UMEM Educational Pearls

ACE-inhibitor (ACEi) induced angioedema is mediated by bradykinin and there are no proven medications for the treatment of this disease. Theoretically, a C1-esterase inhibitor (C1INH) could be beneficial; however, data has not demonstrated any efficacy for these agents.  

Strassen et al. recently published a double-blind, randomized, controlled, multicenter trial of 30 patients comparing C1NH (Brand Name: Berinert) to placebo. In addition to standard treatment, a dose of C1INH (Berinert) 20 IU/kg or placebo (0.95% NaCl) was administered intravenously.

The primary endpoint was the time to complete resolution of signs and symptoms of edema (TCER). When compared to placebo, the original primary analysis demonstrated that the placebo arm (15 hours) resolved faster than the C1INH arm (24 hours, p=0.046).

This study is further evidence against the use of C1INH for ACE-inhibitor induced angioedema. The primary focus in the treatment of ACEi induced angioedema should continue to be airway management.

For reference, at our institution we have both C1INH (Berinert) and icatibant on formulary and they are restricted to only being used for acute hereditary angioedema attacks and cannot be used for ACEi induced angioedema.

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Otitis media is a common pediatric complaint seen in the primary care, urgent care, and ED settings. Recommendations for timing of treatment and deferral of treatment have emerged over the last several years, as have recommendations for regimens for recurrent infections in the age of resistant organisms.

When to consider observation over antibiotics:

• If symptoms <48 hours, no severe pain, and fever < 39C and child is 2 years or older (either unilateral or bilateral AOM) OR unilateral AOM with symptoms <48 hours, no severe pain, and fever < 39C and child is 6 months to 2 years
• If observing, consider either a prescription that parents can fill if symptoms persist or ensure prompt primary care follow up

Initial treatment

High dose amoxicillin (90 mg/kg/day divided BID)

• If true penicillin allergy, can use cefdinir or cefpodoxime if tolerated or trimethoprim-sulfamethoxazole or a macrolide (e.g. azithromycin) but rates of resistance are higher
• Cefdinir and azithromycin are the most commonly used  
• Levofloxacin is also an option for age >8 years

Recurrent Otitis Media

If less than 30 days from initial treatment, presumed to be persistent

• If previously on amoxicillin, start amoxicillin-clavulanate (extra strength suspension has highest amoxicillin to clavulanate ratio and should be used)
• If previously on amoxicillin-clavulanate, ceftriaxone either for 3 days or 2 doses 36 hours apart

If greater than 30 days from initial treatment can treat as new episode (so amoxicillin unless previous documented resistant infections)

Duration of Antibiotics

• Less than 2 years, 10 days
• 2 years and up, 5-7 days

Other Considerations

• Amoxicillin-clavulanate should be used as an initial agent if there is concurrent purulent conjunctivitis
• Children with tympanostomy tubes and purulent otorrhea may be treated with otic fluoroquinolones (with or without dexamethasone), as long as debris does not obstruct entry of antibiotic drops
• Remember that the otic canal and TM can become red with fever and non-purulent effusion is common with URI
• Remember to treat pain and fever!

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When managing a hypotensive patient who may have some element of cardiogenic shock, it has long been debated whether it is better to start an inodilator like dobutamine, and use a true vasopressor like norepinephrine to offset the vasodilation, or start an inopressor like epinephrine.  Currently, this is largely a practice pattern issue, with different providers and specialties tending to make different choices (in my anecdotal experience, medical intensivists tend to do norepi+dobutamine, whereas cardiac surgeons and intensivists tend to use epi).  

Banothu et al recently studied this question in children with "cold" septic shock (they do not specify how this was defined) and found quicker time to resolution of shock with norepi+dobutamine vs epinephrine.  It should be noted that this was a secondary outcome, was a small study, was in children (who I'm told are not just little adults), and no difference in mortality or patient oriented outcomes was found.  However, this is a good opportunity to review what is known on this topic:

-A small RCT in Lancet 2007 by Annane et al found no difference

-A very small RCT in Acta Pharmacologica Sinica 2002 by Zhou et al suggested norepi-dobutamine has favorable effects on gastric mucosa and tissue oxygenation relative to epi or dopamine

-A small RCT in Intensive Care Medicine 1997 similarly suggested that oxygenation in the splanchnic circulation may be better with norepi+dobut than epi.

Take Home: There is very limited evidence in either direction when choosing between an inodilator + vasopressor (e.g. norepi + dobutamine) vs single inopressor (e.g. epi) strategy for a hypotensive patient in which inotropy is desired.  There is some weak evidence that norepi + dobutamine may be better for maintaing gut oxygenation and may resolve shock faster.  Personally, I would weakly recommend norepi + dobutamine over epinephrine, but continuing to follow provider preference and go with the agent(s) you're most comfortable with is also very reasonable.  If using the inodilator/vasopressor combination, it is recommended to titrate the vasopressor (e.g. norepi) to MAP and inodilator (e.g. dobutamine) to a measure of cardiac function such as CO/CI.  

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Missing blunt cervical vascular injuries can lead to delayed catastrophic sequela such as stroke. Usie the epanded Denver criteria to help you identify these injuries.

Expanded Denver criteria for BCVI

-Signs/symptoms of BCVI

Potential arterial hemorrhage from neck/nose/mouth
Cervical bruit in patient less than 50 years old
Expanding cervical hematoma
Focal neurologic defect: TIA, hemiparesis, vertebrobasilar symptoms, Horner's syndrome
Neurologic deficit inconsistent with head CT
Stroke on CT or MRI

-Risk factors for BCVI

High-energy transfer mechanism
Displaced midface fracture (LeFort II or III)
Mandible fracture
Complex skull fracture/basilar skull fracture/occipital condyle fracture
Severe TBI with GCS less than 6
Cervical spine fracture, subluxation, or ligamentous injury at any level
Near hanging with anoxic brain injury
Clothesline type injury or seat belt abrasion with significant swelling, pain, or altered mental status
TBI with thoracic injuries
Scalp degloving
Thoracic vascular injuries
Blunt cardiac rupture
Upper rib fractures

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In a recent study in The Lancet, researchers at NIH attempted to test the hypothesis that optimal hydration may slow down the aging process. 

A large proportion of people do not consume the recommended fluid amounts. This has likely become worse with our masking during the pandemic.

Previous studies in a mouse model showed that water restriction, increasing serum sodium by 5 mmol/l, shortened the mouse lifespan by 6 months which corresponds to about 15 years of human life.

Population:  Data from Atherosclerosis Risk in Communities (ARIC) study: an ongoing population-based prospective cohort study in which 15,792 45-66 year-old black (African American) and white men and women were enrolled from four US communities in 1987–1989 and followed up for more than 25 years.

Variables:  15 biomarkers and serum sodium (as a proxy for the hydration habits of study participants).

They attempted to exclude people whose serum sodium could be affected by factors other than the amount of liquids they consume. After these exclusions, 11,255 participants remained in the datase.

Authors also calculated ones biologic age by sampling 15 biomarkers characterizing performance of multiple organ systems and processes: cardiovascular (systolic blood pressure), renal (eGFR, cystatin-C, urea nitrogen, creatinine, uric acid), respiratory (FEV), metabolic (glucose, cholesterol, HbA1c, glycated albumin, fructosamine), immune/inflammatory (CRP, albumin, beta 2-microglobulin).

Conclusions: The analysis showed that middle age serum sodium >142 mmol/l is associated with a 39% increased risk to develop chronic diseases (hazard ratio [HR] = 1.39, 95% confidence interval [CI]:1.18–1.63) and >144 mmol/l with 21% elevated risk of premature mortality (HR = 1.21, 95% CI:1.02–1.45). People with serum sodium >142 mmol/l had up to 50% higher odds to be older than their chronological age (OR = 1.50, 95% CI:1.14–1.96).

Limitations:  Observational study. No firm conclusions without intervention studies.

Summary: Serum sodium concentration exceeding 142 mmol/l is associated with increased risk to be biologically older, develop chronic diseases and die at younger age.

Take home:  Drink more water

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An Uncommon Cause of Shock

• Sepsis is the most common cause of distributive shock encountered in the emergency department and intensive care unit.
• Notwithstanding, it is important to consider other etiologies of shock, especially when the patient is not responding to resuscitation.
• Adrenal crisis is one uncommon etiology of distributive shock whereby the diagnosis is often delayed.
• Risk factors for adrenal crisis can include recent GI illness, thyrotoxicosis, recent surgery, and physical or psychological stress.
• Patients often have nonspecific symptoms of generalized weakness, abdominal pain, vomiting, fever, and altered mental status.
• Current guidelines recommend the administration of 100 mg of hydrocortisone in adults suspected of having adrenal crisis.   

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At this month’s Eastern Association for the Surgery of Trauma annual meeting there was a presentation asserting that hemodynamically unstable trauma patients have worse outcomes when intubated in the emergency department vs the operating room. This was not a study diminishing the intubating skills of EM providers but a look at the fact that hemorrhaging patients will crash after intubation and if they are not in a position for immediate surgical intervention they will die. The loss of sympathetic tone, positive inter-thoracic pressure, loss of muscle tone as well as the agents used all contribute to peri-intubation arrest. This month’s EmCrit episode tackled this topic as well. 

Synthesizing all of the opinion and literature regarding hemodynamically unstable trauma patients requiring operative intervention the take home points are:

1. Resuscitate with mass transfusion and TXA
2. If the OR is ready, do nothing else but facilitate rapid transfer to the OR
3. If there is a delay in going to the OR, carefully monitor the patent's work of breathing and CO2. If they are tiring or have normal or rising CO2 then intubate.
   1. Weingart suggests that Ketamine dissociative intubation is the safest and most physiologic neutral way to accomplish airway control in these patients. (A skill that must be practiced!)
   2. Consider push dose pressors at the time of intubation

Much of this is counter to historical teaching of early airway management on ED arrival. It certainly fits with recent literature supporting resuscitation prior to airway management whenever feasible. 

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Should EMS place an advanced airway in out of hospital cardiac arrests?  Current studies suggest that advanced airway management is not superior to BVM in pediatric out of hospital cardiac arrest (OHCA).  

Pediatric OHCA carries a high mortality rate and those that do survive often have a poor neurologic outcome.  This study evaluated BVM vs supraglottic airway (SGA) placement vs endotracheal intubation (ETI) in relation to one month survival and favorable neurological outcomes.  SGA and ETI were also grouped together and categorized as advanced airway management (AAM).

This study was conducted using the Pan Asian Resuscitation Outcomes Study Clinical Research Network.  3131 pediatric patients were included.  85% received BVM, 11.8% SGA and 2.6 % ETI.  In a matched cohort, one month survival and survival with favorable neurological outcome was higher in the BVM group compared to the AAM group and in the BVM group compared to the SGA group.  There was no significant difference noted between the ETI group and BVM group.

Bottom line: In this study, AAM was associated with decreased one month survival and less favorable neurological status in pediatric OHCA.

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A systemic review and meta-analysis revealed that the literature and science surrounding timing and effectiveness of prophlactic antibiotic use in tube thoracotomy for trauma is not robust.  The heterogeneity of the antibiotics used, the duration of antibiotics and the nature of the trauma (majority penetrating) make it very difficult to give an iron clad recommendation. The authors conclusion, which is the practice management guideline from the Eastern Association for the Surgery of Trauma, ultimately was:

“We conditionally recommend that antibiotic prophylaxis be given at the time of insertion to reduce empyema in adult patients who require TT for traumatic hemothorax or pneumothorax.”

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Humor me and imagine that your birth certificate vanished, and your age was based on the way you feel inside. How old would you say you are (subjective age) versus your actual age?

In a few studies, those individuals reporting a younger subjective age had a lower risk of depression, greater mental well-being, better physical health, and a lower risk of dementia. These individuals also had improved episodic memory and executive functioning. Subjective age also predicts incident hospitalization.

Three longitudinal studies tracked more than 17,000 middle aged and elderly individuals.

Over a 20-year period, researchers tracked:  Subjective age, demographic factors, disease burden, functional limitations, depressive symptoms, and physical inactivity.

Researchers found that those who felt approximately 8, 11, and 13 years older than their actual age had an 18%, 29%, and 25% higher risk of mortality, respectively. They also had a greater disease burden even after controlling for demographic factors such as education, race and marital status. Multivariable analyses showed that disease burden, physical inactivity, functional limitations, and cognitive problems, but not depressive symptoms, accounted for the associations between subjective age and mortality.

This study provides evidence for an association between an older subjective age and a higher risk of mortality across adulthood. These findings support the role of subjective age as a biopsychosocial marker of aging. This may allow for early intervention for select individuals who may have a higher association with poor health outcomes.

Your subjective age can better predict your overall health than the date on your birth certificate.

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Title:

The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study

Settings: 4 hospitals (3 in Netherlands and 1 in Italy)

Participants: All adults patients who were admitted to the ICU but patients who died within 8 hours of thoracic ultrasound were excluded.

Thoracic ultrasound procedure: cardiac, lung, diaphragm, inferior vena cava. The main indicators were Respiratory, Cardiac and Volume status.

Study Results:

725 thoracic ultrasound examinations and 534 patients.  Clinical management occurred in 247 (88.5%) patients within 8 hours of ultrasound.

Thoracic ultrasound was performed by 111 operators, ranging from inexperienced to very experienced.

Common findings from thoracic ultrasound among these ICU patients.

• Atelectasis 233 (32.1%)
• Pleural effusion 221 (30.5%)
• Pulmonary edema 120 (16.6%)
• Pneumonia 107 (14.8%)

Discussion:

• There was a major impact in fluid management.
  • Patients who needed more fluid (N=63) would have a balance of +907 ml within 8 hours.
  • Patients who need euvolemia (N = 28) would have a balance of +80ml within 8 hours.
  • Patients who need less fluid (N=45) would have a balance of -411ml within 8 hours.
• There was no information regarding management change according the experience of the operators.
• The authors did not assess patient-centered outcomes from these management changes.

Conclusion: Thoracic ultrasound provided a significant change in management of critically ill patients.

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These two pieces from Becker’s Hospital Review demonstrate significant areas of weakness within the American healthcare system. Hospitals that care for underserved as well as medically and socially complicated patients should be afforded protection and financial security. Not only do they care for the most complex patients, they often educate the next generation of health care providers. 

The loss of small community or rural hospitals also has a major negative impact on the US health care system. For time sensitive conditions such as trauma, myocardial infarction or stroke these facilities are often the first, closest facility to initiate care or stabilization. The loss of these critical smaller hospitals also adds to the burden at already overwhelmed larger facilities. 

As medical providers, we are in a unique position to advocate for our patients, our co-workers and our communities. Join your professional societies (ACEP, AAEM, SAEM etc.), write your local and national representatives, find like minded colleagues, please get involved with the process any way you can.  As a nation we can not afford to lose large essential hospitals or small critical access, rural hospitals.

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Magnesium has been associated with function of serotonin and vascular tone regulation, both of which are mechanisms that implicate there may be a role in treatment of migraine. As this is a well-tolerated medication with a good safety profile, there is interest in utilizing this medication in the treatment of migraines. However, studies comparing magnesium to standard migraine treatments are lacking.

A recent single-center, double-blinded, randomized controlled trial compared magnesium, metoclopramide and prochlorperazine for treatment of migraine in the ED. Patients received either magnesium sulfate 2 grams, metoclopramide 10 mg or prochlorperazine 10 mg intravenously over 20 minutes. Adjunctive and rescue medications could be used at the providers discretion.

Pain was assessed with the 11-point Numeric Rating Scale at baseline and at several timepoints after completion of the infusion. Median change in pain score was found to be -3 in all groups at 30 minutes. Post-hoc analysis found magnesium to be non-inferior to prochlorperazine and metoclopramide at this time point. No difference in ED length of stay was found between groups. Adverse events were reported in 5% of patients receiving magnesium, 4.5% in patients receiving metoclopramide and 11.5% in prochlorperazine patients (p = 0.51). The most common adverse events were dizziness, akathisias, and anxiety.

Bottom Line: Magnesium can be used as an adjunctive agent in the treatment of migraines, and may also be considered as an alternative agent when other options such as prochlorperazine and metoclopramide are not appropriate. A reasonable dose would be 2 grams IV infused over 20 minutes. The team should follow-up 30-60 minutes after infusion to assess response to therapy.

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Pelvic fractures caused by large force compression (open book) and vertical sheer injuries can lead to life threatening massive hemorrhage from arterial injury, venous injury (most common), bone bleeding or muscle hemorrhage. Advanced Trauma Life Support and many other trauma organizations recommend pelvic binding be applied after the secondary survey is complete. This should preferentially happen in the pre-hospital envirnonment. The literature has not shown a mortality benefit to pelvic binding. One reason that external compression has not been shown to be of benefit is the high percentage of incorrectly applied compression devices. Commercial pelvic compression devices are superior to the old sheet method. If the device is not applied with maxim compression over the greater trochanters the benefit of pelvic compression is lost.

Beser et al. demonstrated in their recent study in the Journal of Trauma Nursing that it takes about 8 attempts to learn to properly place the binder over the greater trochanters. This adds to the literature that appropriate education and continuing education is needed to assure that these devices are appropriately applied.

It is this pearl author’s recommendation that new EMS, nursing and ED and trauma provider staff receive training on these devices with repetitive application until proficient and that yearly competency be performed to maintain our skills in this low frequency potentially high yield procedure.

Open to thoughts and comments.

Happy New Year!

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Universal Human Rights

• Human rights are rights inherent to all human beings, whether our nationality, place of residency, sex, national or ethnic origin, color, religion, language defines , or any other status 

• The United Nations Human Rights Council (UNHRC) defines seven substantive rights: the right to life, freedom from torture, freedom from slavery, right to a fair trial, freedom of speech, freedom of thought, conscience and religion, and freedom of movement 

• The right to life is the essential right that a human being has a right not to be killed by another human being. This has been central in debates on issues of abortion and euthanasia. 

• Emergency care is an often overlooked, but essential component of the right to life in the highest attainable standard of health and universal health coverage (UHC - a WHO description used to describe access to care). Particularly for vulnerable and disadvantaged populations, emergency care is often the last chance for the health system to save a life.

• The focus on vulnerable populations with little access to care and subsequent poor health outcomes has many similarities to the delivery of emergency care. Emergency conditions, such as traumatic injuries, disproportionately affect people in low- and middle-income countries. About 90% of the burden of death and disability from injuries occurs in low- and middle-income countries

• COVID-19 emphatically highlighted how far countries (and differences in regulations between states in the US) are from meeting the supreme human rights command of non-discrimination, from achieving the highest attainable standard of health that is equally the right of all people everywhere, and from taking the human rights obligation of international assistance and cooperation seriously. 

•  Implementation of a rights-based framework for emergency care requires countries to enact legislation that ensures access to non-discriminatory emergency care and establish a regulatory body with appropriate oversight and authority to enforce these laws.

In this retrospective chart review, 3720 admitted trauma patients with rib fractures were looked at for 30 day readmission. 206 patients in the group were readmitted within 30 days.

The authors concluded:

In patients with traumatic rib fractures, those with anticoagulant use, those who actively smoke, those with a psychiatric diagnosis, or those with associated abdominal injuries are at the highest risk of re-hospitalization following discharge. 

While this study is retrospective and looks at patients that were sick enough to be admitted, it is a good reminder that patients with rib fractures can have high morbidity and mortality and it gives us certain patient populations in which to show extra concern.

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Over half of U.S. adults in the United States consume dietary supplements. 

Study design:  A quality improvement study using data from the FDA’s Center for Drug Evaluation and Research, Tainted Products Marketed as Dietary Supplements

Dates:  2007 through 2016. 

Results:  Unapproved pharmaceutical ingredients were identified in 776 dietary supplements.

146 different dietary supplement companies were involved.

Most of these products were marketed for sexual enhancement (353 [45.5%]), weight loss (317 [40.9%]), or muscle building (92 [11.9%].

157 adulterated products (20.2%) contained more than 1 unapproved ingredient.

A 2015 NEJM study estimated that 23,000 ED visits per year are attributed to adverse effects associated with dietary supplements.

Estimated 2154 hospitalizations annually.

Frequently involve young adults between 20 and 34 years of age in addition to unsupervised children.

Excluding children, almost 66% of ED visits involve herbal or complementary nutritional products and 31.8% involved micronutrients.

Products for weight loss or increased energy were commonly implicated.

Finally, herbal and dietary supplements now account for 20% of cases of hepatotoxicity in the US.

The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements.

Anabolic steroids (marketed as bodybuilding supplements) typically induce a prolonged cholestatic, self-limiting liver injury.

Green tea extract and many other products, in contrast, tend to cause an acute hepatitis like injury.

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Thrombolytic-induced angioedema is a known complication of alteplase or tenecteplase administration, occurring in 0.9-5.1% of patients who received thrombolytics due to ischemic stroke. Angioedema occurs due to activation of the kinin and complement pathway by plasminogen, leading to both bradykinin and histamine release.

Swelling most commonly occurs acutely while the t-PA is infusing, but can have a delayed presentation up to 24 hours post administration. It normally has an orolingual distribution, although in severe cases there can be laryngeal involvement as well. There is a 4-fold-increase occurrence in patients who take ACE inhibitor medications ^[1] with some studies noting a high prevalence in strokes involving the right insular brain region ^[2].

Once identified, the t-PA infusion should be immediately discontinued. As there may be histamine involvement in angioedema formation, patients are initially treated with steroids, H1, and H2 blockers with as needed epinephrine injections.

Given the orolingual predominance, airway obstruction must be ruled out and the patient closely monitored with emergent intubation performed if necessary.

As the kinin pathway (bradykinin) appears to play the largest role in angioedema formation, C1 esterase inhibitors and bradykinin inhibitors can be used in severe or refractory cases ^[3,4].

However, most cases are mild and resolve with t-PA discontinuation and the initial steroid and histamine blockade.

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The use of a serratus anterior plane nerve block has previously been described as effective for anterior and lateral rib fracture pain control. A new, small study by Singh et al. shows efficacy in using this block for posterior rib fractures as well.

The reference link to the ACEPNow website shows how to perform this block using ultrasound guidance.

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