Drug-induced hypoglycemia is an important cause of hypoglycemia which should be considered in any patient presenting with altered mental status. In one study, drug-induced hypoglycemia represented 23% of all hospital admissions attributed to adverse drug events. Risk factors for developing hypoglycemia include older age, renal or hepatic insufficiency, concurrent use of insulin or sulfonylureas, infection, ethanol use, or severe comorbidities. The most commonly cited drugs associated with hypoglycemia include:

• Quinolones
• Sulfonylureas* either alone or with a potentiating drug 
• Insulin
• Pentamidine
• Quinine
• B-blockers
• ACE Inhibitors
• Tramadol**

*In Glipizide users, there was 2-3 fold higher odds of hypoglycemia with concurrent use of sulfamethoxale-trimethoprim, fluconazole, and levofloxacin compared with patients using Cephalexin.

**Tramadol potentially induces hypoglycemia by effects on hepatic gluconeogenesis and increasing insulin release and peripheral utlizilation. Was seen in elderly at initiation of therapy within first 30 days.

BOTTOM LINE:

Take care in prescribing drugs known to increase risk of hypoglycemia in elderly patients, with comorbidities, or those already taking medications associated with hypoglycemia. 

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Guanfacine is a presynaptic alpha-2 adrenergic receptor agonist (similar to clonidine) that is FDA approved to treat ADHD in pediatric patients 6 years of age and older. A recently published study characterized the pediatric exposure to guanfacine between 2000 and 2016.   

• 10927 single exposures to guanfacine were identified.
• Guanfacine exposure increased in all age group starting 2009
• Highest exposure rate was in 6-12 years old population

Most frequently reported clinical effect (n=10927)

• Drowsiness (n=4262; 39.0%)
• Bradycardia (n=1696; 15.5%)
• Hypotension (n=1127; 10.3%)
• Dizziness (n=279; 2.6%)
• Hypertension (n=199; 1.8%)

Severe clinical effects (n=10927)

• Respiratory depression (n=47; 0.43%)
• Coma (n=24; 0.22%)
• Respiratory arrest (n=5; 0.05%)
• Cardiac arrest (n=1; 0.01%)

Duration of clinical effect

• 8 to 24 hours: > 80%

Conclusion

• Severe toxicity (respiratory depression/arrest and cardiac arrest) is rare with unintentional guanfacine exposure.
• If symptomatic, majority of the patients were asymptomatic within 24 hours.

Single use laundry pods are readily available in many homes. Due to their bright colors, they have been mistaken for edible products (e.g. candy) by children.

A recent study reviewed 4652 laundry pod exposures from United Kingdom.

95.4% involved children aged < 5 years via oral route (89.7%).

• Asymptomatic: 1738 (37.4%)
• Minor symptoms: 2728 (58.6%)
• Moderate symptoms: 107 (2.3%)
• Severe symptoms: 19 (0.4%)
• Death: 1 

Common symptoms in moderate/severe symptom groups, including fatality (n=127)

• Vomiting: 75
• Stridor: 34
• CNS depression: 22
• Keratitis/corneal damage: 21
• Coughing: 18
• Conjunctivitis: 13
• Hypersalivation: 12
• Foaming from the mouth: 11
• Hypoxemia: 11

Conclusion

• The majority of the laundry pod exposure occurs via oral route and result in no or minor symptoms
• Although rare, respiratory, GI and ocular effect can occur after laundry pod exposure.

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Intravenous lipid emulsion (ILE) is use as a therapy of last resort in refractory cardiovascular shock from toxicity of select agents (e.g. calcium channel blockers, beta blockers and select Na-channel blocking agents). There are number of case reports/series that showed positive cardiovascular/hemodynamic response after ILE, which are prone to publication bias. Results from limited number of human trials  have shown mixed results.

A study reviewed fatal cases of poisoning that received ILE from the National Poison Data System to characterize the clinical response of ILE therapy.

Results

N=459 cases from 2010 to 2015.

Most common substance involved

*Use of ILE supported by Lipid work group

Response rate

• No response: 45%
• Unknown response: 38%
• Transient/minimal response: 7%
• ROSC: 7%
• Immediate worsening: 3%

Possible adverse reactions (n)

• ARDS: 39
• Lipemia: 3
• Failure of CRRT filter: 2
• Worsening/new seizure: 2
• Asystole immediately after administration: 2
• Fat embolism: 1

Conclusion

• The number of failed cases of ILE therapy outnumbers the published cases of ILE success.
• Currently, there is a lack of data that shows the efficacy of ILE therapy.

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Scromboid (histamine fish poisoning) can be easily misdiagnosed since its' clinical presentation can mimic that of allergy. Seen most frequently in the summer and occurring with Scombroideafish (tuna, mackerel, bonito, skipjack) but also with large dark meat fish (sardines and anchovies) and even more commonly with nonscromboid fish such as mahi mahi and amber jack. In warm conditions when fish is improperly refrigerated, bacterial histidine decarboxylase converts muscle histidine into histamine which quickly accumulates. Histamine is heat stable and not destroyed with cooking. 

• Clinical features: Intense flushing of face, neck, and upper torso, urticaria, abdominal cramps, headache, palpitations, diarrhea, nausea, vomiting, burning of the mouth and throat.
• Symptoms begin within minutes of ingestion and typically last several hours
• Self limiting condition. Mainstay of treatment is H1 blockers (antihistamines) and good supportive care. If bronchospam present steroids and inhaled B2 agonists should be administered.

Bottom Line:

Scromboid poisoning is due to histamine ingestion and is often misdiagnosed as allergic reaction. It is preventable with proper fish storage.

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Kratom (Mitragyna speciosa) has been used for centuries in Southeast Asia to manage pain and opium withdrawal. It is increasingly being used in the U.S. for similar purpose. The U.S. DEA lists Kratom as a “drug of concern”.

Effects of Kratom leaves

• 1 – 5 gm: mild stimulatory effects
• 5 – 15 gm: opioid-like effects
• >15 gm: sedative effects

A study reviewed National Poison Data System (2011 to 2017) to evaluate the clinical effects/outcomes of Kratom exposure.

Finding: (N=1807; single-substance: 1174; multiple-substance: 633])

• 2/3 of all exposure occurred in 2016 – 2017 via oral route (83.0%)
• 88.9% were adults (> 20 years old) 
• 86.1% of the exposures occurred in private residence
• Fatality: 11 (2 deaths occurred after an isolated exposure to Kratom)

Common symptoms

• Agitation: 22.9%
• Tachycardia: 21.4%
• Drowsiness/lethargy: 14.3%
• Nausea/vomiting: 13.2% - 14.6%
• Confusion: 10.6%
• Hypertension: 10.1%
• Seizure (single/multiple): 9.6%
• Respiratory depression: 3.6%

Disposition

• Admitted to a health care facility: 31.8% (n=498)
  • Critical care unit: 14.0%
  • Non-critical care: 13.1%
  • Psychiatric facility: 4.7%

Bottom line:

• Kratom use is associated with a wide spectrum of clinical signs/symptoms.
• Death from isolated exposure to Kratom is rare. 

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The primary tenet of poisoning treatment is to separate the patient from the poison. Gastric decontamination has been the cornerstone of poisoning treatment throughout history and methods include induced emesis, nasogastric suctioning, EGD or gastrostomy retrieval, activated charcoal, and whole bowel irrigation. Current guidelines for gastic decontamination are limited to few clinical situations. The detection of residual life threatening poisons in the stomach would be of value in predicting who might benefit from gastric decontamination in overdose.

Plain radiographs have variable sensitvity in detecting radioopaque pills. Computed tomography (CT) has been successful and gained wide acceptance in the detection of drug in body packers. In a recent study, authors studied the usefulness of non-contrast abdominal computed tomography for detection of residual drugs in the stomach in patients  presenting over 60 minutes from acute drug overdose:

• 140 patients were included in this study
• Median ingested drug amounts were 28 tablets or capsules
• Median time until CT scan was performed after drug ingestion was 4 hours
• Multiple types of drugs were ingested in 53.6%
• Sustained-release drugs  were ingested in 17.1 %
• Gastric lavage and WBI were performed on 32.9% patients
• Drugs were detected in 25.7% in the non-contrast CT scan performed over 60 min after ingestion.
• Total duration of hospital stay was significantly longer in the “presence of drugs” group

BOTTOM LINE:

Non-contrast CT may help to predict which patients would benefit from gastric decontamination in acute life-threatening drug poisonings.

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Physostigmine is a cholinergic agent that can be administered to reverse delirium associated with anticholinergic toxicity. However, it is infrequenly used since the reports of cardiac arrest in patients with TCA overdose.

A recently published study reviewed 161 articles – involving 2299 patients – to determine the adverse effects and their frequency after the administration of physostigmine. 

Findings

Adverse effects were observed in 415 patients (18.1%)

• In patients with anticholinergic overdose: 7.7%
• In patients with non-anticholinergic agent overdose: 20.6%

Specific adverse effects

• Hypersalivation: 206 (9%) 
• Nausea/vomiting: 96 (4.2%)
• Seizure: 14 (0.61%)
• Symptomatic bradycardia: 8 (0.35%) – including 3 with bradyasystolic arrest
• Asymptomatic bradycardia: 4 (0.17%)
• Ventricular fibrillation: 1 (0.04%) patient had a history of coronary artery disease
• Cardiac arrest: 4 (0.17%)
• Death: 5 (0.22%)

Of 394 TCA overdose, adverse effects occurred in 14 patients (3.6%)

Conclusion

• Adverse effects from physostigmine occurs infrequently. 
• However, inappropriate dosing or use of physostigmine can result in cholinergic toxicity.
• For isolated anticholinergic toxicity (e.g. antihistamine overdose): physostigmine dosing: 0.5 mg (dilute in 5 – 10 mL normal saline) IV over 2 -5 minutes. May repeat every 5-10 minute to max dose total of 2 mg. (patient needs to be on cardiac monitor with atropine at bedside) 
• Therapeutic goal: reversal of delirium
• Avoid physostigmine in the presence of QRS widening (cardiac Na-channel blockade) and patients with history of underlying coronary artery disease.

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Most clinicians are familiar with use of methylene blue for the treatment of methemoglobinemia, as a urinary analgesic, anti-infective, and anti-spasmodic agent, or for its use in endoscopy as a gastrointestinal dye, but this compound also has a role as a rescue antidote in life threatening poisonings causing refractory shock states and other shock states.

• Nitric Oxide plays an important role in the regulation of vascular tone.
• Metylene blue inhibits the NO-cGMP pathway which decreases vasodilitation and increases responsiveness to vasopressors.
• Several case reports document hemodynamic improvement in recalcitrant shock states form calcium channel and beta blockers despite multiple therapies including vasopressors, glucagon, high dose insulin, and fat emulsion therapy.
• Dosing is 1-2 mg/kg (0.1-0.2 ml/kg) of 1% solution given IV over 5 minutes folllowed by continuous infusion.

Bottom Line: 

Methylene blue should be considered when standard treatment of distributive shock fails. 

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Therapeutic use or overdose of tramadol has been associated with seizure.  However, it is unknown if there are any specific predisposing factor that increases a patient’s risk of seizure after tramadol use/overdose.

In a recently published study, eighty patient data with single ingestion of tramadol were reviewed.

• 52.5% of the patient developed seizure
• 11% developed serotonin syndrome

Risk of seizure

• Higher risk of seizure were found in Asian patients (OR=7.1, 95% CI: 1.9 – 27.3) and patients with abuse/misuse of tramadol (OR=3.2, 95% CI: 1.2-8.3)
• Patients who presented with opioid toxidrome were less likely to develop seizure (OR=0.12, 95% CI: 0.02 – 0.71) 
• Acute overdose and age were not associated with increased risk of seizure.

Conclusion

In this small study, Asian patients and patients with abuse/misuse were at higher risk of developing seizure compared to patients who overdose tramadol.

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Take home naloxone (THN) programs have been expanded to help reduce the opioid overdose-related deaths. A study was done in Australia to characterize a cohort of heroin overdose deaths to examine if there was an opportunity for a bystander to intervene at the time of fatal overdose.

235 heroin-overdose deaths were investigated during a 2 year study period in Victoria, Australia.

• 79% (n=186) of fatality occurred at a private residence
• 83% (n=192) of the decedents were alone at the time of the fatal overdose
• In 34 cases, decedent was with someone else.
  • Half of these witnesses were also significantly impaired at the time of the fatal overdose.
• The opportunity for intervention by a bystander was present in only 19 cases.

Conclusion

1. There was no witness or bystander in majority of overdose deaths.
2. THN alone may only lead to modest reduction in fatal heroin overdose.

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Taking a double-dose of a single medication is presumed to be safe in most cases. However, there is limited data to support this assumption.

A retrospective study of the California Poison Control System was performed to assess adverse effects of taking double dose of a single medication. During a 10-year period, 876 cases of double-dose ingestion of single medication were identified.

Adverse effects were rare (12 cases). However, medication classes that were involved in severe adverse effects included: 

1. Propafenone: ventricular tachycardia and syncope
2. Beta blockers (BB): bradycardia and hypotension
3. Calcium channel blockers (CCB): bradycardia and hypotension
4. Bupropion: seizure 
5. Tramadol: ventricular tachycardia

Conclusion:

• Adverse effect from double dosing is rare.
• Cardiovascular collapse can occur with BB and CCB
• Seizure can occur with tramadol and bupropion.

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Selective serotonin reuptake inhibitors are the most common anti-depressant used today. However, the use bupropion in adolescents is increasing due the belief that it has fewer side effects than TCAs.

Using the National Poison Data System (2013 – 2016), the adverse effects of bupropion were compared to TCA in adolescents (13 – 19 years old) with a history of overdose (self harm). 

Common clinical effects were:

TCA:  n=1496; Bupropion: n=2257

Conclusion:

Bupropion overdose results in significant adverse effects in overdose; however, death is relatively rare.

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Alcohol withdrawal syndrome is frequently treated with benzodiazepines following CIWA-Ar (Clinical Institute Withdrawal Assessment of Alcohol scale). There are other medications that are used as either second line or as adjunctive agents along with benzodiazepines. A retrospective study compared the clinical outcomes between phenobarbital vs. benzodiazepines-based CIWA-Ar protocol to treat AWS. 

The primary was ICU length of stay (LOS); secondary outcome were hospital LOS, intubation, and use of adjunctive pharmacotherapy.

Study sample: 60 received phenobarbital and 60 received lorazepam per CIWA-Ar.

Phenobarbital protocol:

• Active DT: 260 mg IV x 1 dose -> 97.2 mg PO TID x 6 doses -> 64.8 mg PO TID x 6 doses -> 32.4 mg PO TID x 6 doses
• History of DT: 97.2 mg PO TID x 6 doses -> 64.8 mg PO TID x 6 doses -> 32.4 mg PO TID x 6 doses
• No history of DT: 64.8 mg PO TID x 6 dose -> 32.4 mg PO TID x 6 doses.

Results

Conclusion

Phenobarbital therapy appears to be a promising alternative therapy for AWS. However, additional studies are needed prior to adapting phenobarbital as first line agent for AWS management. 

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The management of pediatric hydrocarbon ingestion has not changed significantly over the past several decades. One of the earlier study that helped established the management approach is by Anas N et al. published in JAMA, 1981.

It was a retrospective study of 950 children who ingested household hydrocarbon containing products.

Discharged patients: n=800

• They asymptomatic at their initial presentation and after 6-8 hours of observation.
• All had normal CXR

Admitted patients: n=150

• 79 symptomatic patients at the time of initial evaluation with abnormal CXR.
• 71 patients were asymptomatic but CXR showed pulmonary involvement/pneumonitis or had pulmonary symptoms prior to hospital presentation
• 7 symptomatic patients developed pneumonia

This study recommended that hospitalization is required in patients…

1. Who are symptomatic at the time of initial evaluation
2. Who become symptomatic during the 6-8 hour observation period.

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• History of regular cannabis use at least weekly for any duration of time.
• Compulsive hot water bathing multiple times per day for symptom relief which is mediated by the TRPV capsaicin receptors.
• Resolution of symptoms with cannabis cessation.
• Prior nonrevealing extensive diagnostic work up.

CHS Treatment:

• Definitive and most effective treatment is to stop cannabinoid use which provides complete relief within 7–10 days.
• Temporary relief occurs with hot water bathing, Capsaicin topical cream, Haldol administration, and fluid resuscitation.

Bottom line: Patient education should be provided on the paradoxical and recurrent nature of the symptoms of CHS to discourage relapse of use often stemming from false preception of beneficial effects of cannabis on nausea. 

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Question

A 19 year old male presents confused and very agitated complaining of seeing things and stomach pain. His friends report he ingested a naturally occurring plant to get high a few hours ago but is having a "bad trip".  His physical exam :

Temp 100.3, HR 120, RR 14, BP 130/88. Pulse Ox 98%.

Skin: Dry, hot , flushed

HEENT: Marked mydriasis 6mm

Lungs: Clear

Heart: Tachycardic

Abdomen: Distended tender suprapubic with absent bowel sounds,

Neuro: Extremely agitated pacing, no muscular rigidity.

What has he ingested and what is the treatment?

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Analphylatoid reaction is caused by non-IgE mediated histamine released. Intravenous N-acetylcysteine (NAC) infusion is well known to cause analphylatoid reaction. However, it’s incidence is unknown.

Recently, a large retrospective study of all patients who received 21-hour IV NAC in 34 Canadian hospitals (1980 to 2005) was performed. 

Anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses

• Cutaneous reaction (urticarial, pruritus and angioedema) occurred in 398 (75.4%)
• Systemic reaction (respiratory symptoms or hypotension): 34 (6.4%)
• Both reactions: 96 (18.2%)

Over 90% patients developed analphylatoid reaction within 5 hours.

Onset of reaction: 

• 1^stNAC dosing (150 mg/kg over 1 hour): 133/528
• 2^ndNAC dosing (50 mg/kg over 4 hours): 371/528
• 3^rdNAC dosing (100 mg/kg over 16 hours): 24/528

Administered medication for treatment

• Antihistamine: 371
• Beta-2 agonist: 15
• Epinephrine: 10
• Corticosteroids: 7

Patient characteristics that were associated with higher incidence of Anaphylactoid reaction includes

• Female
• Single acute ingestion
• Low serum acetaminophen level.

Bottom line

1. Anaphylactoid reaction to NAC is uncommon
2. Cutaneous symptoms are most common
3. Female, single acute ingestion and low serum acetaminophen levels are associated with incidence of anaphylactoid reaction. 

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 A 68 year old male presents to the ED complaining of weakness to his legs. He states today his yard chores took him over 2 hours to complete instead of the usual 15-20 minutes due need to take frequent breaks for rest due to leg pain. He denied any chest pain or shortness of breath. Past medical history included hypercholesteremia, HTN,  and CAD. He is taking aspirin and recently started on rosuvastatin.

His physical exam was unremarkable.

Results showed normal EKG and CBC. Bun was 70, Creatinine was 3.4, and CPK of 1025.

This patient has statin induced rhabdomyolysis and acute renal failure.

Take Home Points:

• Rhabdomyolysis is characterized by muscle necrosis which causes the release of myoglobin into the bloodstream.
• Clinical manifestations can range from asymptomatic elevation of CPK to life-threatening cases with extremely high CPK levels, electrolyte imbalance, and acute renal failure.
• Classic triad is: muscle aches and pains, weakness, and tea-colored urine.
• Numerous recreational drugs, pharmaceuticals, and toxins can alter myocyte function. Ethanol, statins, and cocaine in particular have high risk to cause rhabdomyolysis.
• 50% of cases of statin-induced-rhabdomyolysis were due to drug interactions.

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Various intial doses of naloxone (0.4 to 2 mg) are administered to reverse the signs and symptoms of opioid toxicity. However, there is limited data regarding the duration of action of naloxone is correlated to the administered dose.

A recently published retrospective study investigated whether initial naloxone doses (IV), low-dose (0.4 mg) vs. high-dose (1-2 mg), lead to different time to recurrence of opioid toxicity.

Study sample: 274 patient screened but 84 patients were included.

1. Low-dose naloxone (0.4 mg IV): 42
   • Mean age: 50
   • History of opiod/heroin use: 33 (78.6%)
   • Positive opioid/opiate on drug screening: 27 (64%)
   • Median time to repeat naloxone dose: 72 min (IQR: 46 - 139)
   • 12 patients (29%) required continuous naloxone infusion

2. High-dose naloxone (1 - 2 mg IV): 42

• Mean age: 48
• History of opiod/heron use: 32 (76.2%)
• Positive opioid/opiate on drug screening: 26 (62%)
• Median time to repeat naloxone dose: 77 min (IQR: 44 - 126)
• 17 patients (41%) required continuous naloxone infusion

Higher rate of adverse effects (withdrawal symptoms - vomiting, agitation, tachycardia, etc.) were observed in high-dose group (41% vs. 31%) but this was not statistically signficant. 

Conclusion:

1. High-dose naloxone (1 - 2 mg) does not result in longer duration of reversal of opioid toxicity.
2. Duration of opioid toxicity reversal by naloxone administration were similar to previously reported duration of action of naloxone (30 to 90 min).
3. Note: there are several lmitations to the study study including retrospective design - documentation issues, small sample size, patient selection - patients were included if positive response to naloxone was observed, unknown opioid exposure, variable dosing in high-dose group (1 to 2 mg vs. 0.4 mg) and naloxone was given via IV only.   

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