SCCM Resource Library-The Effect of Hydrocortisone Versus Hydrocortisone Plus Fludrocortisone on Shock-Free Days

Video Transcription

Hello, my name is Kayla John, and I am a critical care clinical pharmacy specialist at the University of North Carolina Medical Center.  Today, I'll be talking about the effect of hydrocortisone versus hydrocortisone plus glucocortisone on shock-free days.  I have no actual or potential conflicts of interest in relation to this presentation. To briefly review, sepsis is an overwhelming, dysregulated host response to an infection  resulting in systemic inflammation and activation of pro-inflammatory mediators, which ultimately leads to tissue damage.  It is hypothesized that a subset of patients develop relative adrenal insufficiency as a result of a dysregulated hypothalamic pituitary adrenal axis and therefore have a suboptimal  cortisol production. The most recent surviving sepsis campaign recommends the use of corticosteroids in patients  who remain hemodynamically unstable despite adequate volume resuscitation and vasopressor therapy.  Specifically, they recommend hydrocortisone despite available literature looking at both hydrocortisone and fludrocortisone.  Despite this recommendation and the available literature, the timing, agents, and use of corticosteroids remain somewhat controversial, particularly with the use of fludrocortisone  as an adjunct of therapy to hydrocortisone. The ANON trial was one of the first to investigate hydrocortisone plus fludrocortisone, which  was initiated early within 8 hours of shock onset and demonstrated a mortality benefit in addition to a quicker time-to-shock reversal.  The trials following ANON investigated hydrocortisone at various doses. Corticus trial looked at hydrocortisone at an intermittent dosing strategy initiated  within 72 hours of shock onset, followed by the HYPRS trial, which utilized a continuous infusion of hydrocortisone initiated within 48 hours.  Neither of these trials found a benefit in mortality, and only the Corticus trial found a difference in time-to-shock reversal.  The CORTIS trial, however, is the only study to date that compared hydrocortisone versus hydrocortisone plus fludrocortisone.  However, it is a subgroup analysis and found no difference in mortality or shock reversal.  The most recent trials, ADRENAL and APPROACHES, both looked at initiating hydrocortisone within 24 hours.  However, the APPROACHES trial did include fludrocortisone, and they did find similar results to the original ANON trial, with a mortality benefit and shorter time-to-shock reversal.  From these trials, steroids appeared to lead to quicker shock reversal, decreased vasopressor needs, increased ventilator-free days, and less time in the ICU, particularly if they  were initiated early. Only two of these trials included fludrocortisone, however, leaving its benefit and role as an adjunct of therapy to question.  Which leads us to our research question, does the addition of fludrocortisone to hydrocortisone reduce the duration of shock in patients with septic shock?  To investigate this, we completed a retrospective propensity match analysis at a tertiary academic  medical center within the medical intensive care unit, equating to approximately 80-90 medical intensive care unit beds.  We looked from 2011 to 2020 for these patients admitted, and they had to be 18 to 89 years old, admitted to the medical intensive care unit with a diagnosis of septic shock, and  receipt of hydrocortisone at a dose of greater than or equal to 200 mg per day, initiated within 72 hours of vasopressor initiation or shock onset.  We excluded patients if they were pregnant, incarcerated, had a mixed shock diagnosis per progress note, cardiac arrest or acute myocardial infarction prior to the ICU admission,  had chronic steroid use per admission home medication list, transitioned to comfort care within 24 hours of hydrocortisone initiation, had vasopressors initiated prior to arrival,  received any glucocorticoids for any other reason than septic shock, and had fludrocortisone initiated greater than 24 hours from hydrocortisone.  Our primary outcome was 14-day shock-free days, which is defined as days alive without vasopressor therapy.  If a patient was in shock for 4 days and died on vasopressors, their shock-free days would be 0. If their duration of shock was 4 days and they survived, their shock-free days would  be 10 days. Our secondary outcomes included duration of shock, which we defined as total time on vasopressors,  and they had to be off vasopressors for greater than or equal to 24 hours to be considered hemodynamically stable.  We measured SOFA score from day of steroid initiation to 72 hours, a maximum daily vasopressor  dose from days 1 to 7 in norepinephrine equivalents, hospital and ICU length of stay, and hospital mortality.  We calculated our sample size of 224 patients, assuming a median 11 shock-free days, and we based this on internal data, estimated an 80% power to detect a plus or minus 3-day  difference with a 5% type 1 error rate, equating to 112 patients in each group. Our baseline characteristics were analyzed via descriptive statistics.  Our primary and secondary outcome were estimated from an ANCOVA model adjusted for potential baseline confounders, a logistic regression analysis assessed hospital mortality, and  we completed a propensity score matching analysis utilizing inverse probability of treatment weighting technique based on potential baseline confounders.  We screened 611 patients and excluded 383 patients, with the most common reason being  receipt of systemic glucocorticoids for another indication, followed by a mixed shock diagnosis.  We included 228 patients with 116 in the hydrocortisone group and 112 in the hydrocortisone plus flutricortisone group.  After the inverse probability of treatment weighting, we were left with 111 in the hydrocortisone group and 101 in the hydrocortisone plus flutricortisone group.  Overall, looking at our baseline characteristics, we have both the unadjusted cohort on the left and the inverse probability of treatment weighting adjusted cohort on the right.  We found no differences between the two. Of note, our APACHE2 score with our patient population was approximately 27 to 28, correlating  to about a 50% mortality rate, and had a SOFA score at initiation of about 12.4 in both groups.  Looking at our steroid intervention baseline characteristics, the total duration of hydrocortisone  was similar between the two groups at about 4.9 and 4.8 days, and then the duration of flutricortisone remained the same with a duration of about 4.7 days.  Approximately 50% of patients in each group had hydrocortisone tapered, and then looking  at the time to initiation of hydrocortisone from shock onset was 18 hours in the hydrocortisone group and 15 hours in the hydrocortisone plus flutricortisone group.  The sepsis parameters baseline characteristics, again, no major differences between the two groups, but did want to highlight the time to initiation of antibiotics from the first  fluid bolus was 0.1 hours in both groups, and then the volume of initial fluid bolus within the first three hours standardized for weight was approximately 20 milliliters  per kilogram in both groups as well. Looking at our primary outcome of 14-day shock-free days, we found no difference between the two  groups with about six shock-free days in both groups. One of our secondary outcomes of maximum vasopressor dose, which we censored for survival, meaning  patients who died were excluded in the analysis on each day. So from days one to six, we found no differences between the maximum daily vasopressor dose,  again, in norepinephrine equivalents. However, on day seven, we did find a statistically significant difference between the two groups  with 0.022 micrograms per kilogram per minute in the hydrocortisone group and 0.067 micrograms per kilogram per minute in the hydrocortisone and flutricortisone group.  The remainder of our secondary outcomes had no differences between the two groups with  ICU and hospital length of stay trending to be longer in the hydrocortisone plus flutricortisone  group, and in-hospital mortality was similar between the two groups with about 50% mortality rate.  So in conclusion, we found no difference between hydrocortisone alone and hydrocortisone plus flutricortisone on shock-free days.  We also found no difference in mortality, ICU or hospital length of stay, change in SOFA score from baseline to 72 hours, or duration of shock.  These results suggest that the addition of flutricortisone to hydrocortisone may not shorten the duration of shock, and the use of hydrocortisone alone may be adequate.  However, larger randomized controlled trials are needed to confirm these results. Thank you for your time.

Video Summary

In this presentation, Kayla John discusses the use of hydrocortisone and fludrocortisone in the treatment of septic shock. She reviews the literature on the topic and presents the findings of a retrospective study conducted at a medical center. The study compared the outcomes of patients treated with hydrocortisone alone versus hydrocortisone with fludrocortisone. The primary outcome measured was the number of shock-free days, and secondary outcomes included duration of shock, mortality, and length of stay in the ICU and hospital. The results of the study showed no difference in shock-free days or mortality between the two treatment groups. Further research is needed to confirm these findings.

Asset Subtitle

Sepsis, Pharmacology, 2022

Asset Caption

INTRODUCTION: The aim of this study is to assess the impact of the addition of fludrocortisone to hydrocortisone on shock-free days in patients with septic shock. METHODS: A single-center, retrospective propensity score weighted cohort study was conducted to compare hydrocortisone versus hydrocortisone plus fludrocortisone in patients with septic shock. Adult patients aged 18-89 years admitted to a tertiary academic medical center medical intensive care unit (MICU) from 2015-2020 and diagnosed with septic shock were included if they received ≥200 mg/day hydrocortisone for at least 24 hours ± fludrocortisone initiated within 72 hours of vasopressors. Propensity score matching utilizing inverse probability weighting and trimming was performed. The primary outcome was the number of shock-free days by day 14. Secondary outcomes included duration of shock, change in Sequential Organ Failure Assessment (SOFA) score, maximum daily vasopressor dose in norepinephrine equivalents on days 1-7, hospital and ICU length of stay, and in-hospital mortality. RESULTS: A total of 228 patients met inclusion criteria. 212 patients were retained after propensity score matching with 111 in the hydrocortisone group and 101 in the hydrocortisone plus fludrocortisone group. Three hundred and eighty-three patients were excluded with the most common reasons being receipt of glucocorticoids for any indication other than septic shock during study period (n=139) and mixed shock diagnosis (n=74). After score weighting, there were no significant differences in baseline characteristics between groups. There was no statistical difference between treatment groups in regard to 14-day shock-free days (6.3 vs 6.1 days; p=0.781) or in-hospital mortality (46.7 vs 52.2%, p=0.477). Furthermore, there were no significant differences observed regarding the secondary outcomes of ICU and hospital length of stay, duration of shock, or change in SOFA score. With respect to maximum daily vasopressor doses, days 1-6 were not significantly different, however, day 7 did have a significant difference between the two groups (0.00 vs 0.1 NEeq p=0.03). CONCLUSIONS: The addition of fludrocortisone to hydrocortisone in septic shock did not increase the number of shock-free days. Further studies are needed to assess the clinical utility of these findings.

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Tag Shock

Tag Pharmacology

Tag Corticosteroid

Year 2022

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hydrocortisone

fludrocortisone

septic shock

treatment

retrospective study

Sepsis

Pharmacology

Shock

Pharmacology

Corticosteroid

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2022

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Sepsis Resources

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