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Envenomation, Poisoning, and Toxicology

Michelle Strong, MD, PhD¹ and Elaine Cleveland, MD²

¹ Trauma and Acute Care Surgeon, Austin, TX, USA

² William Beaumont Army Medical Center, El Paso, TX, USA

Regarding opioid overdose, which statement is correct?
1. Oral opioids have standard pharmacokinetics and elimination that is unrelated to dosage.
2. Chronic opioid users develop tolerance and have less risk of developing respiratory failure.
3. Co‐ingestion with alcohol or benzodiazepines is common and increases risk of death.
4. Concomitant use of cytochrome P450 inhibitors and oxycodone decreases plasma levels of oxycodone.
5. Intravenous hydromorphone has the shortest half‐life compared to intravenous morphine or fentanyl.
Co‐ingestion is common and alcohol is involved in 1 of 5 opioid‐related deaths. Ninety‐one percent of co‐ingestions (often suicide attempts) required mechanical ventilation and ICU admission. Oral opioids have variable pharmacokinetics. At low dosage, they are eliminated through first‐order kinetics, and therefore elimination is exponential. At high doses, opioids are eliminated via zero‐order kinetics, which means there is fixed elimination per unit time and the rate of elimination is independent of concentration. This can lead to late‐onset opioid toxicity. While chronic opioid users develop tolerance, the tolerance to respiratory depression is less than the tolerance to the analgesic effects of opioids and are at greater risk for respiratory failure. Concomitant use of cytochrome P450 inhibitors such as macrolides increase plasma levels of oxycodone. The most common cytochrome P450 involved in drug metabolism is 3A. Intravenous hydromorphone has a half‐life of 4 hours, while intravenous morphine and fentanyl have half‐lives of 2–3 hours.

Answer: C

Parthvi R, Agrawal A, Khanijo S, Tsegaye A, Talwar A, Parthvi R, et al. Acute opiate overdose: an update on management strategies in emergency department and critical care unit. American Journal of Therapeutics 2019May/Jun; 26 (3):e380–e387.
A 24‐year‐old woman was assaulted several hours ago and is found down in a park. She has a Glasgow Coma Scale (GCS) score of 5, ecchymosis to the right side of her face, a right scalp laceration, pinpoint pupils, and track marks down both arms. There are needles found near her. Her vitals are HR 60 beats/minute, BP 90/40 mm Hg, RR 6 breaths/minute, and pulse oximetry of 82% on room air. EMS personnel intubate the patient and give her 0.4 mg of naloxone. Which statement is true regarding the management of this patient?
1. She should have gastrointestinal decontamination with charcoal.
2. She can receive one more dose of 0.4 mg of naloxone, and then alternative reversal agents should be` used.
3. The most common arrhythmia is a narrow complex atrial fibrillation.
4. Patients typically develop respiratory alkalosis and metabolic acidosis.
5. Alpha‐agonists can be used to assist with symptoms of opioid withdrawal.
After giving naloxone, patients can experience severe opiate withdrawal symptoms to include fever, tachycardia, restlessness, insomnia, diaphoresis, rhinorrhea, nausea, vomiting, and myalgias. Clonidine and dexmedetomidine (both alpha agonists) may help manage some of these symptoms but should be given in a monitored setting. This patient likely took intravenous opioids, i.e. heroin. Gastrointestinal decontamination is only indicated if within 1 hour of oral opioid ingestion. In patients who develop cardiac arrest due to opioids, patients should receive 2 mg of naloxone initially. Naloxone can be repeated every 2–3 minutes as needed, up to 10 mg. If a long‐acting opioid is suspected, patients may require additional dosing or IV infusion, as naloxone only lasts about 20–90 minutes. The most common arrhythmia is wide complex bradycardia, which can be managed with a bolus of 1–2 mEq/kg of sodium bicarbonate. Patients typically develop respiratory acidosis due to CO₂ retention. They can develop either metabolic acidosis if they are experiencing diarrhea, or metabolic alkalosis if they have emesis.

Answer: E

Donroe JH, Tetrault JM, Donroe JH, et al. Substance use, intoxication, and withdrawal in the critical care setting. Critical Care Clinics 2017 Jul; 33 (3):543–558.

Parthvi R, Agrawal A, Khanijo S, Tsegaye A, Talwar A, Parthvi R, et al. Acute opiate overdose: an update on management strategies in emergency department and critical care unit. American Journal of Therapeutics 2019May/Jun; 26 (3):e380–e387.
A 26‐year‐old man, with long‐standing depression, ingests a large quantity of lorazepam and alcohol and walks into traffic on a busy highway. When EMS arrives, the patient has a GCS score of 10, obvious facial fractures, bruising to the left chest, and an open left tibia fracture. What should be the initial management of this patient in the trauma bay?
1. Supplemental oxygen, continuous cardiac monitoring, and intubation if needed for hypoventilation or mental status decline
2. Intubation followed by gastrointestinal decontamination with activated charcoal
3. Whole bowel irrigation with polyethylene glycol electrolyte solution via nasogastric tube
4. Flumazenil 0.2 mg with repeat dosing as needed, up to 1 mg
5. Naloxone 0.4 mg and repeat dosing as needed until mental status improves
Benzodiazepine overdose in isolation has a low morbidity and mortality rate. However, when combined with alcohol or opioids, profound respiratory depression can result. The typical management for benzodiazepine overdose is supportive care and intubation as needed. There is no role for either activated charcoal or whole bowel irrigation in isolated benzodiazepine overdose. Whole bowel irrigation is typically used for iron, lithium, illicit drug packets, or sustained‐released medications (such as diltiazem). Flumazenil, a competitive antagonist of the benzodiazepine receptor, is controversial since it can lower the seizure threshold, especially in someone who is chronically taking benzodiazepines. Flumazenil is typically used to reverse procedural sedation when a known quantity of benzodiazepines has been given. While opioids and benzodiazepines are often co‐ingested, there is no history that this patient also consuming opioids. Naloxone would be used for opioid overdose.

Answer: A

Donroe JH, Tetrault JM, Donroe JH, et al. Substance use, intoxication, and withdrawal in the critical care setting. Critical Care Clinics 2017 Jul; 33 (3):543–558.

Weinbroum AA, Flaishon R, Sorkine P, Szold O, Rudick V . A risk‐benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Safety 1997; 17 (3):181.
A 37‐year‐old man used cocaine and drank alcohol earlier in the evening and then drove home. The patient was involved in a motor vehicle collision versus a tree, with airbag deployment. He is complaining of severe chest pain and is anxious. His vital signs are HR 145 beats/minute, BP 185/100 mm Hg, RR 20 breaths/minute, pulse oximetry 92% on room air, and temperature 38° C. A chest x‐ray, FAST exam, and CT scan imaging are only notable for a small 4‐mm subdural hematoma and a grade 3 splenic laceration without extravasation. Electrocardiogram shows ST elevation and his troponin I is elevated as well. What should be the initial management of this patient?
1. Dual antiplatelet therapy
2. Beta‐blockers to decrease heart rate and blood pressure, with goal SBP 120 mm Hg and HR <100 beats/minute
3. Benzodiazepines followed by nitroglycerin if patient is still hypertensive
4. Morphine, oxygen, nitroglycerin, and aspirin
5. Percutaneous coronary intervention
Management of cocaine‐induced myocardial infarction is focused on decreasing platelet aggregation with aspirin (if appropriate), decreasing vasoconstriction and hypertension with either nitrates or calcium channel blockers, and decreasing overall sympathetic tone with benzodiazepines. Unfortunately, due to the concurrent injuries of a subdural hematoma and grade 3 splenic laceration, this patient will not be able to start aspirin or undergo percutaneous coronary intervention for at least 24–48 hours after repeat imaging is stable. Beta‐blockers are contraindicated in the initial management because they theoretically increase vasoconstriction due to unopposed alpha‐receptor stimulation. However, multiple patients have inadvertently received beta‐blockers before disclosing cocaine usage and have had no adverse effects. The 2012 American College of Cardiology guidelines state that non‐selective beta‐blockers (such as propranolol) may be considered in persistently hypertensive and tachycardic patients after cocaine use, provided they received a vasodilator prior to treatment with beta‐blocker.

Answer: C

Donroe JH, Tetrault JM, Donroe JH, et al. Substance use, intoxication, and withdrawal in the critical care setting. Critical Care Clinics 2017 Jul; 33 (3):543–558.

Havakuk O, Rezkalla SH, Kloner RA, et al. The cardiovascular effects of cocaine. Journal of the American College of Cardiology 2017 Jul 4; 70 (1):101–113.
A 27‐year‐old man presents to the emergency room after an altercation with another party goer. He admits to taking multiple pills of ecstasy. His vitals are HR 125 beats/minute, BP 100/70 mmHg, RR 12 breaths/minute, and temperature is 40 °C. Which of these complications is paired with its appropriate treatment?
1. Hyperthermia: slow cooling with ice packs ± dantrolene
2. Rhabdomyolysis: addressing hyperthermia and aggressive IV fluid resuscitation
3. Serotonin syndrome: diphenhydramine and IV fluid resuscitation
4. Hypernatremia: rapid correction of sodium
5. MDMA withdrawal: haloperidol
Ecstasy or methylenedioxy‐methylamphetamine (MDMA) intoxication is associated with hyperthermia, rhabdomyolysis, and multi‐organ failure. The hyperthermia must be managed with rapid (not slow) cooling and dantrolene, though dantrolene has not been subject to randomized controlled trials. Rhabdomyolysis requires hyperthermia management and aggressive IV fluid hydration. Serotonin syndrome is more common with co‐ingestion of other drugs, especially selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) and results in altered mental status, increased muscle tone, clonus, and hyperreflexia. The treatment of serotonin syndrome is benzodiazepines ± cyproheptadine. Severe serotonin syndrome may require intubation. Hyponatremia, not hypernatremia, is due to MDMA‐induced antidiuretic hormone release, as well as aggressive crystalloid fluid resuscitation. With any sodium imbalance, you never want to rapidly correct sodium. Management is fluid restriction for mild cases and careful administration of hypertonic saline, not to exceed a 10 mEq increase in 24 hours for severe cases. MDMA has also been associated with acute renal failure and acute liver failure. MDMA withdrawal is relatively mild and usually presents with depression or fatigue for up to 5 days; management is supportive. Haloperidol is contraindicated in the acute setting since it can interfere with heat dissipation, prolongs the QTc interval, and reduces the seizure threshold.

Answer: B

Donroe JH, Tetrault JM, Donroe JH, et al. Substance use, intoxication, and withdrawal in the critical care setting. Critical Care Clinics 2017 Jul; 33 (3):543–558.

Kalant H . The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ 2001; 165 (7):917.

A 75‐year‐old man with a history of hypertension, atrial fibrillation, hyperlipidemia, and gout is admitted to the ICU for a small bowel obstruction and severe hypertension managed with a nicardipine drip. Unfortunately, his oral diltiazem is still on his medication list, and the extended‐release diltiazem is crushed and given to the patient via nasogastric tube. The patient subsequently becomes hypotensive with a BP 70/40 mm Hg and bradycardic with a HR 35 beats/minute. The nicardipine drip is stopped. What is the next step in treatment?

Whole bowel irrigation with polyethylene glycol electrolyte mix
A bolus 3–4 L of crystalloid immediately until blood pressure improves
Atropine and cardioversion if indicated
Epinephrine 2–10 mcg/min followed by an epinephrine IV infusion
Milrinone 0.5 mcg/kg/min IV infusion

For both beta‐blocker and calcium channel blocker overdose, the two basic tenets of management are high‐dose insulin euglycemia therapy (HIET) and catecholamine infusions. The best choice above is epinephrine, as it will provide positive inotrope and chronotrope effects. This patient would also benefit from high‐dose insulin and calcium infusion, with goal calcium 2 times the reference range. For extended‐release medications, whole bowel irrigation can be used, though small bowel obstruction is a contraindication for this therapy. Additionally, once a patient becomes hypotensive and bradycardic, whole bowel irrigation should not be initiated. While fluid bolus can be beneficial, judicious fluid administration is recommended as patients are usually euvolemic and 3–4 L can lead to pulmonary edema. Atropine is rarely effective in calcium channel blocker toxicity. Finally, milrinone might be needed if the patient remains bradycardic; however, this patient is hypotensive as well, and milrinone could exacerbate hypotension.

Suspected cardiogenic shock in beta‐blocker or calcium channel blocker intoxication
Treatment	Dosing	Desired clinical effect	Adverse events
High‐dose insulin euglycemia	Loading dose 1U/kg; infusion 1–10 U/kg/hr with 50% glucose infusion	Positive inotrope, increased CO, increased BP, reduced catecholamine infusion	Hypoglycemia, hypokalemia, mild vasodilation, no effect on heart rate
Epinephrine	2–10 mcg/min	Increased contractility and heart rate	Hyperglycemia lactic acidemia, limb ischemia
Isoproterenol	0.5–5 mcg/min	Positive inotrope and chronotropic	Ventricular arrhythmias, worsening of hypotension secondary to B2
Calcium infusion	Loading dose 0.6 mL/kg of 10% calcium gluconate; infusion 0.6–1.6 mL/kg/hr Aim for serum Ca 2× reference range	Increased BP from improved CA and SVR	Transient effect. No effect on heart rate

Answer: D

Graudins A, Lee HM, Druda D, Graudins A, et al. Calcium channel antagonist and beta‐blocker overdose: antidotes and adjunct therapies. British Journal of Clinical Pharmacology 2016 Mar ; 81 (3):453–461. https://doi.org/10.1111/bcp.12763. Epub 2015Oct 30.

A 44‐year‐old man who works as a park ranger was bit by a rattlesnake just above the right ankle about 2 hours ago and just arrived in the emergency room. His right calf is swollen, firm, and he has pain to passive movement. There does not appear to be any neurovascular compromise. What should be the next step in management?
1. Surgical exploration of the wound with excision of all visibly envenomated tissue.
2. Apply tourniquet above the knee and irrigation of the site of the bite.
3. Incision over the bite and venom extraction.
4. Emergent four compartment fasciotomies of the right lower leg.
5. Antivenom administration and check compartment pressures.
The current recommendation is prompt administration of antivenom (Anavip® or Crofab®). Crotalidae immune F(ab)² is an equine‐derived antivenin and Crotalidae polyvalent immune F(ab) (Crofab®) consists of the purified Fab fragments of sheep immunoglobulin (IgG) raised against the antivenom of four snakes. These F(ab) fragments bind venom in the intravascular space and are renally excreted. Both agents are indicated for the management of adult and pediatric patients with North American pit viper envenomation. Anavip® was recently approved and has significantly longer plasma persistence than Crofab®, and this is associated with a slower decline in platelet count and fibrinogen following hospital discharge. Excision of tissue to remove venom is not recommended because it has not been shown to improve outcomes and can be disfiguring. Placing a tourniquet has been found to worsen tissue outcomes and is currently not recommended. Incision is often ineffective and can be damaging based on location. While snake envenomation can mimic compartment syndrome, the diagnosis of compartment syndrome should not be made on soft signs (firm compartments, pain out of proportion, or pain with passive stretch). Measuring compartment pressures should be performed when possible. Fasciotomies should only be considered if antivenom is given without improvement in symptoms, neurovascular compromise after antivenom is given, or if compartment pressures are greater than 30–40 mmHg following antivenom administration.

Answer: E

Toschlog EA, Bauer CR, Hall EL, et al. Surgical considerations in the management of pit viper snake envenomation. Journal of the American College of Surgeons 2013 Oct; 217 (4):726–735. https://doi.org/10.1016/j.jamcollsurg.2013.05.004
An 18‐year‐old otherwise healthy man is camping in New Mexico when he is stung by a scorpion on the left foot when he was putting on his hiking boots. His vital signs are HR 135 beats/minute, BP 165/85 mm Hg, RR 20 breaths/minute, temperature 37.5°C, and pulse oximetry is 99% on 2L oxygen/nasal cannula. He has some edema, erythema, and pain to the left foot. Calf compartments are soft and the patient is able to move his ankle and toes normally, however, he does report some numbness at the site of the bite. He is calm and able to follow instructions. What is the best treatment?
1. Admission to ICU, mechanical ventilation if needed
2. Oral opioids, oral benzodiazepines, and IV fluid
3. Antivenom, NSAIDs, prazosin
4. Antivenom, mechanical ventilation, and dobutamine infusion
5. Antivenom, mechanical ventilation, and benzodiazepine infusion
Most scorpion bites only cause localized pain, however, about 10% of stings result in severe systemic envenomation. This patient has both local effects and autonomic excitation with resultant tachycardia and hypertension, giving him a clinical classification of grade 2 (see chart below). For this patient, he should receive antivenom (Anascorp®), NSAIDs, and prazosin to help lower his blood pressure. His current vital signs do not suggest cardiogenic shock, pulmonary edema, or multi‐organ failure that would necessitate ICU care. As he is currently calm without severe neuromuscular excitation, there is no role for benzodiazepines. The use of antivenom for scorpion stings remains controversial; however, current recommendations are for its use. There is also concern that once a patient develops severe envenomation symptoms, antivenom may be less effective.

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