In September 2018, Dr. Bram Rochwerg and I wrote a blog post on the treatment of patients with sepsis and septic shock. Much of this was based on the 2016 Surviving Sepsis Campaign (SSc) Clinical Practice Guidelines . However, in a little over a year, significant new research has already changed the way we care for patients with sepsis and septic shock, highlighting the dynamic and exciting nature of this field. While we await the next SSc guidelines, I will share with you some emerging literature that I hope will help you in the care of patients with septic shock. It would not surprise me if much of this work will be highlighted by the next iteration of the SSc.
Vasopressin – Striving for Second
In the care of patients with sepsis and septic shock, Norepinephrine (levophed) is the vasoactive medication of choice. The use of Norepinephrine as a first-line agent in septic shock is supported by both the SSc, as well as the CAEP consensus guidelines on vasopressor and inotrope use in the Emergency Department [1, 2]. But what happens in the patient with persistent shock despite high doses of norepinephrine? Second-line recommendations are not as clear.
Epinephrine Vs. Vasopressin: SSc has recommended either epinephrine or vasopressin as a second-line agent (weak recommendation). The use of epinephrine is potentially problematic, as it is more arrhythmogenic than norepinephrine, and is associated with increased lactate production . Recent evidence is beginning to support the use of vasopressin among patients with vasodilatory shock, and specifically septic shock. Here’s why:
- Vasopressin was associated with reduced mortality and reduced incidence of new-onset atrial fibrillation in patients with vasodilatory shock . This data comes from a recent high-quality systematic review and meta-analysis published in 2018. New-onset atrial fibrillation in septic shock has been associated with mortality and downstream complications [5, 6].
- Vasopressin may help improve hemodynamics in patients with septic shock, particularly when high-dose catecholamines (such as norepinephrine) are used.
- Based on this existing evidence, the Canadian Critical Care Society recently released a clinical practice guideline making a conditional recommendation for the use of vasopressin in addition to catecholamines for the treatment of vasodilatory shock .
Clinicians caring for patients with septic shock should consider vasopressin as a second-line vasopressor, and may even use it to reduce doses of norepinephrine.
Steroids in Septic Shock – The Pendulum Swings Back
As mentioned in our previous blog, steroids have become a rather contentious issue in the care of patients with septic shock. Initially considered a potential panacea, many began to sour on its use once data began to emerge that steroids did not appear to be beneficial  (Side note: This does NOT refer to patients using regular steroids, as those patients should always be stress-dosed).
However, in early 2018, two major trials were published in the New England Journal of Medicine that together were larger than all previous trials in this area combined – ADRENAL (from Australia and New Zealand) and APPROCCHSS (from France) [9, 10]. The differences between the two trials are outlined below.
- ADRENAL enrolled patients with septic shock, but also receiving invasive mechanical ventilation. They provided hydrocortisone as an infusion, as opposed to the interrupted dosing that is commonly used in trials and clinical practice.
- APPROCCHSS, on the other hand, added fludrocortisone in addition to hydrocortisone, and patients were enrolled within 24 hours of the onset of shock.
- While ADRENAL found no difference in the primary endpoint of 90-day mortality, APPROCCHSS found that use of hydrocortisone and fludrocortisone significantly reduced mortality at 90-days.
- Interestingly, both studies showed that the intervention of steroids was associated with shock reversal and weaning of vasoactive medications.
A recent systematic review and meta-analysis then attempted to combine this new evidence with the many previous trials performed on this topic in the past .
A recent Clinical Practice Guideline, published in 2018 in The BMJ  noted that the benefits appear to outweigh harms, and made a weak recommendation that steroid use should be considered in patients with both sepsis and septic shock.
Vitamin C and the HAT Protocol– The Evidence is Coming
In 2017, our understanding of sepsis and septic shock management changed dramatically when Dr. Paul Marik and his group published their controversial before-and-after study evaluating the use of their HAT cocktail (hydrocortisone, ascorbic acid [aka Vitamin C], and thiamine) in the treatment of patients with septic shock .
- Reduction in organ failure
- Reduction in norepinephrine use
- A remarkable decline in mortality from 40.4% to 8.5%.
Too Good To Be True?
Skepticism appropriately rose to the forefront due to the study’s multiple weaknesses, including the observational, the single-center before-and-after design, and the very small sample size (47 patients in each of the treatment and control groups). Many called for randomized trials to test the efficacy of the treatment .
In October 2019, the first trial was published – CITRIS-ALI . This randomized double-blind trial was conducted at 7 ICUs in the United States, and randomized 167 patients with both septic shock and acute respiratory distress syndrome (ARDS) to either receive an infusion of Vitamin C, or placebo. They importantly did not include the other parts of the HAT protocol (hydrocortisone and thiamine).
- Primary outcome: change in organ dysfunction (measured by the SOFA score) at 96 hours.
- Results: Vitamin C did not result in a statistically or clinically significant difference in SOFA scores at 96 hours
- However, Vitamin C was associated with a statistically significant reduction in mortality at 28-days. This result, albeit highly statistically fragile and one of numerous secondary outcomes, raised the question of how Vitamin C might be associated with reduced mortality despite no improvement in organ dysfunction.
It seems this trial has created more questions than answers. Fortunately, many more randomized trials on this topic are ongoing. Recently published in JAMA was the VITAMINS trial from Australia and New Zealand, which was the first major trial to evaluate the efficacy of the entire HAT protocol. Unfortunately, this was a negative trial demonstrating no significant resolution of shock from the HAT protocol.
Putting It All Together
These studies highlight just a small sample of the major trials in septic shock that have been published in the past year. As the evidence expands, so will our understanding of how to best manage this common but highly lethal disease.
- Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304-377.
- Djogovic D, MacDonald S, Wensel A et al. Vasopressor and Inotrope Use in Canadian Emergency Departments: Evidence Based Consensus Guidelines. CJEM 2015;17 Suppl 1:1-16.
- Myburgh JA, Higgins A, Jovanovska A et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008;34:2226-2234.
- McIntyre WF, Um KJ, Alhazzani W et al. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA 2018;319:1889-1900.
- Walkey AJ, Wiener RS, Ghobrial JM et al. Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA 2011;306:2248-2254.
- Walkey AJ, Hammill BG, Curtis LH et al. Long-term outcomes following development of new-onset atrial fibrillation during sepsis. Chest 2014;146:1187-1195.
- Honarmand K, Um KJ, Belley-Cote EP et al. Canadian Critical Care Society clinical practice guideline: The use of vasopressin and vasopressin analogues in critically ill adults with distributive shock. Can J Anaesth 2019.
- Sligl WI, Milner DA, Jr., Sundar S et al. Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis. Clin Infect Dis 2009;49:93-101.
- Venkatesh B, Finfer S, Cohen J et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018;378:797-808.
- Annane D, Renault A, Brun-Buisson C et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med 2018;378:809-818.
- Rochwerg B, Oczkowski SJ, Siemieniuk RAC et al. Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med 2018;46:1411-1420.
- Lamontagne F, Rochwerg B, Lytvyn L et al. Corticosteroid therapy for sepsis: a clinical practice guideline. BMJ2018;362:k3284.
- Marik PE, Khangoora V, Rivera R et al. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest 2017;151:1229-1238.
- Moskowitz A, Andersen LW, Huang DT et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care 2018;22:283.
- Fowler AA, 3rd, Truwit JD, Hite RD 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 2019;322:1261-1270.
- Fujii T, Udy AA, Deane AM et al. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc 2019;21:119-12