Naloxone distribution programs have been expanding to promote the naloxone adminstration by laypersons, usually intranasal (IN) device, to victims of opioid overdose. A recent study analyzed the reports of prehospital naloxone administration reported to a regional poison center.

• 1139 cases of prehospital naloxone administrations were identified between 2015 and 2017.
• 98.2% had ventilatory depression
• 97% were unresponsive
• Law enforcement officers administered 91% of the naloxone, 97.9% via IN route

Opioid toxicity revesal:

• Opioid-induced ventilatory or CNS depression was reversed in 79.2% after administering a mean naloxone dose of 3.12 mg. 
• EMS administered additional naloxone (mean dose: 2.2 mg) to 291 due to lack of or partial reversal of opioid toxicity. 
• 254 out of 291 (92.4%) regained normal/improved mental and ventilatory status.  
• 95.9% of the overdose victims survived.

However, between 2015 and 2017, the reversal rate decreased (82.1% to 76.4%) while mean administered naloxone dose increased (2.12 mg to 3.63 mg). The cause of this trend is unknown but the dose of commercially available IN naloxone kit increased from 2 mg to 4 mg in 2016.

Bottom line:

• IN naloxone administration is an effective intervention to reverse opioid toxicity.
• However, larger naloxone doses were administered between 2015 and 2017 while the reversal rate decreased.
• It is essential for bystander/witness of overdose to notify EMS as overdose victims may require additional naloxone administration/medical attention.

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Since 2013, the availability of fentanyl has been increasing in the illicit drug supply, especially in heroin supply. Fentanyl and its analogs have been responsible for the dramatic increase in opioid overdose death over the past 5 years. 

Two recent cross-sectional studies screened ED patients with opioid use disorder for fentanyl exposure.

Study 1:

• Of 165 patients, urine samples were obtained from 129 participants.
• 80.6% tested positive for fentanyl from urine sample when over 95% reported preference for heroin in the fentanyl positive group.
• 85.7% of the overdose group (n=42) was positive for fentanyl.
• Over 84% recognized fentanyl’s high potency and high risk of death in overdose.
• 29.7% (n=49 of 165) intentionally purchased fentanyl for use.  
• Intentional fentanyl purchase was more common in non-overdose group(34.1% vs. 16.7%).

Study 2: 

• 76 ED patients were screened.
• 83% showed presence of fentanyl in urine.
• 5% reported knowledge of using fentanyl (i.e. intentional use).

Bottom line:

• Fentanyl exposure is common among opioid users in Baltimore
• Up to 30% of ED patients with opioid use disorder intentionally purchase fentanyl although majority recognize the higher risk of overdose death from fentanyl compared to other opioids.

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Many chemicals and substances - both legal and illegal - can be purchased from an online retailer. A recent study searched Amazon.com to see if any of the "extremely hazardaous substances" identified by Environmental Protection Agency (EPA) were available for purchase.

Amazon.com was searched over 10-month period.

Result:

• 79 of 340 substances listed as "extremely hazardous by the EPA were available for purchse. 
• 1/3 of the products/substances possess sufficient dose to be considered toxic in single unit purchase
• Only 4 substances required a bussiness account to be purchase. 

Bottom line:

Toxic substances are readily available from many online retailers that can potentially cause serious toxicity. Online retailers should consult with experts and governmental agencies to limit the availability of such products.

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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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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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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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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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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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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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Elevated transaminases are found in both rhabdomyolysis and delayed acetaminophen (APAP) toxicity. Establishing the cause of elevated transaminase can be difficult when there is unclear history of acetaminophen ingestion.

A retrospective study of patients with delayed acetaminophen toxicity or rhabdomyolysis from 2006 to 2011 was recently published.

The authors compared AST/ALT, CK/AST and CK/ALT ratio of 

• 160 in the rhabdomyolysis group
• 68 in the acetaminophen overdose (all)
• 29 in the delayed acetaminophen overdose group

Results

AST/ALT ratio

• Rhabdomyolysis group: 1.66
• APAP overdose (all): 1.38
• Delayed APAP overdose: 1.3

CK/AST ratio

• Rhabdomyolysis group: 21.3
• APAP overdose (all): 5.49
• Delayed APAP overdose: 3.8

CK/ALT ratio

• Rhabdomyolysis group: 37.1
• APAP overdose (all): 5.77
• Delayed APAP overdose: 5.03

Conclusion

• Significantly higher ratio of AST/ALT, CK/AST and CK/ALT were found in rhabdomyolysis patients than delayed APAP overdose patients.
• These finding are based on small study population and need further validation/research before clinical application.

From 1960s to 1970s, physostigmine was routinely administered as part of the "coma cocktail." Since the publication of two cases by Pentel (1980) that resulted in asystole after administration of physostigmine in TCA poisoned patient, its use has declined significantly.

However, physostigmine still possess limited but clinically useful role in the management of patients with antimuscarinic/anticholinergic induced delirium.

Recently, a prospective observational study was performed in the use of physostigmine when recommended by a regional poison center.

In 1 year study period, physostigmine was recommended by a regional poison center in 125 of 154 patients with suspected antimuscarinic/anticholinergic toxicity. 

common exposures were

1. antihistamines (68%)
2. analgesics (19%)
3. antipsychotics (19%)

57 of 125 patients received physostigmine per treating team.

• median dose of physostigmine administered: 2 mg

Of the remaining patients,

• 35 patients did not receive any sedative agents
• 55 received benzodiazepines (56%)
• others received propofol (n=10), haloperidol (n=8), olanzapine (n=4), dexmedetomidine (n=3), etc.

Delirium control

• Physostigmine group 79% (45 of 57)
• No-physostigmine group: 36% (35 of 97)

Adverse events (physostigmine group vs. non-physo group) - no statistically significant difference.

• Intubation (n=7): 2 (3.5%) vs. 5 (5.2%)
• physical restraints (n=10): 3 (5.3%) vs. 7 (7.2%)
• vomiting (n=4): 3 (5.3%) vs. 1 (1.0%)

Conclusion:

Physostigmine can safely control antimuscarinic/anticholinergic-induced delirium.

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Acutely agitated patients in the emegency room receive single or combination of benzodiazepine (lorazepam vs. midazolam) and antipsychotic (e.g. haloperidol) agents. Recently, use of ketamine has also been advocated to sedate agitated patients.

A recently published article compared IM administration several medications to treat acutely agitated patients in the ED. According to established protocol, each medication was administered in predetermined 3 week blocks:

1. Haloperidol (5 mg)
2. Ziprasidone (20 mg)
3. Olanzapine (10 mg)
4. Midazolam (5 mg)
5. Haloperidol (10 mg)

Results

N=737 with median age of 40 years, 72% men.

Midazolam resulted in greater proportion of patients with "adequate" sedation (altered mentatl status scale <1) compared to antipsychotics at 15 min post administration. Among antipsychotics, olanzapine resulted in greater proportion of patient with sedation. 

• Midazolam (71%)
• Haloperidol - 5 mg (40%)
• Haloperidol - 10 mg (42%)
• Olanzapine (61%)
• ziprasidone (52%)

Adverse effect were limited

• extrapyramidal AE: 0.3%
• hypotension 0.5%
• hypoxemia 1%
• intubation 0.5%

Conclusion:

Midazolam 5 mg IM achieve more effective sedation at 15 min in agitated ED patients than antipsychotics.

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On May 3, the FDA approved adexanet alfa, the reversal agent for factor Xa inhibitors - apixaban and rivaroxaban. It received both U.S. Orphan Drug and FDA Breakthrough Therapy designations. 

Unlike indarucizumab (a monoclonal antibody fragment) to reverse dabigatran (direct thrombin inhibitor) associated bleeding, adexanet alfa is a recombinant modified human factor Xa decoy protein. 

A phase 3 study showed that adexanet alfa decreased the anti-factor Xa activity of rivaroxaban by 92% from baseline and by 94% in apixaban treated participants.

ANNEXA-4 study involving participants with acute major bleeding (GI and intracranial) showed a significant decrease in the anti-factor Xa activity after the bolus dose of adexanet alfa and "effective" hemostasis was noted in 79% of the participants at 12 hours post infusion.

Andexanet alfa is expected to become available in June 2018.