COVID-19 Updates – Co-infections, pediatrics, and ibuprofen

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We are going to try to bring you daily updates on COVID-19. There is a firehose of information and most of us are too busy to read and digest it all. 

Note: If you are listening to these more than a few days in the future, please beware that information may have changed and check subsequent episodes.

Shah, N. Higher co-infection rates in COVID19. https://medium.com/@nigam/higher-co-infection-rates-in-covid19-b24965088333

Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020; doi: 10.1542/peds.2020-0702 


Fang et al. Lancet March 11 wrote that ace-inhibitors should be avoided due to concern for worsening COVID-19 severity. This was immediately debunked by the European Society of Cardiology as without any evidence.

An article in the BMJ, mistaken in the news for a study (which it is not), in addition to comments by the Health Minister in France, created a viral panic to avoid ibuprofen for fever of severity. Initially reports stated the WHO recommended individuals avoid ibuprofen, however 3/18/20, the WHO reversed this statement.



Community Acquired Pneumonia (CAP)

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In this episode, we reivew the evaluation and management of community acquired pneumonia (CAP), including the 2019 guidelines from the Infectious Disease Society of America (IDSA) / American Thoracic Society (ATS) [1].CAP IDS

Regarding Biomarker Recommendation

Regarding the recommendation against using procalcitonin (PCT) to guide decision making to initiate antibiotics in CAP, the guidelines reference an older Cochrane review. The newer review (2017) claims a mortality benefit but combines trials from ICU/ED/primary care that use PCT to both initiate and/or guide antibiotic treatment. Amongst ED trials, the OR was 0.97 (95 CI 0.70,1.36) for 30-day mortality (I2=0%). For all trials combined, the forest plot demonstrates an OR 0.89 (95CI 0.78, 1.01). However, when adjusted this resulted in an aOR 0.83 (95CI 0.70 ,0.99) [2]. A meta-analysis recently published Ebell et al claims of C-reactive protein (CRP), PCT, and leukocytosis, CRP has promising utility in the diagnosis of CAP [3]. However, no single threshold had adequate operating characteristics (for any of the biomarkers), as the sensitivity/specificity trade-off was quite large. The ACEP draft clinical policy for CAP recommends against the use of biomarkers (Level C recommendation)

Regarding Pneumonia Severity Index (PSI) Recommendation

The IDSA/ATS guidelines recommend use of PSI or CURB-65 to identify patients who should be admitted or treated as outpatients. A draft of the American College of Emergency Physicians CAP clincial policy (not yet finalized) did not come to this same recommendation and had a more tempered recommendation – “Use the PSI or CURB-65 CAP mortality decision tools to help identify low-risk patients who may be appropriate for outpatient treatment.” The PSI is long and cumbersome. While it may identify a larger number of patients that can be treated as outpatient, we believe that not all of these test are necessary if you believe a patient can be treated as an outpatient.

References:

  1. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67.
  2. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;10:CD007498.
  3. Ebell MH, Bentivegna M, Cai X, Hulme C, Kearney M. Accuracy of Biomarkers for the Diagnosis of Adult Community-acquired Pneumonia: A Meta-analysis. Acad Emerg Med. 2020; In Press

Top 5 Articles of 2019

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In this episode, we summarize some of our favorite articles from 2019.

Roc vs Sux: Guihard B et al. Effect of rocuronium vs succinylcholine on endotracheal intubation success rate among patients undergoing out-of-hospital rapid sequence intubation: A randomized clinical trial. JAMA 2019 Dec 17; 322:2303. (https://doi.org/10.1001/jama.2019.18254)

This trial may be difficult to interpret as non-inferiority trials operate under a different set of principles than typical superiority studies. An example of how the interpretation may differ had the results varied is seen below

Targeted Temperature Management after Cardiac Arrest: Lascarrou JB, Merdji H, Le gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019.

Probability Adjusted D-Dimer in the Evaluation of PE: Kearon C, De wit K, Parpia S, et al. Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability. N Engl J Med. 2019;381(22):2125-2134. For more on this topic, see this review.

Pregnancy and Evaluation of PE van der pol LM, Tromeur C, Bistervels IM, et al. Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism. N Engl J Med. 2019;380(12):1139-1149.

For more, see this review.

Righini M, Le gal G. Diagnosis of Pulmonary Embolism During Pregnancy. Ann Intern Med. 2019;171(2):148.

Additionally, Langlois E et al. retrospectively evaluated YEARS in their cohort of pregnant patients in the Righini study cohort and found a miss rate of 0%. Some have argued that the DiPEP study demonstrated that the D-dimer cannot be reliably used to exclude PE in pregnant patients (Goodacre. Diagnosis of Suspected Pulmonary Embolism in Pregnancy. Reply. N Engl J Med. 2019;380(25):e49). However, this study was significantly different. Over 60% of patients received empiric anticoagulation which may decrease the D-dimer results. Additionally, this likely reflects a different patient population (higher risk).

The CRASH-3 Trial Collaborators. Effects of Tranexamic Acid on Death, Disability, Vascular Occlusive Events and Other Morbidities in Patients with Acute Traumatic Brain Injury (CRASH-3): A Randomised, Placebo-Controlled Trial. Lancet 2019

VITAMINS Trials – Vitamin C + Hydrocortisone + Thiamine in Septic Shock

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In 2017, Dr. Paul Marik published astonishing results describing one center’s experience implementing the “metabolic cocktail” (Vitamin C 1.5 g q6 hours, hydrocortisone 50 mg q6 hours, thiamine 200 mg q12 hours) in patients with septic shock [1]. News outlets hailed this treatment as a miracle drug. However, this study was a before-and-after single-center study and this trial been discussed elsewhere, including on the Skeptics Guide to Emergency Medicine and Pulmcrit. Essentially all trials have predominantly assessed some variation of length of time on vasopressors as a primary outcome (or one of the primary outcomes), but several have reported on mortality. Now, we have the VITAMINS trial, as detailed below, the first rigorous study to evaluate metabolic resuscitation in a general septic shock population [2].

The authors published their protocol in advance (VITAMINS trial protocol) and appeared to follow it. Despite falling completely flat, this trial may not be sufficient for some individuals to give up belief in this treatment.The VICTAS trial (multicenter blinded RCT in the US) has enrolled ~500 of the 2000 estimated patients (VICTAS trial protocol.).

So, how does this compare in the landscape of Vitamin C? See the table below. Many of the historical studies are not RCTs and the ones that are, many these studies have unclear methods sections or significant design limitations, are small, and have discordant results [3-7].

  1. Marik PE et al. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238.
  2. Fujii et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock The VITAMINS Randomized Clinical Trial. JAMA. 2020: In Press.
  3. Fowler et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. October 1, 2019.
  4. Shin TG, Kim YJ, Ryoo SM, et al. Early Vitamin C and Thiamine Administration to Patients with Septic Shock in Emergency Departments: Propensity Score-Based Analysis of a Before-and-After Cohort Study. J Clin Med. 2019;8(1)
  5. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5(2):94-100.
  6. Habib et al. Early Adjuvant Intravenous Vitamin C Treatment in Septic Shock may Resolve the Vasopressor Dependence. International Journal of Microbiology & Advanced Immunology (IJMAI)j. 2017  05(1), 77-81.
  7. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.

Olanzapine + Benzodiazepines – What is the FDA warning about?

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At ACEP 2019, a talk by Bryan Hayes (@PharmERToxGuy) was captivating. He addressed use of medications with black box warnings in the ED. One particular warning caught our eye – olanzapine + benzodiazepine.

The FDA has warned of the risk of potentially fatal respiratory depression with concomitant administration of antipsychotics and benzodiazepines, stating “Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended.”

References:

  1. Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation. J Clin Psychiatry. 2010;71(4):433-41.
  2. Cole JB, Moore JC, Dolan BJ, et al. A Prospective Observational Study of Patients Receiving Intravenous and Intramuscular Olanzapine in the Emergency Department. Ann Emerg Med. 2017;69(3):327-336.e2.

Vaping Associated Lung Injury (VALI)

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Vaping associated lung injury (VALI) has become a frequent topic in the news in the United States (US). The Centers for Disease Control and Prevention (CDC) has released new guidance for clinicians that we review in this episode. We also discuss problems with widespread concern (potential over-screening and radiation exposure) as well as the available evidence on diagnosis and treatment of VALI.

References:

  1. Morbidity and Mortality Weekly Report (MMWR). 2019; 68(40)
  2. Layden JE, Ghinai I, Pray I, et al. Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin – Preliminary Report. N Engl J Med. 2019; Sept 6.
  3. Maddock SD, Cirulis MM, Callahan SJ, et al. Pulmonary Lipid-Laden Macrophages and Vaping. N Engl J Med. 2019;381:1488-1489.

Emergent Treatment of Hyperkalemia – Insulin/Dextrose

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Insulin is a mainstay in the emergent treatment of hyperkalemia but comes at the cost of increased risk of hypoglycemia, which is quite common.

References:

  1. Scott NL, Klein LR, Cales E, Driver BE. Hypoglycemia as a complication of intravenous insulin to treat hyperkalemia in the emergency department. Am J Emerg Med. 2019;37(2):209-213.
  2. Apel J, Reutrakul S, Baldwin D. Hypoglycemia in the treatment of hyperkalemia with insulin in patients with end-stage renal disease. Clin Kidney J. 2014;7(3):248-50.
  3. Coca A, Valencia AL, Bustamante J, Mendiluce A, Floege J. Hypoglycemia following intravenous insulin plus glucose for hyperkalemia in patients with impaired renal function. PLoS ONE. 2017;12(2):e0172961.
  4. Larue HA, Peksa GD, Shah SC. A Comparison of Insulin Doses for the Treatment of Hyperkalemia in Patients with Renal Insufficiency. Pharmacotherapy. 2017;37(12):1516-1522.
  5. Jacob BC, Peasah SK, Chan HL, Niculas D, Shogbonnwaesei A. Hypoglycemia Associated With Insulin Use During Treatment of Hyperkalemia Among Emergency Department Patients. Hosp Pharm. 2019;54(3):197-202.
  6. Harel Z, Kamel KS. Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review. PLoS ONE. 2016;11(5):e0154963.
  7. Pierce DA, Russell G, Pirkle JL. Incidence of Hypoglycemia in Patients With Low eGFR Treated With Insulin and Dextrose for Hyperkalemia. Ann Pharmacother. 2015;49(12):1322-6.