UMEM Educational Pearls

The much anticipated REMAP-CAP trial was epublished ahead of print July 12th in Intensive Care Medicine.  It was an RCT investigating four antiviral strategies in critically ill adults with COVID-19: lopinavir-ritonavir, hydroxychloroquine, a combination of the two, and no antiviral therapy (control group).  

Despite the hype around protease inhibitors, hydroxychloroquine, and other unproven therapies in COVID (lookin at you next, Ivermectin...), all three strategies had WORSE outcomes than placebo.  They all decreased organ-support-free days (all reaching statistical significance), which was the primary outcome.  They also all led to longer ICU time, longer time to hospital discharge, and reduced 90 day survival.  Not only does this study show no benefit, it shows fairly convincing signs of harm to these therapies.

Bottom Line: Protease inhibitors (e.g. lopinavir-ritonavir) and hydroxychloroquine are unproven therapies for critical COVID-19 infection, and are not recommended.  Providers should focus on interventions with demonstrated benefit, most notably steroids and good supportive/critical care.  

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Low dose ketamine was compared  to morphine for the treatment of patients with long bone fractures

126 patients with upper and lower extremity long bone fractures were divided into two treatment groups

1. IV morphine at a dose of 0.1 mg/kg
2. IV ketamine at a dose of 0.5mg/kg

Pain scores were compared pre and at 10 minutes post treatment

Pain severity significantly decreased in both groups to a similar degree

Increase adverse effects (emergence phenomenon) noted in ketamine group but all effects resolved spontaneously without intervention.

Conclusion:  Analgesic effect of ketamine is similar to morphine in patients with long bone fractures.

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Hemophagocytic Lymphohistiocytosis (HLH)

• HLH is a hematologic disorder that results from overactivation of the immune response (macrophages and cytotoxic T cells).
• HLH is often underrecognized and has a mortality that can be as high as 75%.
• Secondary HLH is most commonly associated with infection (sepsis), malignancy (lymphoma), and autoimmune disorders (SLE, RA).
• Hallmark features of HLH include fever, splenomegaly, hepatomegaly, cytopenias, coagulopathy, elevated ferritin, elevated triglycerides, and decreased fibrinogen levels.
• ED resuscitation of patients with suspected HLH includes Hematology consultation, treatment of the underlying disorder (infection), and potentially corticosteroids and chemotherapeutic agents.

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NSAIDs for lower back pain (LBP)

NSAIDs are recommended for first line treatment of lower back pain.

Ibuprofen (600mg), ketorolac (10mg) and diclofenac (50mg)  were compared.

3 arm, double-blinded study in an ED population with musculoskeletal LBP.

66 patients in each arm.

Outcomes via telephone interview 5 days later

Primary outcome was improvement in Roland-Morris Disability Questionnaire (RMDQ).

Lower scores indicate better LBP functional outcomes.

Secondary outcomes:  Pain intensity and the presence of stomach irritation.

Baseline characteristics similar in 3 groups.

Results:  No significant differences between 3 arms in primary outcome.

Ibuprofen 9.4, ketorolac 11.9, and diclofenac 10.9 (p = 0.34).

Ketorolac group reported less overall pain intensity at day 5.

Ketorolac group reported less stomach irritation that the other drugs ((p < 0.01).

While there was no differences in terms of functional outcomes, there may be a benefit of using ketorolac in terms of overall pain intensity and stomach irritation. This would benefit from further study in a larger population in order to draw definitive conclusions.

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Canada legalized recreational cannabis use in 2017. A retrospective study of children (0-18 years) who presented to pediatric ED with cannabis intoxication/exposure was performed between Jan 1, 2008 to Dec 21, 2019 to assess the trend/severity of intoxication.

Methods

• Single center study: Hospital for Sick Children, Toronto
• Case identification by ICD 10 code for cannabis intoxication and positive urine drug screening test
• Pre-legalization period was defined as 1/1/2008 to 4/12/2017
• Peri-post legalization period was defined as 4/13/2017 to 12/31/2019

Result

A total of 298 patients were identified

• Pre-legalization period: 232 (77.8%)
• Peri-post legalization period: 66 (22.1%)
• Male: 150 (50.3%)
• Median age: 15.9 years (IQR: 15.0-16.8) 

Respiratory symptoms: tachypnea/bradypnea, cyanosis, O2 sat < 92%, bronchospasm, oxygen requirement

• Edible ingestion was a predictor of ICU admission (OR: 4.1; 95% CI: 1.2-13.7)

Conclusion

• Legalization of recreational cannabis in Canada was associated with increased rates of severe intoxication in children.

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Despite the knowledge that minimizing interruptions in chest compressions during CPR is key to maintaing coronary perfusion pressure and chance of ROSC,^1-4 difficulties in limiting hands-off time remain. 

Dewolf et al.⁵ recently performed a prospective observational study using body cameras to find that 33% (623/1867) of their CPR interruptions were longer than the recommended 10 seconds:

• 51.6% Rhythm/pulse checks
• 11.1% Installation/use mechanical CPR device
•   6.7% Manual CPR provider switch
•   6.2% ETT placement

Previous studies have shown an increase in hands-off time associated with the use of cardiac POCUS during rhythm checks as well.^6,7

Bottom Line:

• Physicians must be mindful of hands-off time to improve their chance of obtaining ROSC, minimizing each CPR interruption to <10 seconds, and maintaining a hands-on time (also known as chest compression fraction) of >80%. 
• Change your pulse check to a rhythm check utilizing arterial line placement, end-tidal monitoring, or US/doppler at the femoral artery in order to minimize the search for a pulse as a reason for prolonged CPR interruption.
• Consider having someone on the team count the seconds out loud during pauses so the entire team is aware of the interruption time and will recognize when CPR needs to be resumed.

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Settings: International multicenter trials; 1:1 randomization, blinded assessment of outcomes.

Patients: adults with witnessed OHCA, regardless of initial rhythm.  Patients had more than 20 minutes of CPR.  Eligible patients were unconscious, not able to follow command, no verbal responses to painful stimuli.

Intervention: hypothermia to target of 33C for 28 hours, then rewarming at rate of 1/3C every hour until  37C.

Comparison: maintaining temperature at 37.5C or less.  Cooling if body temperature reached 37.8C to 37.5C

Outcome: primary outcome was Any cause mortality at 6 months; secondary outcome was poor functional outcome at 6 months (modified Rankin Scale 4-6).

Study Results:

1. 930 hypothermia, mortality 465/925 (50%, RR 1.04, 95%CI 0.94-1.14); 488/881 (55%) had mRS 4-6 (RR 1.0, 95%CI 0.92-1.09).

2. 931 normothermia, mortality 446/925 (48%); 479/866 (55%) had mRS 4-6.

Discussion Points:

• Hypothermia would lead to higher rates of arrhythmia-related hemodynamic instability.
• More studies reinforced that preventing fever is beneficial.
• ED clinicians will not have to rush to cool patients while awaiting for ICU beds (Yay).

Conclusion:

Normothermia in coma patients after OHCA did not lead to higher morality or worse neurologic outcomes.

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You are covering a sporting event or working an ED shift when a young adolescent athlete without significant PMH presents with SOB and wheezing associated with exercise.

You immediately think exercise-induced asthma, prescribe a short-acting bronchodilator and pat yourself on the back.

While you may be right, there is increasing recognition of an alternative diagnosis

Exercise-induced laryngeal obstruction (EILO)

During high intensity exercise, the larynx can partially close, thereby causing a reduction in normal airflow. This results in the reported symptoms of SOB and wheezing.

This diagnosis has previously been called exercise induced vocal cord dysfunction. As the narrowing most frequently occurs ABOVE the level of the vocal cord, EILO is a more correct term.

While exercise induced bronchoconstriction has a prevalence of 5-20%, EILO is less common with a prevalence of 5-6%.

Patients are typically adolescents, with exercise associated wheezing and SOB, frequently during competitive or very strenuous events. Wheezing is inspiratory and high-pitched. Symptoms are unlikely to be present at time of medical contact unless you are at the event as resolution occurs within 5 minutes though associated cough or throat discomfort can persist after exercise cessation. EIB symptoms typically last up to 30 minutes following exercise.

Inhaler therapy is unlikely to help though some athletes report subjective partial relief. This may be explained as approximately 10% of individuals have both EIB and EILO.

In athletes with respiratory symptoms referred to asthma clinic, EILO was found in 35%.

Consider EILO in athletes with unexplained respiratory symptoms especially in those with ongoing symptoms despite appropriate therapy for EIB.

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A recent prospective observational study examined the diagnostic usefulness of head-to-pelvis sudden death computed tomography (SDCT) in 104 patients with ROSC and unclear OHCA etiology.

• Obtained within 6 hours of hospital arrival
• Noncontrast head CT + ECG-gated chest CTA with abbreviated coronary imaging + contrasted CT of the abdomen to just below the pelvis. 

Diagnostic performance: 

• Detected 95% of OHCA etiologies diagnosable by CT
• Detected 98% of time-critical diagnoses requiring emergent intervention (including complications of resuscitation)
• The sole reason for diagnosis of OHCA etiology in 13%

Safety:

• 28% of patients with elevated creatinine at 48h (down from 55% at presentation; study excluded GFR < 30ml/min unless treating provider felt the data was needed for care)
• 1% (1 patient) required RRT 
• No false positives noted, no allergic contrast reactions, 1 contrast IV extravasation

Bottom Line: For OHCA without clear etiology, SDCT explicitly including a thoracic CTA may have diagnostic benefit over standard care alone with the added benefit of identification of resuscitation complications. 

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Hand elevation test

• Hand elevation has been known to reproduce the symptoms of carpal tunnel syndrome.

• This phenomenon prompted the idea of developing a simple hand elevation test to diagnose carpal tunnel syndrome. 

• To perform: Ask the patient to elevate both arms in the air for one minute. Hands are raised actively and without strain, keeping the elbows and shoulders relatively loose.

• A positive test reproduces symptoms of carpal tunnel syndrome. 

• The hand elevation test has a high sensitivity (75-86%) and specificity (89-98.5%) and may be comparable to or likely better than other provocative tests.

https://www.youtube.com/watch?v=IO2qC5qHVFE

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• The landscape of acute ischemic stroke treatment changed dramatically with endovascular thrombectomy (EVT).
• However, few patients with basilar artery occlusions were included in major EVT trials.
• Basilar artery occlusion accounts for 10% of large vessel occlusions and can result in devastating neurological deficits.
• The recently published BASICS trial evaluated the efficacy of EVT within 6 hours of symptom onset in 300 patients with basilar artery occlusion strokes.
• 44.2% of the EVT group had a good outcome compared to 37.7% of the medical treatment group (p=0.19).
  • Good outcome was defined as modified Rankin scale of 0 (no symptoms) to 3 (moderate disability but able to walk without assistance) at 90 days.
  • Symptomatic intracranial hemorrhage was higher in the EVT group (4.5% vs. 0.7%, p=0.06).
  • History of AFib was more common in the EVT group (28.6% vs. 15.1%).
• It is important to note that this study did not use advanced neuroimaging for patient selection unlike in landmark EVT trials of anterior circulation large vessel occlusion strokes.

Bottom Line: There is no significant difference between endovascular thrombectomy and medical management for basilar artery occlusion strokes within 6 hours of symptom onset. 

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A recent pilot study was conducted in two centers (Mayo Clinic & Cleveland Clinic Affiliate) and aimed to evaluate if the administration of oral midodrine in early septic shock could decrease the use of IV vasopressors and decrease ICU and hospital length of stay (LOS).  The study was a placebo-controlled, double blinded randomized trial.

This study enrolled:

• 32 adult patients 
• within 24 hours of Sepsis 3 definition who continued to have hypotension (MAP < 70mmHg) after antibiotic & 30mL/kg IVF administration
• 3 doses of midodrine 10mg were administered

The study did not find a statistical difference between the two groups in the use of vasopressors or ICU/Hospital LOS. However, there was a trend in the midodrine group which is suggestive of decreased vasopressor use and ICU/Hospital LOS. 

It is Important to note the study was not powered to determine clinical significance. Overall the trend noted in the midodrine group should encourage further studies that are clinically powered to determine if there is a statistical difference and therefore a potential benefit to early initiation of oral midodrine in septic shock.

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 Vancomycin infusion reactions can manifest as pruritus and an erythematous rash of the neck, face, and torso during or after a vancomycin infusion.  This is a histamine reaction caused by degranulation of mast cells and basophils, and can be caused short infusion times <60 min.  It is commonly treated with antihistamines and/or a slowing of the infusion rate. 

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Norepinephrine is widely considered the first-line vasopressor for patients in septic shock.  Vasopressin is often added to norepinephrine in patients requiring escalating doses, but when to add vasopressin, and what exactly the benefit is (as opposed to just further titrating up the norepinephrine) remain unclear.  Given the limited evidence for a patient-oriented benefit and the increasing cost of vasopressin, some centers are becoming more judicious in the use of vasopressin.  A systematic review in AJEM October 2021 examined the literature on early (< 6 hours of diagnosis) addition of vasopressin to the management of septic shock patients, compared to either no vasopressin or starting it after 6 hours.

Improved with early vasopressin: Need for renal replacement therapy (RRT; secondary outcome)

No difference: mortality, ICU length of stay, hospital length of stay, new onset arrhythmias

Bottom Line: When, and if, to start vasopressin in patients requiring escalating doses of norepinephrine remains controversial.  Based on the prior VASST trial, many providers will start vasopressin when norepi doses reach ~ 5-15 mcg/min (approx 0.1-0.2 mcg/kg/min), but there remains limited data to support this practice, and either starting vasopressin or continuing to titrate the norepinephrine as needed are both reasonable approaches in most patients.

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Question

What is the mechanism of action of N-acetylcysteine that is used to treat acetaminophen induced liver injury/toxicity?

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Refractory Anaphylaxis

• Refractory anaphylaxis is defined as anaphylaxis that does not respond to at least 2 doses of 300 mcg of epinephrine given IM into the anterolateral thigh.
• Refractory anaphylaxis can be due to several factors including patient comorbidities, delayed diagnosis, delayed epinephrine administration, or concomitant beta-blocker or ACE-inhibitor medication use.
• Consider the following treatments in patients with refractory anaphylaxis, persistent hypotension, and shock:
  • Aggressive IVF resuscitation - patients may need up to 7L of IVFs
  • Epinephrine infusion (1-10 mcg/min) to target a MAP of 65 mm Hg
  • Glucagon (1-5 mg via slow IV push) for those taking a beta-blocker and who fail to respond to epinephrine
  • Norepinephrine, vasopressin, angiotensin II, methylene blue, or dobutamine can be administered with epinephrine for persistent hypotension. 
  • VA-ECMO - though there is no prospective evidence on the use of ECMO in anaphylaxis.

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During cardiac arrest, metabolic acidosis develops because of hypoxia-induced anaerobic metabolism and decreased acid excretion caused by inadequate renal perfusion.  Sodium bicarbonate (SB) administration was considered as a buffer therapy to correct metabolic acidosis.  However,  SB has several side effects such as hypernatremia, metabolic alkalosis, hypocalcemia, hypercapnia, impairment of tissue oxygenation, intracellular acidosis, hyperosmolarity, and increased lactate production.  The 2010 Pediatric Advanced Life Support (PALS) guideline stated that routine administration of SB was not recommended for cardiac arrest except in special resuscitation situations, such as hyperkalemia or certain toxidromes.  An evidence update was conducted in the 2020 Pediatric Life Support (PLS) guideline and the recommendations of 2010 remain valid.  This article was a systematic review and meta-analysis of observational studies of pediatric in hospital cardiac arrests.  The primary outcome was the rate of survival to hospital discharge after in hospital cardiac arrests. The secondary outcomes were the 24-hour survival rate and neurological outcomes.   

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