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.

Droperidol (and Haloperidol)

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Droperidol received a black box warning from the US Food & Drug Administration (FDA) in 2001.

 

More on droperidol
Taming the SRU
The Short Coat

References:

  1. Khokhar MA, Rathbone J. Droperidol for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2016;12:CD002830.
  2. Calver L, Drinkwater V, Gupta R, Page CB, Isbister GK. Droperidol v. haloperidol for sedation of aggressive behaviour in acute mental health: randomised controlled trial. Br J Psychiatry. 2015;206(3):223-8.
  3. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56(4):392-401.e1.
  4. Braude D, Soliz T, Crandall C, Hendey G, Andrews J, Weichenthal L. Antiemetics in the ED: a randomized controlled trial comparing 3 common agents. Am J Emerg Med. 2006;24(2):177-82.
  5. Meek R, Mee MJ, Egerton-warburton D, et al. Randomized Placebo-controlled Trial of Droperidol and Ondansetron for Adult Emergency Department Patients With Nausea. Acad Emerg Med. 2019;26(8):867-877.
  6. Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache. 2006;46(5):781-7.
  7. Gaffigan ME, Bruner DI, Wason C, Pritchard A, Frumkin K. A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department. J Emerg Med. 2015;49(3):326-34.
  8. Leong LB, Kelly AM. Are butyrophenones effective for the treatment of primary headache in the emergency department?. CJEM. 2011;13(2):96-104.
  9. Calver L, Page CB, Downes MA, et al. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2015;66(3):230-238.e1.
  10. Jackson CW, Sheehan AH, Reddan JG. Evidence-based review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64(11):1174-86.
  11. Habib AS, Gan TJ. Pro: The Food and Drug Administration Black box warning on droperidol is not justified. Anesth Analg. 2008;106(5):1414-7.
  12. Rappaport BA. FDA response to droperidol black box warning editorials. Anesth Analg. 2008;106(5):1585.
  13. Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of Emergency Medicine Position Statement: Safety of Droperidol Use in the Emergency Department. J Emerg Med. 2015;49(1):91–7.

Thromboelastography (TEG) Guided Resuscitation

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Thromboelastography (TEG) or its related counterpart rotational thromboelastometry (ROTEM) have gained in popularity over the past several years. These tests assess viscoelastic clot strength in whole blood. These tests may offer more granular and potentially reliable information on the patient’s clot formation and fibrinolytic state than traditional measures of coagulation such as International Normalized Ratio (INR), partial thromobplastin time (PTT), and prothrombin time (PT).

One of the primary advantages to TEG/ROTEM is the ability to target transfusion related therapies to the patient’s overall coagulation profile. Below are some common patterns that emerge and the recommended therapies.

Evidence for TEG in Cirrhosis

Additional FOAM resources: PulmCrit

References:

  1. Wikkelsø A, Wetterslev J, Møller AM, Afshari A. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev. 2016;(8):CD007871.
  2. Kumar M, Ahmad J, Maiwall R, et al. Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial. Hepatology. 2019; In Press
  3. Rout G, Shalimar, Gunjan D, et al. Thromboelastography-guided Blood Product Transfusion in Cirrhosis Patients With Variceal Bleeding: A Randomized Controlled Trial. J Clin Gastroenterol. 2019; In Press.
  4. Goodman MD, Makley AT, Hanseman DJ, Pritts TA, Robinson BR. All the bang without the bucks: Defining essential point-of-care testing for traumatic coagulopathy. J Trauma Acute Care Surg. 2015;79(1):117-24.

You are called to the bedside for a postoperative patient who is hypotensive, febrile, and has acute onset of respiratory distress following the initiation of a blood transfusion. Which of the following is the most appropriate initial action in the management of this patient?

A. Apply oxygen

B. Call the blood bank

C. Order steroids

D. Stop the transfusion

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Transfusion-related acute lung injury is a blood transfusion complication characterized by a rapid onset of non-cardiogenic pulmonary edema. The pathogenesis is thought to be a two-part mechanism involving neutrophil sequestration with priming in the lung microvasculature followed by neutrophil activation by a factor in the blood product. Pre-transfusion risk factors include current smoking, chronic alcohol use, liver transplantation surgery, positive fluid balance, shock, and higher ventilated peak airway pressures. Though there is an association of transfusion-related acute lung injury with all blood products, high-plasma-volume products (plasma, apheresis platelet concentrations, and whole blood) have the greatest risk. Clinical presentation may occur immediately after the initiation of the blood transfusion although it can be delayed up to six hours. The patient may rapidly develop acute respiratory distress syndrome, with symptoms that may include hypoxemia, fever, hypotension, cyanosis, pulmonary infiltrates on chest imaging, and if intubated, pink frothy secretions when suctioned. Treatment involves immediate discontinuation of the transfusion followed by supportive care of the acute respiratory distress syndrome. This includes oxygen supplementation and hemodynamic support. Apply oxygen (A), call the blood bank (B), and order steroids (C) are treatments for transfusion-related acute lung injury but are not the most appropriate in the initial management. Discontinuing the transfusion, which is the cause of the acute lung injury, is the immediate need upon identifying the condition.

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Top Literature of 2019 – Mid Year Review

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Risk Stratification and D-dimer in Pregnant Patients With Suspected Pulmonary Embolism (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.

Infectious Disease Society of America (IDSA) Guidelines for Asymptomatic

Nicolle LE, Gupta K, Bradley SF, et al. Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2019.

Benzodiazepine dosing for seizures

Sathe AG, Tillman C, Coles LD, et al. Underdosing of benzodiazepines in patients with status epilepticus enrolled in Established Status Epilepticus Treatment Trial. Acad Emerg Med. 2019 Jun 4.

  • Outcomes after Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in Trauma Patients

Joseph B et al. Nationwide analysis of resuscitative endovascular balloon occlusion of the aorta in civilian trauma. JAMA Surg 2019. Mar 20.

Additional References:

  1. Brophy GM, Bell R, Claasen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-13.
  2. Glauser T, Shinnar S, Gloss D, et al. American Epilepsy Society Guideline Evidence-Based Guideline: Treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61.