ill-defined.
Laboratory interference and pancreatitis were first reported by Levine et al in 2012. This followed the successful resuscitation of a 13-year-old girl with cyclic antidepressant-induced seizures and cardiac arrest. The authors noted that laboratory studies were unable to be interpreted for approximately three hours post-ILE infusion due to lipemia. The patient in this case also developed elevated lipase while intubated and then complained of epigastric pain following extubation, which was suggestive of pancreatitis.57
Subsequently, Grunbaum and colleagues modeled lipemic interference that might result from ILE treatment by spiking serum samples with increasing concentrations of ILE. In their experiment, significant interference developed in albumin, magnesium, and (colorimetric) glucose measurement. Amylase, bilirubin, CK, creatinine, phosphate, and total protein were not measurable in ILE-treated samples. Centrifugation of samples reduced lipid interference significantly.58
Summary. Intravenous lipid emulsion is an antidote for lipophilic drug toxicity. A survey of medical directors of U.S. Poison Control Centers (PCCs) demonstrated that most have a protocol in place for ILE therapy. Further, the majority of directors responded that they would “always” or “often” recommend ILE for cardiac arrest or shock due to bupivacaine, verapamil, or amitriptyline.59
Recent reports show ILE may also be useful in severe cocaine and propranolol poisoning.
When using ILE, be aware that its safety in use as an antidote has not yet been fully established. ILE use may result in transient laboratory interference and may cause pancreatitis.
In cases of cardiac arrest or severe hemodynamic instability, the benefits of ILE far outweigh current known risks of its use. More human experience needs to be reported to better understand the safety profile of ILE as a rescue therapy. ILE should be considered for patients with cardiac arrest or significant hemodynamic instability failing conventional therapy in the setting of known or suspected lipophilic drug poisoning.
Newer Antidiabetic Drugs in Overdose
Background. It is estimated that 25.8 million people, or 8.3% of the United States population, have diabetes. More than one in every four American adults older than age 65 has diabetes.60 It is, therefore, not surprising that diabetes-related visits to U.S. EDs are common. Treated diabetes has been associated with a significant increase in depressive symptoms, and chronic illness is a risk factor for suicide, increasing the likelihood that emergency physicians will continue to treat overdoses of diabetes medications.61
In recent years, several new agents have been approved for the treatment of diabetes mellitus in the United States. These drugs include incretin mimetics and incretin enhancers. The incretin hormone system, broadly speaking, increases the release of insulin in response to enteral glucose loads. This effect is thought to be mediated by two gut-derived hormones: glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The drug exenatide (ByettaTM) is an incretin mimetic, a GLP-1 receptor agonist approved for adjunctive treatment in non-insulin-dependent diabetes mellitus. The drug is derived from the venom of the Gila monster (Heloderma suspectum). Exenatide is approved for use in combination with oral antidiabetic agents, including metformin and sulfonylureas. Dipeptylpeptidase-4 (DPP-4) is the enzyme primarily responsible for breaking down GIP and GLP-1. Thus, inhibition of DPP-4, such as by sitagliptin (JanuviaTM), enhances the incretin effect on moderation of post-prandial blood glucose. Both classes of drugs enhance the hypoglycemic effects of other diabetes agents, including metformin and sulfonylurea drugs.62
Adverse Effects in Therapeutic Use. The most commonly reported nonglycemic side effects of exenatide include gastrointestinal effects such as nausea, vomiting, diarrhea, dyspepsia, and constipation. Other frequently reported effects include headache, dizziness, and feeling jittery.63 For liraglutide, headache, nausea, and diarrhea are most commonly reported. In addition, formation of anti-liraglutide antibodies and urticarial, anaphylactoid, or other immune reactions can occur.64
Commonly reported side effects of the DPP-4 inhibitor sitagliptin include upper respiratory infections, headache, and nasopharyngitis. Saxagliptin has a similar adverse effect profile in therapeutic use, with upper respiratory infection, urinary tract infection, and headache reported.65
The risk of hypoglycemia attributable to incretin-based drugs alone in clinical trials of diabetes treatments appears to be low. For exenatide monotherapy, the incidence of hypoglycemia in clinical trials was approximately 4-5%. Liraglutide-associated hypoglycemia occurred in 8-12% of patients. The DPP-4 inhibitors sitagliptin, saxagliptin, and linagliptin all have reported rates of hypoglycemia similar to placebo.66
None of the GLP-1 agonists or DPP-4 inhibitors have been shown to be directly nephrotoxic, although post-marketing cases of worsening renal function have been reported with use of exenatide, liraglutide, and sitagliptin.66,67
Since exenatide and sitagliptin came to market, case reports have been published reporting pancreatitis associated with therapeutic use of these drugs.68-70 Pancreatitis occurs more frequently among diabetic patients than their non-diabetic counterparts.71 Therefore, numerous studies have attempted to determine if any causal relationship exists between incretin-based diabetes drugs and pancreatitis. To date, the majority of published studies have presented inconsistent results. One study, based on FDA adverse-event reporting, found that the odds ratio for reporting pancreatitis was six-fold higher with use of exenatide or sitagliptin.72 Several other studies found no significant association.73-75 All were limited by methodology and failure to adjust for confounding when applicable. A recent and methodologically robust population-based, case-control study examined more than 2500 patients with diabetes with a primary outcome measure of hospitalization for acute pancreatitis. The authors adjusted for confounders, including hypertriglyceridemia, alcohol use, cystic fibrosis, gallstones, tobacco abuse, obesity, metformin use, and pancreatic and biliary neoplasms. They found that use within 30 days, current use, or any use of exenatide or sitagliptin were associated with significantly greater odds of being hospitalized for acute pancreatitis.76
A volunteer study in which patients received multiple doses of sitagliptin over 10 days demonstrated no adverse effects, including hypoglycemia, among those treated with the drug, In addition, there were no significant effects found on PR or QTc intervals.77 A dedicated study evaluating QTc prolongation following single oral doses of sitagliptin has also been published. In healthy volunteers, the maximal effect was 8 milliseconds prolongation of QTcF that occurred three hours after a supratherapeutic dose. Plasma concentrations at that time were approximately 11-fold higher than those occurring after therapeutic dosing.
Exenatide (Byetta™) Overdose. In an early bioavailability study of exenatide, three patients inadvertently received a 10-fold overdose of the drug. All three experienced severe nausea and vomiting, and one developed “severe hypoglycemia requiring aid.” Blood glucose levels for these patients were not reported. All three patients recovered uneventfully. They were excluded from statistical analysis in the study, and it is unknown if the overdosed patients were among those taking metformin and/or sulfonylureas.78
Cohen and colleagues reported the first probable case of intentional exenatide overdose in the literature. A 40-year-old patient reported injecting 90 mcg of exenatide in a suicide attempt. The patient had dizziness, weakness, nausea, and vomiting. Her fasting blood glucose during hospitalization ranged from 84 to 129 mg/dL, and rose to 162 mg/dL postprandially. She received metoclopramide 10 mg but no exogenous dextrose. Unfortunately, as is often the case, drug levels of exenatide could not be obtained to confirm the overdose, although the patient had a hematoma with the appropriate number of injection marks on her thigh.79
Krishnan et al reported a massive overdose (1800 mcg, or 90 times the maximum recommended daily dose) of exenatide. The 47-year-old diabetic patient had been changed to exenatide from insulin despite poor glycemic control after multiple prior admissions for insulin overdoses. She presented with nausea and vomiting, although hematologic studies and chemistries were reportedly normal. Her blood glucose levels ranged from 292 to 500 mg/dL over a 24-hour period. During this time, she received a single dose of short-acting insulin for glycemic control. She was discharged, asymptomatic, 48 hours after the overdose.80
Sitagliptin Overdose. A single case report of an 86-year-old female patient treated for sitagliptin overdose has been published. In this case, the patient had confirmation of the ingestion, with plasma sitagliptin levels performed 16 hours after the overdose. Despite having a plasma sitagliptin level of 3,793 nM (nearly four times the 16-hour concentration in a study of healthy volunteers), the patient never became hypoglycemic during hospitalization. In this case, the patient received prophylactic 4.5% dextrose infusion overnight, totaling a (modest) 52 g of dextrose and confounding the clinical picture.
Diagnosis. The diagnosis of incretin-based drug overdose is made primarily by history. Although some analytical laboratories are able to quantify plasma levels of incretin mimetics and DPP-4 inhibitors, results are not likely to be available within a clinically relevant time-frame. Point-of-care glucose testing should always be performed. In patients with significant gastrointestinal symptoms, electrolytes, renal function, transaminases, and lipase should be obtained. Additional testing should be directed at excluding common and treatable co-ingestions, including acetaminophen and salicylate levels, and electrocardiography. Further testing should be dictated by the patient’s clinical presentation. For example, a CT scan of the brain may be needed in an obtunded patient to exclude intracranial hemorrhage.
Management. All patients with intentional overdoses should be evaluated in a health care facility. As the clinical experience with these drugs in overdose is limited, asymptomatic patients following GLP-1 agonist or DPP-4 inhibitor overdose should be observed for six hours in a monitored setting, with hourly determinations of blood glucose.
Of critical importance is that incretin-based drugs are labeled for co-prescription with metformin, sulfonylureas, or both. Although the above data suggest that incretin mimetics or DPP-4 inhibitors alone are unlikely to cause significant hypoglycemia in overdose, one must be alert to the possibility of lactic acidosis resulting from metformin co-ingestion, or refractory hypoglycemia resulting from sulfonylurea overdose. If metformin co-ingestion is suspected, asymptomatic patients should have electrolytes and acid-base status determined at six hours post-ingestion prior to medical clearance. Patients with suspected sulfonylurea overdose should be admitted to a monitored setting for at least 18-24 hours due to the possibility of delayed-onset hypoglycemia.
If hypoglycemia develops, glucose replacement via oral intake and/or parenteral dextrose is the first-line treatment. Although it has not been tested specifically in this setting, octreotide (1 mcg/kg by subcutaneous injection) may be beneficial in treating refractory or labile hypoglycemia by limiting pancreatic insulin secretion.
Although the QTc prolongation associated with sitagliptin in trials is clinically insignificant, it could be more important in a massive overdose. If a patient’s QTc interval exceeds 500 milliseconds, magnesium sulfate 2 g IV should be administered to prevent torsades de pointes.
Despite the suggested association between incretin drugs and acute pancreatitis, no case reports have been published of acute pancreatitis linked to overdose, either accidental or intentional. Until there is more experience with these agents, it is prudent to monitor patients for signs and symptoms of pancreatitis and perform laboratory testing and diagnostic imaging as indicated. If pancreatitis occurs following incretin mimetic or DPP-4 inhibitor overdose, treatment is conventional and well-described elsewhere.
Novel Oral Anticoagulants in Overdose
Background. Historically, vitamin K antagonists have been the mainstay of anticoagulation for the prevention of venous thromboembolic disease in the United States. In the past three years, multiple novel anticoagulants have been approved, including dabigatran, rivaroxaban, and apixaban. These medications work via direct inhibition of thrombin (factor IIa) or factor Xa in the final common pathway of the coagulation cascade. Routine coagulation monitoring is not required in patients taking these medications, and dosing regimens are fixed.
Pathophysiology. Dabigatran is an oral, competitive direct thrombin inhibitor approved for use in patients with nonvalvular atrial fibrillation for thromboembolism prophylaxis since 2010. The drug is capable of binding and inhibiting both free and clot-bound thrombin, making it a potent inhibitor of the final common pathway of coagulation and impairing conversion of fibrinogen to fibrin, as well as platelet aggregation.81 Approximately 80% of a dose is renally cleared unchanged, suggesting that the drug accumulates in renal failure. In fact, the manufacturer has labeled the drug for dose adjustment based on renal function, and it is not recommended for patients with creatinine clearance less than 15 mL/min or those on hemodialysis.
Rivaroxaban and apixaban are oral factor Xa inhibitors approved for venous thromboembolism prevention after orthopedic surgery, and stroke prevention in atrial fibrillation patients. Both bind to factor Xa and inhibit the conversion of fibrinogen to fibrin. Both rivaroxaban and apixaban have relatively short half-lives (8.3-9.5 hours and 15.1-17.3 hours, respectively) when compared to warfarin, which become prolonged with worsening renal impairment.
Figure 2: Oral Anticoagulants Pathway
Diagnosis. Diagnosis of novel anticoagulant overdose is primarily made from the history. Supratherapeutic coagulation parameters in the setting of chronic use of these medications should prompt suspicion for either overdose or impaired clearance of these agents. Conventional coagulation studies, including prothrombin time (PT) and activated partial thromboplastin time (aPTT), should be obtained, but when elevated, do not correlate with the degree of anticoagulation or risk of bleeding. Normal aPTT at 12 hours post-ingestion is likely to exclude a significant dabigatran overdose.81 For direct thrombin inhibitors, ecarin clotting time (ECT) and thrombin time (TT) are useful measures of effect, if available. For factor Xa inhibitors, anti-Xa activity can be followed if available.
Management: Interim Guidance. The management guidelines provided below are based on the current best available evidence and are characterized as interim guidance, given the limited post-marketing clinical experience with these drugs in overdose.
Conventional reversal for vitamin K antagonists using vitamin K and FFP are unlikely to be effective in treating overdoses by direct thrombin or factor Xa inhibitors, as these drugs do not reduce circulating clotting factor levels. The existing human data on dabigatran reversal using fresh frozen plasma (FFP) suggest it is ineffective. There are no published data on the use of FFP in rivaroxaban or apixaban reversal.
If performed very early following an intentional overdose of dabigatran, gastric decontamination may be useful. If a patient presents within one hour of ingestion and is awake and alert or has a protected airway, activated charcoal (50 g PO or NG) has been shown in vitro to adsorb dabigatran.82 There are no data regarding activated charcoal and the oral factor Xa inhibitors, but if the above criteria are met, the risk-benefit is likely to be favorable.
For asymptomatic patients with no bleeding, observe in a monitored setting. PT and aPTT should be repeated every six hours. If these labs remain normal for 12 hours post-ingestion, the patient may be medically cleared with regard to anticoagulant overdose.
The pharmacologic properties of dabigatran should make it a reasonable candidate for removal by hemodialysis (HD). The drug has a relatively small molecular weight of 627 amu, with fairly low protein binding of approximately 35%. The volume of distribution is also small, at 50-70 L. Approximately 85% of the drug is renally cleared unchanged. In an industry-sponsored kinetics study, mean terminal elimination half-life doubled in severe renal impairment and the area under the plasma concentration-time curve increased proportional to degree of renal impairment. Hemodialysis treatment removed 62-68% of a dose of dabigatran.83 Several cases have been published using hemodialysis in an attempt to treat bleeding in the setting of anticoagulation with dabigatran.
Recently, Chen et al reported on an 80-year-old man who presented with hemoptysis from a tuberculous lung abscess in the setting of inadvertent overdose of dabigatran. The patient presented with international normalized ratio (INR) of 8.8, aPTT of 132.9 seconds, and worsening pulmonary status. Transfusion of one unit of packed red blood cells (PRBC) and two units of FFP minimally improved his INR and aPTT, and he was subsequently intubated and underwent HD for four hours. At the conclusion of HD, his INR had improved to 2.7 and aPTT had improved to 75.2. The authors presented extraction ratios at the beginning and end of hemodialysis of 0.97 and 0.17, respectively, and hypothesized that diminishing free fraction of drug, dialysis membrane saturation, or fouling of the dialysis membrane via thrombosis may explain this effect. In this case, the half-life of dabigatran was shortened to 45 minutes (versus approximately nine hours after an oral dose), but some rebound increase in dabigatran concentrations did occur, as has been reported elsewhere.84
In the case of dabigatran overdose or inadvertent toxicity with life-threatening bleeding, hemodialysis appears to enhance clearance significantly and reduce terminal elimination half-life and should be considered. Charcoal hemoperfusion may also be considered, but is unavailable at many centers.82,84 The recommendation for hemodialysis does not account for the practical difficulties of obtaining vascular access and performing HD in a patient with ongoing bleeding and instability and this should be assessed on a case-by-case basis.
Rivaroxaban and apixaban exhibit high levels of protein binding, which make them unsuitable for removal via hemodialysis.85
There is no direct antidote to reverse oral direct thrombin or factor Xa inhibitors. In theory, administration of sufficient quantities of prothrombin could via kinetics force forward coagulation and lead to reversal of anticoagulation. Unfortunately, in experimental models this has not been consistently true. In an animal model of intracranial hematoma in the setting of dabigatran, FFP and factor VIIa failed to inhibit hematoma expansion and did not reverse coagulation parameters. Administration of prothrombin complex concentrates (PCC) at 50-100 units/kg limited hematoma size, but coagulation parameters remained elevated. In an in vitro study using the blood of 10 healthy men after a single dose of dabigatran, PCC (25 units/kg) and FEIBA (an activated prothrombin complex concentrate; 80 units/kg) significantly increased thrombin generation. The same study evaluated reversal of rivaroxaban ex-vivo and found that only FEIBA was able to reverse all laboratory measures of thrombin generation.
In a double-blind, placebo-controlled crossover trial in healthy male volunteers, 50 IU/kg of a four-factor PCC immediately and completely reversed PT prolongation induced by rivaroxaban. In the same trial, PCC at the same dose failed to reverse aPTT, ECT, and TT prolongation induced by dabigatran. It is unclear if this dose of PCC, roughly equivalent to 100% factor replacement, would be sufficient to treat bleeding complications in the setting of rivaroxaban overdose.86 There are no human data published on the use of recombinant factor VIIa (rFVIIa) in humans to reverse rivaroxaban or apixaban.
Most human data regarding attempted reversal of novel oral anticoagulants in overdose comes from case reports of dabigatran-associated bleeding complications. These data are mixed, and report highly variable outcomes regarding use of PRBC, vitamin K, FFP, cryoprecipitate, PCCs, FEIBA, and rFVIIa in various combinations. Although there have been case reports suggesting reversal of dabigatran-related bleeding using PCC, all of these reports have been confounded by the relatively shorter half-life of the drug and the use of multiple near-simultaneous interventions. The primary concern with the use of procoagulants (including 3-and 4-factor PCC as well as rFVIIa) for novel oral anticoagulant reversal is an increase in observed thrombotic complications seen with the use of these drugs.85
In the case of a patient with a novel oral anticoagulant overdose or toxicity and active bleeding, a 3-factor PCC in combination with rFVIIa or a 4-factor PCC can be given as a last resort in an attempt to reverse life-threatening bleeding. This should not distract from the mainstay of therapy consisting of withdrawal of the offending agent, replacement of PRBC and blood products, and intensive supportive care to maintain hemodynamic stability.
In summary, the following apply for patients who present to the emergency department following overdose of novel oral anticoagulants:
Those who remain asymptomatic with normal PT and aPTT for 12 hours after ingestion may be medically cleared. For patients with active bleeding, the mainstay of therapy is withdrawal of the anticoagulant and intensive, supportive care. For patients with refractory or life-threatening bleeding, a 3-factor PCC combined with rFVIIa or a 4-factor PCC should be administered, weighing the risk of increased thrombogenesis against that of ongoing bleeding in the individual patient. In the case of dabigatran only, emergent hemodialysis should be considered. Again, the risks of performing this invasive procedure in an unstable patient must be weighed against the potential benefits.
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The past few years have seen a number of emerging household toxins, novel antidotes, and new prescription drugs on which to overdose. The following article reviews the latest updates in medical toxicology, with a focus on accidental exposures and drug overdoses as they pertain to the practicing emergency physician.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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