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A bad trip… to the ICU – A case presentation and general overview of poisonous mushroom ingestion

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A bad trip… to the ICU – A Resident Clinical Pearl  on poisonous mushroom ingestion

Scott Fenwick 

PGY-1 Family Medicine, Dalhousie University

Reviewed by: Liam Walsh, Clinical Pharmacist

Copyedited by: Dr. Mandy Peach

Case Presentation:

A 43yo otherwise healthy female presents to the ED with 30 hours of intractable nausea, vomiting, diarrhea, and diffuse crampy abdominal pain. 12 hours prior to the onset of these symptoms, she had foraged six wild mushrooms, fried them with butter, and ate them with her dinner. She had used a wild mushroom reference guide and thought these “pristine white” mushrooms would be a safe steak topping.

In the ED, she was alert and oriented with a GCS of 15 and no apparent encephalopathy. Her vitals were BP 109/68, P 93, T 37, RR 16, O2 97% RA. She was retching and vomiting clear emesis, which settled some with ondansetron 8mg IV. Clinically, she looked dehydrated but otherwise not toxic. Her abdomen was soft and diffusely tender. Cardiorespiratory exams were unremarkable. There were no skin findings.

A 1L bolus of normal saline was administered. Serum laboratory studies, drawn approximately 42 hours post-ingestion returned as follows:

Urinalysis showed trace blood, ketones and protein. ECG showed normal sinus rhythm.

The marked elevation in liver enzymes and abnormal coagulation studies were concerning for hepatocellular injury and fulminant hepatic failure. The local Internal Medicine consultant was contacted, and the patient was transferred to the ICU at the nearest liver transplant center.

In consultation with pharmacy and poison control, it was determined that the most likely offending mushroom was Amanita virosa, more commonly know as a Destroying Angel.

The patient was started on NAC, activated charcoal, penicillin G, cimetidine, vitamin C, and IV silibinin (milk thistle). Consideration was given to percutaneous cholecystostomy, as the toxin can accumulate in the gallbladder, but this was not anatomically feasible at the time.
Laboratory studies peaked at 72 hours post-ingestion as follows

Vitamin K was given to lower the INR. Creatinine continued to climb and was 835 prior to initiation of hemodialysis. Liver studies slowly trended downward with ALT 9774, AST 4586, and INR 1.7 at 96-hours post-ingestion. Ultimately, liver function values returned to normal and enzymes levels continued to trend downward—making liver transplant not necessary.

Overview of Toxic Mushroom Ingestion:

Epidemiology:

According to the 2019 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, more than half of toxic mushroom ingestions occur in children under the age of 6. Serious toxicity and mortality, however, is more common in foraging adults, as they are more likely to consume larger quantities of a misidentified mushroom. Data for Atlantic Canada was difficult to obtain, but the Ontario Poison Centre received 72 calls related to mushroom exposures in September 2020, generally the peak month for exposures.

Poisoning Syndromes:

Only 20% of the time is the offending mushroom correctly identified, so we often rely on the clinical presentation to identify the likely species and relevant treatment. UpToDate lists 12 different mushroom toxins and 14 unique corresponding syndromes:

  • Acute gastroenteritis (<6hrs) without liver failure
  • Delayed gastroenteritis (6-12hrs) and delayed liver failure
  • Acute gastroenteritis and delayed renal failure
  • Hallucinogenic
  • CNS depression and excitation
  • Disulfiram-like reaction
  • Cholinergic excess
  • Delayed renal failure
  • Delayed rhabdomyolysis
  • Erythromelalgia
  • Delayed encephalopathy
  • Immune-mediate hemolytic anemia
  • Shiitake dermatitis
  • Allergic bronchioalveolitis

The syndrome from this case, bolded above, is delayed liver toxicity and delayed gastroenteritis.

This syndrome follows 3 phases:

  • Phase I: Dysentery – nausea, vomiting, diarrhea (6-24hrs post-ingestion)
  • Phase II: Apparent recovery (24-36hrs post-ingestion)
  • Phase III: Fulminant hepatic and multisystem organ failure (48-96hrs post-ingestion)

Poisonous Mushrooms in New Brunswick:

The New Brunswick Museum has compiled a catalog of the mushroom species discovered in the province. One of the deadliest mushrooms in the province is the Destroying Angel. This nickname refers to a group of mushroom species under the genus Amanita. Amanita virosa is commonly found in New Brunswick and Nova Scotia. They are pristine white and often located in wooded areas or next to trees/shrubs in suburban areas. They are most prevalent in the summer and fall.

In their button stage, Destroying Angels can be confused with white mushrooms that you might buy at the grocery store. Destroying Angels produce an amatoxin—a selective inhibitor of RNA polymerase II, leading to an interruption in protein synthesis and cell death. Amatoxins are especially toxic to the GI tract, liver and kidneys.

Notably, in the NB Museum catalog, there are no reports of Amanita phalloides, aka the Death Cap, in New Brunswick. In Canada, they are more commonly found in British Columbia.

EM Approach:

History:

  1. What did they look like? Ask for photos from the patient’s phone or samples if they have them. Identification assays are available but not always useful in the acute setting.
  2. Were the mushrooms collected in a field or along/underneath trees? Many toxic mushrooms are in wooded areas.
  3. How many types of mushrooms were ingested?
  4. How long after ingestion did symptoms develop? Less than 6hrs is associated with lower risk of—but does not exclude—potentially lethal ingestion.
  5. How much was eaten? Were there multiple times of ingestion?
  6. Did others eat the mushrooms? If so, do they have similar symptoms?

Physical Exam:

  • Assess hydration status
  • Assess for encephalopathy or other signs of fulminant hepatic failure

Laboratory studies:

Treatment:

  • Ondansetron for N/V, do not use anti-diarrheal agents
  • IVF for dehydration and electrolyte abnormalities
  • If a serious ingestion cannot be excluded, patients should be admitted for 24-48hrs for observation and serial bloodwork

Evidence-based recommendations for suspected amatoxin poisoning:
o Multiple dose activated charcoal: 0.5g/kg (max 50g) q4h for 4 days post-ingestion.

o Silibinin: loading dose of 5 mg/kg IV, followed by a continuous infusion at a dose of 20 mg/kg/day for 6 days or until clinical recovery.

If IV silibinin is not available, oral milk thistle capsules (Silymarin) are an effective alternative. The initial dose is 50-100mg/kg q8h, and titrated up to 200mg/kg q8h as tolerated, with a maximum single dose of 2-3g. IV Silibinin is available only through Health Canada’s Special Access Program. Pharmacy should be contacted early to assist with this process if it’s being considered.

o Penicillin G: 300,000 to 1,000,000 units/kg/day given as a continuous IV infusion. A small amount of research shows no benefit to adding this if IV silibinin is available. If penicillin allergy, consider ceftazidime 4.5 g every 2 hours.

o NAC protocol: initial loading dose of 150 mg/kg (max 10g), next a 4-hour infusion at 12.5 mg/kg/hr, then a 16-hour infusion at 6.25 mg/kg/hr. The 16-hour dose may be repeated if significant hepatic dysfunction persists.

o Cimetidine: 300 mg IV every 8 hours until clinical improvement (evidence in animal studies only)

o Vitamin C: 3 g IV daily until clinical improvement (evidence in animal studies only)

o Dextrose for hypoglycemia

o Lactulose for hyperammonemia

o Vitamin K +/- FFP for coagulopathy

o Dialysis for AKI

o Early consultation with liver transplant center

  • Treatments for other mushroom poisoning syndromes can be found in this chart

Bottom Line:

Ask if the patient has photos of the mushrooms on their phone, or if they can describe their appearance. Call local poison control with this information.

Obtain a clear history to determine the interval between time of ingestion and time of symptom onset. Acute gastroenteritis onset (<6hrs from ingestion) is associated with favourable outcomes, and delayed gastroenteritis (usually 6-12hrs from ingestion) is more likely to have liver and/or renal failure.

Liver studies may be normal until 24-36 hours and generally peak at 72-96 hours post-ingestion.

Early treatment and consultation/transfer to a liver transplant center is imperative.

 

References:

Cover photo: https://www.deviantart.com/dreadillustrations/art/Poison-Mushrooms-774297817

Gummin, D. D., Mowry, J. B., Beuhler, M. C., Spyker, D. A., Brooks, D. E., Dibert, K. W., Rivers, L. J., Pham, N., & Ryan, M. L. (2020). 2019 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 37th Annual Report. Clinical toxicology (Philadelphia, Pa.), 58(12), 1360–1541. https://doi.org/10.1080/15563650.2020.1834219

Nelson, L. S., Howland, M. A., Lewin, N. A., Smith, S. W., Goldfrank, L. R., Hoffman, R. S., & Flomenbaum, N. E. (2019). Goldfrank’s toxicologic emergencies (11th ed.). Mc Graw Hill Education.

Shannon, M. (2007). Haddad and Winchester’s clinical management of poisoning and drug overdose (4th ed.). Saunders.

NB Museum Mushroom Checklist: http://website.nbm-mnb.ca/mycologywebpages/Checklists/NBMushrooms/NBMushroomChecklist.html

Tavassoli, M., Afshari, A., Arsene, A. L., Mégarbane, B., Dumanov, J., Bastos Paoliello, M. M., Tsatsakis, A., Carvalho, F., Hashemzaei, M., Karimi, G., & Rezaee, R. (2019). Toxicological profile of Amanita virosa – A narrative review. Toxicology Reports, 6, 143–150. https://doi.org/10.1016/J.TOXREP.2019.01.002

Amanita virosa photo: https://www.tehrantimes.com/news/423947/Mushroom-poisoning-kills-18-in-Iran

White mushroom photo: https://www.stockfood.com/images/00395464-Several-button-mushrooms

Amanita phalloides photo: http://www.bccdc.ca/about/news-stories/stories/2020/death-cap-mushrooms-make-fall-appearance-in-urban-areas

 

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Carbon Monoxide Poisoning

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Carbon Monoxide Poisoning – A Medical Student Clinical Pearl

Mitchell McDonough

DMNB, Class of 2022

Reviewed by Dr. Rachel Goss

Copyedited by Dr. Mandy Peach

Case

A 75 y/o male presented to the Emergency Department one afternoon via EMS with mild confusion and a headache. He recalled a sudden feeling of light-headedness while making breakfast in the morning, lowered himself to the floor, and then has very limited memory of events after this. He did not recall losing consciousness. Given his confusion, he was unable to provide an accurate recount of the events that had initially brought him to the ED and collateral history was required. EMS indicated that he was found by his upstairs neighbour after hearing him yelling. The patient noted that the power went out at his house early during the night, so he turned on his propane stovetop to provide some heat. He admitted to alcohol consumption the night prior but indicated he drinks frequently and that was unlikely to be the culprit of his current state. He had no other complaints at this time and a review of systems was unremarkable apart from a mild headache.

On general assessment the patient appeared well, vital signs were within normal limits. On physical exam he had normal strength in all four extremities. Neurologic, respiratory, cardiac and abdominal exams were unremarkable. The patient was slightly confused but it was difficult to ascertain if this was new or his normal baseline.

Differential for Confusion

Metabolic disorders
• Electrolyte abnormalities
• Endocrine disease
• Hypoglycemia
• Hypoxia

Stroke/CNS structural lesion/Head Injury

Infectious
• Systemic infection
• CNS infection (meningitis, encephalitis)

Intoxication/withdrawal
• Alcohol
• Drugs
• Carbon Monoxide

Investigations

Initial investigations included an ECG, which was normal with no evidence of an ischemic event, a toxicology panel which showed minimal blood alcohol remaining, and a blood gas sample with carboxyhemoglobin. While carbon monoxide poisoning was initially low on our differential, the carboxyhemoglobin level came back severely elevated, at 31%. Interestingly, PO2 from the ABG was within normal limits as the concentration of CO required to cause poisoning is sufficiently low that it does not significantly alter the quantity of oxygen dissolved in the plasma.

Pertinent Arterial Blood Gas Values for our patient:

pH 7.37 [7.35-7.45]
pCO2 36.2mmHg [35-45]
pO2 81.4 mmHg [75-105]
K+ 4.2mmol/L [3.7-4.7]
Na+ 139 mmol/L [136-146]
Ca2+ 1.27 mmol/L [1.15-1.30]
FCOHb 31.4% [0.3-1.8]
ctHb 132g/L [120-150]

 

Carbon Monoxide Poisoning Overview

Carbon monoxide is a gas formed by combustion of hydrocarbons. It is colourless, tasteless and odorless. Carbon monoxide binds to hemoglobin with approximately 200 times greater affinity than oxygen, forming carboxyhemoglobin which results in impaired utilization of oxygen by cells. The mechanism of impaired oxygen usage relates to CO binding cytochrome oxidase in peripheral tissues which prevents cells from using the reduced O2 received.

Potential sources of carbon monoxide include fires, heating systems, stoves, charcoal grills, generators and motor vehicles (1-3).

Figure 1: Oxygen dissociation curve demonstrating the left shift of carbon monoxide (13).

Clinical Presentation

The clinical presentations of carbon monoxide poisoning vary depending on the severity of intoxication and most findings are usually nonspecific (4,5). Patients may describe a general malaise, nausea, dizziness and headaches (6). Depending on the level of intoxication, patients may present with symptoms ranging from confusion to coma, seizures and myocardial ischemia.

Table 2: Symptoms at varying levels of carbon monoxide dissolved in blood. It should be noted that symptoms can vary substantially from individual to individual and that levels of CO do not correlate well with symptoms. For example, a typical cigarette smoker will have up to a 10% level of CO in their blood at baseline. (14).

 

Severe is classified as >30% and the following clinical signs:

  • New neurologic findings
  • Ischaemic ecg
  • Clinically significant metabolic acidosis
  • Requirement for ventilation.

Diagnosis

Diagnosis of carbon monoxide poisoning is based on history, physical exam and elevated carboxyhemoglobin on cooximetry of an arterial or venous blood gas. Due to their similar light absorbancy, standard pulse oximetry is not able to differentiate between carboxyhemoglobin and oxyhemoglobin, and therefore cannot screen for exposure to carbon monoxide (7,8). Because of the similar light absorbancy, SpO2 can also be falsely elevated. It is important to note that even with a normal SpO2 level that the patient is hypoxic.

A non-smoker may have up to 3% carboxyhemoglobin at baseline while a smoker may have 10-15%. Anything above these levels represents carbon monoxide poisoning.

Treatment

Treatment of patients with suspected carbon monoxide poisoning include:

  • removal of the potential source
  • administration of high-flow oxygen by face mask.
  • IV mannitol for any potential cerebral edema.

Indications for treatment with hyperbaric oxygen vary from institution to institution and depend on factors such as symptoms, patient factors, length of exposure to carbon monoxide, as well as COHB levels.

In general, patients that should be considered for hyperbaric oxygen therapy include (4,9-12):

  • carbon monoxide level >25% (>15% in pregnant women)
  • neurosequelae
  • loss of consciousness
  • metabolic acidosis (pH < 7.1)
  • evidence of end-organ ischemia

Case Conclusion

Given their severely elevated carboxyhemoglobin level and prolonged exposure, the patient was given 100% oxygen via a non-rebreather face mask until being transported to a hyperbaric oxygen chamber for further treatment.

This case highlights the importance of carbon monoxide poisoning as a potential diagnosis when a patient presents with a reduced level of consciousness or confusion, especially during the winter months when the risk of exposure is higher.

References

  1. Thomassen Ø, Brattebø G, Rostrup M. Carbon monoxide poisoning while using a small cooking stove in a tent. Am J Emerg Med 2004; 22:204.
  2. Centers for Disease Control and Prevention (CDC). Carbon monoxide poisoning from hurricane-associated use of portable generators–Florida, 2004. MMWR Morb Mortal Wkly Rep 2005; 54:697.
  3. Hampson NB, Dunn SL. Carbon Monoxide Poisoning from Portable Electrical Generators. J Emerg Med 2015; 49:125.
  4. Harper A, Croft-Baker J. Carbon monoxide poisoning: undetected by both patients and their doctors. Age Ageing 2004; 33:105
  5. Kao LW, Nañagas KA. Carbon monoxide poisoning. Emerg Med Clin North Am 2004; 22:985.
  6. Tomaszewski C. Carbon monoxide poisoning. Early awareness and intervention can save lives. Postgrad Med 1999; 105:39.
  7. Bozeman WP, Myers RA, Barish RA. Confirmation of the pulse oximetry gap in carbon monoxide poisoning. Ann Emerg Med 1997; 30:608.
  8. Tremper KK, Barker SJ. Pulse oximetry. Anesthesiology 1989; 70:98.
  9. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med 1998; 339:1603.
  10. Weaver LK. Carbon monoxide poisoning. Crit Care Clin 1999; 15:297.
  11. Hampson NB, Dunford RG, Kramer CC, Norkool DM. Selection criteria utilized for hyperbaric oxygen treatment of carbon monoxide poisoning. J Emerg Med 1995; 13:227.
  12. Huang CC, Ho CH, Chen YC, et al. Hyperbaric Oxygen Therapy Is Associated With Lower Short- and Long-Term Mortality in Patients With Carbon Monoxide Poisoning. Chest 2017; 152:943.
  13. https://www.pulmonologyadvisor.com/home/decision-support-in-medicine/pulmonary-medicine/thermal-injury-and-smoke-inhalation/
  14. https://www.cfinotebook.net/notebook/aeromedical-and-human-factors/carbon-monoxide-poisoning

 

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Tardive Dyskinesia in an Emergency Setting

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Medical Student Clinical Pearl – October 2019

Faith Moore

Faculty of Medicine
Dalhousie University
CC3
Class of 2021

Reviewed and Edited by Dr. David Lewis

All case histories are illustrative and not based on any individual

Case

A 48-year-old female was brought to the emergency department by EMS after developing dystonia that morning, a couple hours earlier, following a restless night. The dystonia had begun affecting her arms, torso and buccal region, but eventually moved to also involve her legs. She had a history of recurrent tardive dyskinesia for the past 20 years since taking stelazine and developing tardive dystonia. She was switched to olanzopine after developing dystonia and stayed on it until two months ago. Her citalopram and clozapam dosing had been increased two weeks ago, and she had also started Gingko biloba extract two weeks ago. She had started Nuplazid 3 days ago.

Upon exam she was diaphoretic with no other abnormal findings other than dystonia affecting the entire body.

Tardive Dyskinesia

Pathophysiology

    • Tardive dyskinesia is a hyperkinetic movement disorder that is associated with the use of dopamine receptor-blocking medications.1 The exact mechanism is under debate, but the main hypotheses include an exaggerated response by dopamine receptors due to a chronic dopamine blockade, oxidative stress, gamma-aminobutyric acid (GABA) depletion, cholinergic deficiency, altered synaptic plasticity, neurotoxicity and defective neuroadaptive signaling. 2 The most accepted theory of the mechanism is that the chronic dopamine blockade caused by the dopamine receptor-blocking medications results in a hypersensitivity of the receptors, specifically at the basal ganglia. 1
    • The medications that are known to have the possibility to cause tardive dyskinesia include antipsychotic drugs, anticholinergic agents (ex. Procyclidine), antidepressants, antiemetics (ex. Metoclopramide), anticonvulsants, antihistamines, decongestants (ex. pseudoephedrine and phenylephrine), antimalarials, antiparkinson agents, anxiolytics, biogenic amines, mood stabilizers and stimulants.1

Who is most at risk?

    • The medications that are the most common culprits are first- and second-generation antipsychotics and metoclopramide. The incidence of tardive dyskinesia from chronic first-generation antipsychotic exposure is 5-6% 3, and is 4% for second generation antipsychotics 4. There is no prospective research on chronic metoclopramide use and the risk for tardive dyskinesia at this point and time5, but a study in the UK in 1985 showed 1 case of tardive dyskinesia for every 35 000 prescriptions6.
      • Most prominent risk factors
        • Old age5
        • Chronic exposure5
        • Patients who develop extrapyramidal symptoms while on antipsychotic drugs.7

Signs and Symptoms

      • Repetitive involuntary body movements that may involve the face, tongue, eyes, arms, torso and legs

Diagnosis

    • The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classifies tardive dyskinesia as “involuntary movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphragmatic, or trunk muscles), developing in association with the use of a neuroleptic medication for at least a few months” and that persists for at least one month after the medication is stopped.8

Differential Diagnosis

    • Acute dyskinesia
    • Akathisia
    • Parkinsonism and tremor
    • Perioral tremor
    • Stereotypies and mannerisms
    • Spontaneous or idiopathic dyskinesias
    • Isolated dystonia
    • Primary movement disorders
    • Chorea from systemic causes 9

Key Questions for History and Physical

    • Are the movements voluntary?
    • Is there an accompanied feeling of restlessness?
      • If yes, might point towards akathisia.
    • When did these movements began?
    • What is the body distribution of the involuntary movements?
    • Are there any extrapyramidal signs and symptoms?
    • Are there any associated features?
    • Have there been any drug changes in the past few months?

 

Management in the Emergency Department

    • First line treatment of tardive dyskinesia generally begins with discontinuation of the offending drug. In the emergency department this should be done after consulting with the treating physician. These patients are often being treated for psychiatric disorder and the treatment of the psychiatric disorder must be balanced with the risk of tardive dyskinesia. It may be appropriate to switch from a first generation antipsychotic medication to a second generation antipsychotic generation medication.
    • If the symptoms of tardive dyskinesia need to be treated, like in our case with this patient, there are various drugs that can be tried.
    • Tetrabenazine is considered first line.10
      • Suggested doses of 12.5-25 mg starting daily dose with a 25-200 mg/day dose range.10
    • Other treatment options
      • Dextromethorphan11
        • In a recent case study patients took under 1mg/kg, not exceeding 42 mg/day.11
        • This was recommended by a local neurologist here at the Saint John Regional Hospital.
      • Valbenazine 12
        • Suggested dose of 40 mg UID, increasing to 80 mg UID after one week.12
      • Amantadine10
        • Suggested dose of 100 mg starting daily dose with a dose range of 100-300 mg/day 10
      • Benzodiazepines12
        • Clonazepam initiated at 0.5 mg and titrated by 0.5 mg increments every 5 days to response up to a maximum dose of 3-4 mg/day. 12
      • Diphenhydramine suggested dose of 25-50 mg IV13
      • Botulinum toxin injections12
    • Commonly used treatments lacking evidence of efficacy
      • Benztropine10
Drug Starting Dose Recommendations Dose Range
1st Line
Tetrabenazine 12.5-25 mg UID 25-200 mg UID
Other options
Dextromethorphan Under 1 mg/kg Not exceeding 42 mg UID
Valbenazine 40 mg UID Increase to 80 mg after 1 week
Amantadine 100 mg UID 100-300 mg UID
Clonazepam 0.5 mg 0.5-4.0 mg UID
Diphenhydramine 25 mg IV 25-50 mg IV
Botulinum toxin injection local injection to treat specific painful dystonia resistant to systemic therapy

 

Case Continued

The patient was given 2mg of Benztropine IV with no effect. Twenty minutes later he was then given 1mg of Ativan SL with no effect. Thirty minutes later the patient was given 150 mg Benadryl IV, and some improvement was then witnessed, the patient was allowed to sleep and was discharged approximately 5 hours after his arrival with no symptoms.

External Resources

Treatment strategies for dystonia

Diagnosis & Treatment of Dystonia

References

  1. Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-Induced Tardive Dyskinesia: A Review and Update.Ochsner J. 2017 Summer;17(2):162-174. Review. PubMed PMID: 28638290; PubMed Central PMCID: PMC5472076.
  2. Kulkarni SK, Naidu PS. Pathophysiology and drug therapy of tardive dyskinesia: current concepts and future perspectives.Drugs Today (Barc). 2003 Jan;39(1):19-49. Review. PubMed PMID: 12669107.
  3. Glazer WM.Review of incidence studies of tardive dyskinesia associated with typical antipsychotics. J Clin Psychiatry. 2000;61 Suppl 4:15-20.  PubMed PMID: 10739326.
  4. Correll CU, Schenk EM.Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry. 2008 Mar;21(2):151-6. doi: 10.1097/YCO.0b013e3282f53132.  PubMed PMID: 18332662.
  5. Rao AS, Camilleri M.Review article: metoclopramide and tardive dyskinesia.Aliment Pharmacol Ther. 2010 Jan;31(1):11-9. doi: 10.1111/j.1365-2036.2009.04189.x.  PubMed PMID: 19886950.
  6. Bateman DN, Rawlins MD, Simpson JM.Extrapyramidal reactions with metoclopramide. Br Med J (Clin Res Ed). 1985 Oct 5;291(6500):930-2. doi: 10.1136/bmj.291.6500.930. PubMed PMID: 3929968; PubMed Central PMCID: PMC1417247
  7. Novick D, Haro JM, Bertsch J, Haddad PM.Incidence of extrapyramidal symptoms and tardive dyskinesia in schizophrenia: thirty-six-month results from the European schizophrenia outpatient health outcomes study. J Clin Psychopharmacol. 2010 Oct;30(5):531-40. doi: 10.1097/JCP.0b013e3181f14098. PubMed PMID: 20814320.
  1. American Psychiatric Association, Medication-induced movement disorders and other adverse effects of medication, Diagnostic and Statistical Manual of Mental Disorders, fifth edition, American Psychiatric Association, 2013.
  2. Tarsy D, Deik A. Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis. In: UpToDate, Eichler A (Ed), UpToDate, Waltham, MA. (Accessed on September 9, 2019.)
  1. DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No.T113751, Tardive Dyskinesia; [updated 2018 Nov 30, cited September 9, 2019]. Available from https://www.dynamed.com/topics/dmp~AN~T113751. Registration and login required.
  1. Kim J. (2014). Dextromethorphan for Tardive Dyskinesia. International Neuropsychiatric Disease Journal. 2. 136-140. 10.9734/INDJ/2014/7970.
  2. Tarsy D, Deik A. Tardive dyskinesia: Prevention, prognosis, and treatment. In: UpToDate, Eichler A (Ed), UpToDate, Waltham, MA. (Accessed on September 9, 2019.)
  1. Buttaravoli P, Leffler SM. Chapter 1 – dystonic drug reaction. 2012:1-3. doi:https://doi.org/10.1016/B978-0-323-07909-9.00001-5 “.
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Approach to Resuscitation in Severe Calcium Channel Blocker Poisoning

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Medical Student Clinical Pearl

J.L. Dobson

Faculty of Medicine
Memorial University of Newfoundland
M.D. Candidate 2020

Reviewed and Edited by Dr. Luke Taylor and Dr. David Lewis

and Liam Walsh. Pharmacist HHN

 

Introduction:

Calcium channel blockers (CCBs) have multiple clinical uses, including the management of hypertension, angina, and cardiac arrhythmias. [1] While CCBs are no longer the most widely prescribed antihypertensive as they were in the 1990s, their prevalence remains high. [2] This along with the existence of both immediate release and long-acting forms poses a challenge for the Emergency Physician faced with a case of CCB poisoning.

Physiology:

Myocardium in the sinoatrial and atrioventricular nodes uses the slow action potential created by calcium currents to conduct. CCBs act on this tissue by inhibiting this current, thus slowing conduction through the SA and AV nodes. This results in a decreased heart rate, prolonged PR intervals, and lengthened refractory periods through the AV node. Conversely, they also inhibit calcium flow in smooth muscle, resulting in coronary and peripheral artery dilation. This ultimately provides the mechanism for reflex tachycardia, increased AV conduction, and improved myocardial contractility. [3]

Adverse reactions to the physiological effects of CCBs include vasodilatory effects (peripheral edema, headache, palpitations), gastrointestinal effects (nausea, diarrhea, constipation), and negative inotropic effects (hypotension, bradycardia). [4]

 

Case Report:

A 80-year-old male is brought in to Trauma by ambulance with hypotension, bradycardia, and an altered level of consciousness. Report from EMS reveals the patient called about half an hour prior stating that he had taken medications in an attempt to commit suicide. Upon arrival, the pt was alert and oriented, and endorsed taking an unknown quantity of clonazepam and citalopram, and a deficit of up to four grams of Diltiazem was noted from his medications. He denied further substance use. Though initially stable, the patient deteriorated rapidly upon arrival to the emergency department.

In the Emergency Department, initial vitals revealed a BP of 88/68, P of 52 bpm and SPO2 of 93% on RA and a BG of 15. As such nasal prongs were placed and she was immediately given atropine as well as push dose epinephrine. Within ten minutes, there was further decline in mental status of the patient corresponding to a blood pressure of 83/61 and a heart rate persisting in the low 40s bpm. He was successively given further epinephrine, atropine and calcium chloride while toxicology was contacted. Despite recurrent doses of epinephrine and atropine, the patient remained profoundly hypotensive and bradycardic. Insulin (Humulin R) and dextrose were started at 0.5U/kg/hr with a 1U/kg bolus. This infusion was titrated up every thirty minutes with minimal improvement in vitals. At this point, remaining bradycardic at 37bpm, intralipid therapy was deemed necessary and so a bolus of 105mL was given. Having received epinephrine bolus along with a 0.2mcg/kg/hr infusion, maximum dose of atropine, 3g of Calcium chloride, with minimal clinical improvement cardiac pacing was initiated. Once good electrical and mechanical capture were achieved the patient underwent and RSI with ketamine and rocuronium. Once stabilized, he was transferred to ICU for further management. In ICU, the patient had a transvenous pacemaker floated successfully followed by a transitioning off the epinephrine to norepinephrine and vasopressin. Intralipid infusion was started and the insulin and glucose therapy was titrated up to a maximum of 4U/kg/hr. The patient unfortunately did not tolerate whole bowel irrigation. Despite the critical nature of their condition, the patient did slowly improve and pressors were weaned.

 

Discussion:

History & Primary Survey

This patient experienced negative inotropic effects of the extended release calcium channel blocker, resulting in cardiogenic shock. Ingestion of more than 5-10 times the usual dose of CCB results in severe intoxication: this patient was thought to have consumed four grams of Diltiazem, over eleven times the maximum recommended dose. [5] While any CCB can result in hypotension, knowledge of which CCB was taken is useful to set expectations for the patient’s progression: unlike dihydropyridine-type CCBs which would more likely present with reflex tachycardia, non-dihydropyridine CCBs like verapamil and diltiazem result in bradycardia. [6] Another crucial point in the primary survey is that, due to the neuroprotective effects of CCBs, mental status may initially be preserved until cerebral perfusion is severely affected. [5]

Initial Resuscitation

While the patient may initially be able to maintain their airway, mental status and vitals may deteriorate rapidly. [5] It is important to note that like any critical ill patient,  intubation may result in a further drop in heart rate and blood pressure via vagal stimulation. It is crucial to have adequate resuscitation prior to intubation. IV crystalloid fluids , IV atropine (up to three 1mg doses), as well as push dose epinephrine are interventions that can be used quickly at bedside to maintain circulation and heart rate while further investigations and treatments can be organized. [5,8]

Specific Treatments

For a severe CCB poisoning in which hypotension is refractory to IV fluids and atropine, all of the following treatments should be administered simultaneously. If the severity is milder, these treatments should be approached in a stepwise fashion, progressing to the next if the preceding treatment is ineffective. [5]

IV Calcium salt:

As a first line recommendation, a calcium chloride bolus (10-20mL 10%) followed by a continuous infusion (0.5 mEq Ca2+/kg/hr) or the equivalent of calcium gluconate is recommended, though often ineffective. [5] Mortality has been shown to be reduced with its administration, and hypercalcemia occurs only rarely. [7] [8]

IV Insulin with dextrose:

High-dose insulin therapy (1 u/kg bolus and 0.5 u/kg/hr infusion up to 10 u/kg/hr) has been shown to be safe and effective at improving hemodynamics, though response is delayed for 30-60 minutes. [5,7] It should be used with calcium and a vasopressor in the presence of myocardial dysfunction. [8] Blood glucose levels should be monitored every 15-30 minutes for hypoglycemia, and 50mL boluses of dextrose (D50W) given accordingly to maintain levels above 8.25 mM. [5] Hypokalemia is another risk of insulin therapy, therefore electrolytes should be monitored every 30 minutes and 20 mEq of potassium chloride given if needed. [5,7]

IV Vasopressor:

Administration of IV epinephrine has shown improvement in cardiac output. [7,8] In the setting of severe CCB poisoning, doses as high as 150mcg per minute of epinephrine may be needed. It is suggested to start the infusion at 2mcg per minute and titrate up to a systolic blood pressure of 100 mmHg, or a MAP of 65 mmHg. [5] These higher doses may result in a large improvement in patient MAP with minimal change in heart rate.

IV Lipid emulsion therapy:

If the patient is refractory to first-line treatments above, or upon consultation with medical toxicology centre, IV lipid emulsion therapy may be recommended. [8] Most commonly, this is given as a bolus of 1.5 mL/kg of 20% lipid emulsion, repeated up to every three minutes for three total boluses. An infusion of 0.25-0.5 mL/kg/minute may be started. [5] Complications of this treatment are still being studied.

Other considerations:

Studies most often show improvement of hemodynamics and no adverse effects with temporary cardiac pacing for bradycardia refractory to first-line treatments. [7,8] Extracorporeal membrane oxygenation may also be necessary if the patient is near cardiac arrest and remains refractory to previous treatments. [8] Dialysis provides no benefit. [5]

Decontamination:

If the patient is asymptomatic and/or hemodynamically stable, 50g of activated charcoal should be given. In the case of ingestion of extended-release CCBs, whole bowel irrigation should be performed regardless of the presence of symptoms. An asymptomatic patient should be monitored for 6-8 hours for immediate release and 24 hours for extended release forms. [5,8]

Investigations:

ECG may reveal PR interval prolongation due to CCB actions on the SA and AV nodes. Frequent blood glucose measurements are crucial to monitor for the effects of insulin treatment and the need for glucose replacement. Serum electrolytes, notably potassium levels, must be assessed for developed hypokalemia secondary to insulin treatment.

Conclusion:

We present a case and review the physiology of a severe calcium channel blocker poisoning. Key considerations in managing a CCB poisoning include specific dosage and form, initial resuscitation with a low threshold for intubation, fluids, and atropine. Further treatments will be required based on severity, such as intravenous calcium, insulin with dextrose, and lipid emulsion therapy, all of which should be initiated promptly if there is concern for massive over dose and patient declining. Other considerations include the need for further vasopressors and temporary cardiac pacing.

 

FIGURE: Society of Critical Care Medicine key recommendations for management of CCB poisoning. Source: “Experts consensus recommendations for the management of calcium channel blocker poisoning in adults.” Crit Care Med. 2017;45(3):e306-e315. DOI: 10.1097/CCM.0000000000002087

 

References:

[1] Elliott, WJ & Ram,CV. J Clin Hypertens (Greenwich). 2011;13:687–689.

[2] Eisenberg, MJ; Brox, A. & Bestawros, AN. Am J Med. 2004;116(1):35-42.

[3] Singh, BN; Hecht, HS; Nademanee, K. & Chew, CYC. Progress in Cardiovascular Diseases. 1982;15(2):103-132.

[4] Russell, RP. Hypertension. 1988;11(3):II42-44.

[5] Barrueto, F. “Calcium channel blocker poisoning.” UpToDate. 2019.

[6] Hofer, CA; Smith, JL & Tenholder, MF. Am J Med. 1993;95(4):431.

[7] St-Onge, M; Dubé, PA; Gosselin, S; Guimont, C; Godwin, J; Archambault, PM; Chauny, JM; Frenette, AJ; Darveau, M; Le Sage, N; Poitras, J; Provencher, J; Juurlink, DN & Blais, R. Clin Toxicol (Phila). 2014;52(9):926.

[8] St-Onge, M; Anseeuw, K; Cantrell, FL; Gilchrist, IC; Hantson, P; Bailey, B; Lavergne, V; Gosselin, S; Kerns, W; Laliberté, M; Lavonas, EJ; Juurlink, DN; Muscedere, J; Yang, CC; Sinuff, T; Rieder, M & Mégarbane, B. “Experts consensus recommendations for the management of calcium channel blocker poisoning in adults.” Crit Care Med. 2017;45(3):e306-e315.

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EM Reflections – June 2019 – Part 1

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Thanks to Dr. Joanna Middleton for leading the discussions this month

Edited by Dr David Lewis 

Discussion Topics

  1. When is a pregnancy not a pregnancy?
  2. Caustic Ingestions
  3. Transient Ischemic Attack – Emergency Medicine (see part 2)

When is a pregnancy not a pregnancy?

Molar Pregnancy

Hydatidiform mole (molar pregnancy) is a relatively rare complication of fertilization with an incidence in the United States of 0.63 to 1.1 per 1000 pregnancies, although rates vary geographically. It is included in the spectrum of gestational trophoblastic diseases and is comprised of both complete molar pregnancies (CM) and partial molar pregnancies (PM).

The most well characterized risk factor for CM is extreme of maternal age. Maternal ages less than 20 or greater than 40 years have been associated with relative risks for CM as high as 10- and 11-fold greater respectively. Other potential risk factors include oral contraceptive use, maternal type A or AB blood groups, maternal smoking, and maternal alcohol abuse.

Molar pregnancy typically presents in the first trimester and may be associated with a wide array of findings, including vaginal bleeding (most common), uterine size larger than expected according to pregnancy date (CM), uterine size smaller than expected according to pregnancy date (PM), excessive beta-human chorionic gonadotropin (β-hcg) levels, anemia, hyperemesis gravidum, theca lutein cysts, pre-eclampsia, and respiratory distress.Studies comparing modern clinical presentations of CM with historical presentations have demonstrated a significant reduction in many of the classic presenting signs and symptoms such as vaginal bleeding and excessive uterine size. This reduction is attributed to early detection by transvaginal ultrasound and increasingly sensitive β-hcg assays. Numerous studies evaluating the efficacy of ultrasound in detecting molar pregnancy demonstrate a 57–95 percent sensitivity for the detection of CM compared to only 18–49 percent sensitivity for PM.

More here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791738/

PoCUS – Normal Early Pregnancy

Arrow = Yolk sac (YS) within Gestational sac (GS), note the hyperechoic decidual reaction surrounding GS, Arrow head = Fetal Pole

PoCUS – Molar Pregnancy

 

PoCUS SIgns:

  • enlarged uterus
  • may be seen as an intrauterine mass with cystic spaces without any associated fetal parts
    • the multiple cystic structures classically give a “snow storm” or “bunch of grapes” type appearance.
  • may be difficult to diagnose in the first trimester 6
    • may appear similar to a normal pregnancy or as an empty gestational sac
    • <50% are diagnosed in the first trimester
  • More on Radiopedia.org

Useful post from County EM blog- click here

 

Caustic Ingestions

 

 

Hydrochloric Acid – pH 1-2

Dangerous if pH <2 or >11.5-12

For alkaline – higher percent, shorter time to burn – 10%NaOH – 1 min of contact to produce deep burn, 30% within seconds

 

Acid – painful to swallow so usually less volume, bad taste so more gagging/laryngeal injury, more aqueous so less esophageal injury, pylorospasm prevents entry into duodenum producing stagnation and prominent antrum injury.  Food is protective.  Acid ingestion typically produces a superficial coagulation necrosis that thromboses the underlying mucosal blood vessels and consolidates the connective tissue, thereby forming a protective eschar.  In enough amount – perforation.

Alkali – burns esophagus more, neutralized in stomach.  Liquefaction necrosis.

Management

Decontamination: Activated charcoal / GI decontamination / neutralisation procedures are contraindicated

Obtaining meaningful info from endoscopy after treatment with charcoal is very difficult

If asymptomatic – observe, trial of oral intake at 4 hours after exposure, earlier if low suspicion or likely benign ingestion after discussion with Poisons Centre

Symptomatic patients or those with a significant ingestion

(high-concentration acid or alkali or high volume [>200 ml] of a low-concentration acid or alkali)

Upper GI endoscopy should be performed early (3 to 48 hrs) and preferably during the first 24 hrs after ingestion to evaluate extent of esophageal and gastric damage and guide management.  Endoscopy is contraindicated in patients who have evidence of GI perforation. (Ingestion of >60 mL of concentrated HCl leads to severe injury to the GI tract with necrosis and perforation, rapid onset of MODS and is usually fatal – endoscopy within 24 hours (unless asymptomatic at 4 hours)

Complications – 1/3 develop strictures – directly related to depth/severity of injury, years later

 

 

TAKE HOME POINTS

  1. PV Bleed, Hyperemesis, PoCUS = bunch Grapes or Snowstorm – consider Molar Pregnancy
  2. Don’t use Activated Charcoal for Caustic Ingestions
  3. Discuss Caustic Ingestions with Poisons Centre
  4. Consider early endoscopy
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