UMEM Educational Pearls - By Bryan Hayes

In a precursor to a forthcoming international guideline on the management of calcium channel blocker poisoning, a new systematic review has been published assessing the available evidence.

A few findings from the systematic review:

• The majority of literature on calcium channel blocker overdose management is heterogenous, biased, and low-quality evidence.
• Interventions with the strongest evidence are high-dose insulin and extracorporeal life support.
• Interventions with less evidence, but still possibly beneficial, include calcium, dopamine, norepinephrine, 4-aminopyridine (where available), and lipid emulsion therapy.

Stay tuned for the international guideline coming out soon. One treatment recommendation from the new guideline, reported at the 8th European Congress on Emergency Medicine last month, is not to use glucagon.

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Beta-lactam antimicrobials (penicillins, cephalosporins, and carbapenems) are frequently used for empiric and targeted therapy in critically ill patients. They display time-dependent killing, meaning the time the antibiotic concentration is above the minimin inhibitory concentration (MIC) is associated with improved efficacy.

Two new pharmacodynamic/pharmacokinetic studies suggest that current beta-lactam antimicrobial dosing regimens may be inadequate.

• In patients from 68 ICUs across 10 countries, use of intermittent infusions (compared to extended and continuous infusions) and increasing creatinine clearance were risk factors for MIC target non-attainment. [1]
• A second group specifically investigated the pulmonary penetration of piperacillin/tazobactam in critically ill patients and found that intrapulmonary exposure is highly variable and unrelated to plasma exposure and pulmonary permeability. [2]

Antimicrobial dosing in critically ill patients is complex. Current dosing of beta-lactams may be inadequate and needs to be studied further with relation to clinical outcomes.

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Digoxin-specific antibody fragments (Fab) are safe and indicated in all patients with life-threatening dysrhythmias and an elevated digoxin concentration. However, full neutralizing doses of digoxin-Fab are expensive and may not be required (not to mention cumbersome to calculate).

Based on pharmacokinetic modeling and published data, a new review suggests a simpler, more stream-lined dosing scheme as follows:

• In imminent cardiac arrest, it may be justified to give a full neutralizing dose of digoxin-Fab.

• In acute poisoning, a bolus of 80 mg (2 vials), repeat if necessary, titrated against clinical effect, is likely to achieve equivalent benefits with much lower total doses.

• With chronic poisoning, it may be simplest to give 40 mg (1 vial) at a time and repeat after 60 min if there is no response.

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In May 2014, the U.S. Public Health Service released the first comprehensive clinical practice guidelines for PrEP.

Pre-Exposure Prophylaxis (PrEP) has been shown to decrease the risk of HIV infection in people who are at high risk by up to 92%, if taken consistently.

How this applies to the ED patient:

• You may start seeing more patients on only one HIV medication. The PrEP recommendation is once daily emtricitabine/tenofovir (Truvada) 200/300 mg. 
• This is not a therapy that should generally be initiated in the ED as close outpatient monitioring and follow up is essential.

For more information, the CDC has a comprehensive website dedicated to PrEP.

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Since synthetic cannabinoids arrived on the scene, we have become familiar with their sympathomimetic effects such as emesis, tachycardia, hypertension, agitation, hallucinations, and seizures.

Acute kidney injury is also being linked to synthetic cannabinoid use. Several clusters have been described in a handful of states, the most recent coming from Oregon with 9 patients.

AKI seems to be one more adverse effect to be on the lookout for when evaluating patients after synthetic cannabinoid use.

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Despite the lack of strong evidence to support the recommendation, the severity of the 2009 influenza pandemic prompted the World Health Organization (WHO) to advise that higher doses of oseltamivir (150 mg twice daily) and longer treatment regimens (> 5 days) should be considered when treating severe or progressive illness.

So, does the data support higher dosing in critically ill influenza patients?

A new systematic review concluded that "the small body of literature available in humans does not support routine use of high-dose oseltamivir in critically ill patients."

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In a single academic medical center, 273 poisonings required Pediatric ICU (PICU) admission over a 5-year period. This represented 8% of total PICU admissions during that time. Key findings include:

1. Most poisonings occurred in patients either ≤3 years or ≥13 years. 
2. Most admissions were for less than 48 h and 41% were for less than 24 h. Mean PICU length of stay was 1.2 + 0.7 days.
3. Analgesics and antidepressants were the most common substances.
4. 27 patients received mechanical ventilation. 

The majority of poisonings were non-fatal and required supportive care, close monitoring, and some specific treatment. Drug classes causing poisonings have changed to a higher percentage of opioids in younger patients and atypical antidepressants in adolescents.

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Clindamycin used to be a first-line agent for many SSTIs, particularly where MRSA was suspected. With growing resistance to staph species, the 2014 IDSA Guidelines recommend clindamycin as an option only in the following situations:

• Nonpurulent SSTI (primarily strep species)
  • Mild - oral clindamycin
  • Moderate - IV clindamcyin
  • Severe, necrotizing infections - adjunctive clindamycin only with suspected or culture-confirmed strep pyogenes
• Purulent SSTI (primarily staph species)
  • Clindamycin only recommended in moderate or severe cases if cultures yield MSSA

* Clindamycin may be used if clindamycin resistance is <10-15% at the institution.

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Methadone prolongs the QTc interval. Is the degree of QTC widening correlated to worse outcomes after overdose?

The authors of a new study concluded the triage QTc can predict death, intubation, and respiratory arrest. QTc thresholds of 470, 447.5, and 450 msec had sensitivity (95 % CI) and specificity (95 % CI) of 87.5 (47.3-99.7), 86.8 (74.7-94.5), and 77.3 (62.2-88.5), respectively.

My Thoughts

Respiratory depression is the predominant cause of death in methadone overdoses. QTc interval prolongation may have the potential to help predict outcomes, but the QTc thresholds in this study were really not that prolonged. Patients on chronic methadone without overdose have baseline QTc intervals longer than those in this study after overdose.

Application to Clinical Practice

Many factors contribute to the ultimate disposition of methadone overdose cases. Even if QTc widening is correlated to outcomes, it really won't change our management.

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In a prospective cohort of 598 ED patients, 5 risk factors were independently associated with uncomplicated cellulitis patients who fail initial antibiotic therapy as outpatients and require a change of antibiotics or admission to hospital: 

1. Fever (temperature > 38°C) at triage (OR = 4.3, 95% CI = 1.6 to 11.7)
2. Chronic leg ulcers (OR = 2.5, 95% CI = 1.1 to 5.2)
3. Chronic edema or lymphedema (OR = 2.5, 95% CI = 1.5 to 4.2)
4. Prior cellulitis in the same area (OR = 2.1, 95% CI = 1.3 to 3.5)
5. Cellulitis at a wound site (OR = 1.9, 95% CI = 1.2 to 3.0)

Patients presenting with uncomplicated cellulitis and any of these risk factors may need to be considered for observation +/- IV antibiotics.

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A placebo-controlled treatment trial in 26 cocaine-addicted subjects aimed to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). 

Key Findings

• Low-dose dexmedetomidine (0.4 µg/kg) abolished cocaine-induced increases in MAP (+6 ± 1 versus -5 ± 2 mm Hg; P<0.01), but had no effect on HR (+13 ± 2 versus +9 ± 2 bpm; P=ns).  
• Skin sympathetic nerve activity and skin vascular resistance were significantly reduced.
• A higher sedating dose of dexmedetomidine (1.0 μg/kg) was needed to counteract the modest HR rise, but at the expense of increasing BP in one third of patients.

Application to Clinical Practice

In a low nonsedating dose, dexmedetomidine may be a potential (adjunct) treatment for cocaine-induced acute hypertension. However, higher sedating doses can increase blood pressure unpredictably during acute cocaine challenge and should be avoided.

Generous benzodiazepine should remain first-line therapy.

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Four small case series (one prospective, 3 retrospective) have concluded that dexmedetomidine (Precedex) may be a useful adjunct therapy to benzodiazepines for ethanol withdrawal in the ED or ICU. They are summarized on the Academic Life in EM blog.

A new randomized, double-blind trial evaluated 24 ICU patients with severe ethanol withdrawal.

Group 1: Lorazepam + placebo

Group 2: Lorazepam + dexmedetomidine (doses of 0.4 mcg/kg/hr and 1.2 mcg/kg/hr).

• 24-hour lorazepam requirements were reduced from 56 mg to 8 mg in the dexmedetomidine group (p=0.037).
• 7-day cumulative lorazepam requirements were similar.
• Clinical Institute Withdrawal Assessment or Riker sedation-agitation scale scores were similar within 24 hours.
• Bradycardia occurred more frequently in the dexmedetomidine group.

Take Home Points

1. Dexmedetomidine reduced short-term benzodiazepine requirements, but not long-term when using symptom-triggered approach.
2. Monitor for bradycardia when using dexmedetomidine.

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In a 12-week treatment course,150 alcohol-dependent patients were randomized to receive placebo, gabapentin 900 mg/day, or gabapentin 1,800 mg/day.

• The abstinence rate was 4.1% (95%CI, 1.1%-13.7%) in the placebo group, 11.1% (95%CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95%CI, 8.9%-30.1%) in the 1,800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1,800 mg).

• The no heavy drinking rate was 22.5% (95%CI, 13.6%-37.2%) in the placebo group, 29.6% (95%CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95%CI, 31.4%-58.8%) in the 1,800-mg group (P = .02 for linear dose effect; NNT = 5 for 1,800 mg).

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A new study of almost 2 million prescriptions in VA patients compared the risk of cardiovascular death or dysrhythmia in patients receiving azithromcyin, levofloxacin, and amoxicillin.

What they found

Compared with amoxicillin, azithromycin was associated with a significant increase in mortality (HR = 1.48; 95% CI, 1.05-2.09) and dysrhythmia risk (HR = 1.77; 95% CI, 1.20-2.62) on days 1 to 5, but not 6 to 10.

Levofloxacin was associated with an increased risk throughout the 10-day period. Days 1-5 mortality (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac dysrhythmia (HR = 2.43, 95% CI, 1.56-3.79). Days 6-10 mortality (HR = 1.95, 95% CI, 1.32-2.88) and dysrhythmia (HR = 1.75; 95% CI, 1.09-2.82).

Important limitations

This study did not have a comparator group of patients getting no antibiotics. Previous data suggest patients on any antibiotic (eg, penicillin) have a higher risk of death or dysrhythmia.

The supplemental index shows that patients receiving azithromycin and levofloxacin had more serious infections (eg, PNA, COPD, etc.) which may have put them at higher risk for worse outcome irrespective of antibiotic choice.

What it means

It seems azithromycin and levofloxacin may contribute to a small increase in cardiovascular mortality and dysrhythmia during their use. A previous study found this is more likely in those with existing cardiovascular disease.

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In a collaborative effort between the Illinois Poison Center and the Illinois Hospital Association, a new study sought to determine a poison center's effect on hospital length of stay (LOS) and hospital charges.

While the methodology was understandably complex, the authors compared ~5,000 toxicology inpatients with poison center assistance to 5,000 toxicology inpatients without poison center assistance.

After adjusting for confounders, the LOS among patients with posion center assistance was 0.58 days shorter compared to that of patients without poison center assistance (CI 95%: -0.66, -0.51, p<0.001). Though hospital charges for poison center-assisted patients in the lower quintiles were significantly higher than patients without poison center-assistance (+$953; p<0.001), they were substantially lower in the most costly quintile of patients (-$4852; p<0.001).

Poison center assistance was associated with lower total charges only among the most expensive to treat. However, this outlier group is very important when discussing medical costs.

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Background

The ACLS recommendation for epinephrine dosing in most cardiac arrest cases is 1 mg every 3-5 minutes. This dosing interval is largely based on expert opinion.

Primary Outcome

A new study reviewed 21,000 in-hospital cardiac arrest (IHCA) cases from the Get With the Guidelines-Resuscitation registry. The authors sought to examine the association between epinephrine dosing period and survival to hospital discharge in adults with an IHCA.

Methods

• For 6 to <7 min/dose, adjusted OR, 1.41 (95%CI: 1.12, 1.78)
• For 7 to <8 min/dose, adjusted OR, 1.30 (95%CI: 1.02, 1.65)
• For 8 to <9 min/dose, adjusted OR, 1.79 (95%CI: 1.38, 2.32)
• For 9 to<10 min/dose, adjusted OR, 2.17 (95%CI: 1.62, 2.92)

This pattern was consistent for both shockable and non-shockable cardiac arrest rhythms.

• This study only included in-hospital cardiac arrests.
• The data was retrospectively reviewed from a registry of prospectively collected data.
• This is certainly an interesting finding that needs to be explored further.
• Given that epinephrine in cardiac arrest has never been proven to work (and may cause harm), it's not too suprising that giving less of a potentially harmful drug portends better outcomes.

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Seizures can be the presenting manifestation of acute poisoning in children.

A 3-year data set from the Toxicology Investigators Consortium (ToxIC) Case Registry identified 142 cases of drug-induced seizures in children < 18 years old. 75% were teenagers.

Antidepressants were most commonly associated with causing seizures, especially bupropion and citalopram. Diphenhydramine was also a commonly identified cause.

The authors conclude that clinicians managing teenagers presenting with seizures should have a high index of suspicion for intentional ingestion of antidepressants.

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In most situations (dependant on state laws and institutional policies), methadone-maintained patients enrolled in a drug abuse program are best managed by continuing methadone at the usual maintenance levels with once-a-day oral administration.

Pearl: In the event the methadone clinic is closed and/or the dose cannot be verified, 30-40 mg (10-20 mg IM) is generally enough to prevent withdrawal in most patients.

This is only a short-term measure and some patients may require additional methadone. Full doses of methadone should be reinstituted as soon as possible.

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Current evidence does not support the use of fasciotomy or dermotomy following North American Crotalinae envenomation with elevated intracompartmental pressures. [1]

A new case report of a 17-month old bitten by a copperhead snake reinforces that early and adequate administration of crotaline Fab antivenin is the treatment of choice. [2]

Many experts recommend against measuring compartement pressures altogether; we know it will be elevated.

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46 patients treated with high-dose droperidol (10-40 mg) were studied prospectively with continuous holter recording.

What they did

Patients initially received 10 mg droperidol as part of a standardized sedation protocol (for aggression). An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist's discretion.

Continuous 12-lead holter recordings were obtained for 2-24 hours. QTc > 500 msec was defined as abnormal (with heart rate correction - QTcF).

What they found

Only 4 patients had abnormal QT measurements, three given 10 mg and one 20 mg. All 4 had other reasons for QT prolongation. No patient given > 30 mg had a prolonged QT. There were no dysrhythmias.

What it means

There was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.

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