April 2017 E-Journal Club
Greetings,
We hosted 3 wonderful trainees in April who hailed from Columbia, SC; Oklahoma City, OK and Calgary, Canada. Our journal club article this month has attracted quite a bit of attention recently, to the point that it has gained mention in the popular press (1,2).
April Citation:
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. 2016 Dec 6.[Epub ahead of print]
Summary:
This was a before-after cohort study of 94 total adult medical ICU patients admitted with severe sepsis or septic shock, to investigate the effectiveness of a combination of intravenous hydrocortisone, vitamin C and thiamine within 24 hours of ICU admission. Study patients received parenteral vitamin C (1.5 gm every 6 hours X 4 days or until ICU discharge), hydrocortisone (50 mg every 6 hours X 7 days, or until ICU discharge) and thiamine 200 mg every 12 hours X 4 days or until ICU discharge. The control population was a cohort of similar patients admitted in the 6 month period prior to adopting the corticosteroid-vitamin protocol. Patients during the control period could receive hydrocortisone (50 mg every 6 hours) at the discretion of attending physician.
The primary study outcome was hospital survival. Secondary outcomes included the duration of vasopressor therapy, requirement for renal replacement therapy, ICU length of stay and change in procalcitonin and SOFA score over the first 72 hours.
Statistical adjustments for baseline differences between the control and treatment groups was attempted using a propensity score that included age, weight, gender, APACHE 4 score, mechanical ventilation requirement on admission, vasopressor requirement, WBC count, serum lactate, procalcitonin and creatinine.
Inclusion and Exclusion Criteria:
Inclusion criteria:
Consecutive adult medical ICU patients with a diagnosis of severe sepsis or septic shock and a procalcitonin ≥2 ng/ml admitted between January 2016 and July 2016.
Exclusion criteria:
Patients < 18 years of age, pregnant, or with limitations of care.
Major Results:
There were 47 patients in each group. Baseline characteristics and predicted mortality of the 2 groups were similar. Twenty-eight (59.6%) of the control patients received hydrocortisone as part of their care. Only 22 patients in each group (47%) met the criteria for septic shock, and were treated with vasopressor agents. In the 22 treatment group patients that had a baseline vitamin C checked, the mean vitamin C was 14.1 ±11.8 umol/l (normal 40-60 umol/l) and no patient had a normal vitamin C level.
The hospital mortality was significantly less in the treatment group (8.5%, 4 patients) compared to the control group (40.4%, 19 patients) (p < 0.001). The authors reported that none of the treatment group who expired succumbed to the direct effects of sepsis, but all 4 were made “comfort care” after they left the ICU. Logistic discriminant analysis identified the vitamin C protocol, APACHE IV Score and need for mechanical ventilation as independent predictors of mortality. There was no significant difference in the number of patients that developed AKI between the treatment and control group, but there were significantly less patients with AKI in the treatment group that required renal replacement therapy, compared to the control group (3 (10%) treatment group versus 11 (37%) control group, p=0.02). The 24-hour and 72-hour fluid balances were not different between the groups.
The mean duration of vasopressor therapy was significantly less in the treatment group (18.3 ± 9.8 hours treatment versus 54.9 ± 28.4 control group, p<0.001). The 72-hour decrease in SOFA score was significantly greater in the treatment group compared to the control group (4.8 ±2.4 treatment versus 0.9 ±2.7 control group, p<0.001). The median 72 hours procalcitonin clearance was significantly greater in the treatment group (86.4%) compared to the control group (33.9%)(p<0.001).
The median ICU length of stay was not significantly different between the groups.
Author’s Conclusions:
“…the early use of intravenous vitamin C, together with moderate-dose hydrocortisone and thiamine may prove to be effective in preventing progressive organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock…”
Evaluation:
This was a single-center, unblinded cohort study with a very small number of patients to investigate outcomes in critically ill patients. The history of critical care in the past 30 years is filled with examples of treatments for critically ill patients that looked promising in small studies, which turned out to be unhelpful, or even harmful once studied in adequately large randomized studies.
Certainly, it is possible that this combination of parenteral vitamins and corticosteroid could have dramatic benefits, but the results of the current study seem too good to be true, since they suggest that no one who is treated with parenteral vitamin C, thiamine and hydrocortisone will die of sepsis. It will take much larger studies before we can know if the effect is real, if all of the vitamin/corticosteroid components of the treatment group are necessary, or what the optimal doses may be.
I recommend that you read over the news stories via the links listed in the references below. There are some quotes and thoughts from several different physicians that are worth reading.
Our Take Home Message(s)
- This study is too small to make strong conclusions regarding the safety and effectiveness of this parenteral vitamin/corticosteroid combination in patients with sepsis and septic shock.
- This study does provide support for the need to conduct a larger, multicenter, randomized study.
- Future studies should investigate if all of the components of the parenteral vitamin/corticosteroid protocol are necessary, and, if effective, what are the ideal doses.
References:
- http://www.npr.org/sections/health-shots/2017/03/23/521096488/doctor-turns-up-possible-treatment-for-deadly-sepsis (downloaded 5/16/2017)
- http://www.npr.org/sections/health-shots/2017/03/30/521918863/why-the-newly-proposed-sepsis-treatment-needs-more-study (downloaded 5/16/2017)
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
Upcoming Webinars 2017:
June 6: Critiquing Critical Care Guidelines by Joe Krentisky, MS, RD
Latest Practical Gastroenterology article: Pancreatogenic Type 3c Diabetes: Underestimated, Underappreciated and Poorly Managed
Joe Krenitsky MS, RDN
PS – Please feel free to forward on to friends and colleagues.