effects of hydrocortisone on development of shock among patients with severe sepsis the HYPRESS Randomized Clinical Trial American Medical Association caring for the critically ill patients Surviving sepsis campaign, to determine weather hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock

1. Effect of Hydrocortisone on
Development of Shock
Among Patients With Severe Sepsis
The HYPRESS Randomized Clinical
Trial
Dr Fakhir Raza Haidri
25-Oct-2016
Keh. JAMA 2016. Published online October 3, 2016.doi:10.1001/jama.2016.14799

2. Introduction

3. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with
septic shock. JAMA. 2002;288(7):862-871.

4. Conclusion
• In our trial, a 7-day treatment with low doses of hydrocortisone and
fludrocortisone significantly reduced the risk of death in patients with
septic shock and relative adrenal insufficiency without increasing
adverse events.

6. Conclusion (CORTICUS)
• Hydrocortisone did not improve survival or reversal of shock in
patients with septic shock, either overall or in patients who did not
have a response to corticotropin, although hydrocortisone hastened
reversal of shock in patients in whom shock was reversed.

8. Conclusion (CIRCI)
• The task force coined the term critical illness-related corticosteroid
insufficiency to describe the dysfunction of the hypothalamic-
pituitary-adrenal axis that occurs during critical illness
• The role of glucocorticoids in the management of patients with
community-acquired pneumonia, liver failure, pancreatitis, those
undergoing cardiac surgery, and other groups of critically ill patients
requires further investigation.

10. Conclusion
• Lancet: Prednisone treatment for 7 days in patients with community-
acquired pneumonia admitted to hospital shortens time to clinical stability
without an increase in complications. This finding is relevant from a patient
perspective and an important determinant of hospital costs and efficiency.
• JAMA: Among patients with severe community-acquired pneumonia and
high initial inflammatory response, the acute use of methylprednisolone
compared with placebo decreased treatment failure.
• Ann intern med: For hospitalized adults with CAP, systemic corticosteroid
therapy may reduce mortality by approximately 3%, need for mechanical
ventilation by approximately 5%, and hospital stay by approximately 1 day

11. Today’s topic

12. Clinical Question
• In patients with severe sepsis does hydrocortisone compared to
placebo prevent the development of septic shock?

13. Method: Design
• Randomised, double-blind, placebo-controlled, multicentre trial
• Internet-based randomisation stratified by participating centre and
sex
• All patients, study personnel, staff were blinded for the entire study
• Intention to treat (and per protocol) analysis
• Assuming 40% of the patients in the placebo group would develop
septic shock, to detect a 15% difference with the intervention arm
(p<0.05, power of 80%), 169 patients per arm were required.
Accounting for a drop out of ~10%, 190 patients per arm (380 total)
were included.

18. Setting
• 34 study sites in Germany
• January 13 2009 to August 27 2013

19. Population
• Inclusion:
• Evidence of infection (1 of: micro-organism identified in normally sterile body
fluid, identified focus of infection, granulocytes in sterile body fluid, clinically
suspected infection without microbiological evidence)
• Evidence of SIRS (2 of: fever >38°C or hypothermia <36°C, tachycardia
>90bpm, tachypnea >20/min or CO2<33mmHg or mechanically ventilated,
leukocytosis >12000/ul or leucopenia <4000/ul or >10% immature forms)
• Evidence of Organ Dysfunction for not longer than 48 hours (1 of:
encephalopathy, AKI, coagulopathy, pulmonary dysfunction, microcirculatory
dysfunction)
• Informed consent possible from patient or NextOfKin

20. Population
• Exclusion:
• Patients with septic shock, ie patients who are hypotensive despite adequate fluid
resuscitation (MAP<65Hg, SBP<90mmHg) or those needing vasopressors for more
than 4 hours. Transient use of vasopressors ok whilst fluid resuscitation occurs.
• Patients with hypersensitivity to the hydrocortisone or placebo (mannitol)
• Patients regularly on glucocorticoids
• Patients with a condition indicating glucocorticoid therapy
• DNR or moribund patients
• <18 years
• Recent trial participation (30 days)
• Pregnant/Breast-feeding
• Related to study personnel

21. Population
• Patients were NOT EXCLUDED for using etomidate or a short course of
glucocorticoids within 72 hours before enrollment OR using topical or
inhaled glucocorticoids
• 9953 patients with severe sepsis or septic shock were screened and
380 randomized to receive hydrocortisone n=190 or placebo n=190

22. Intervention
• Bolus of hydrocortisone iv 50mg followed by a 24 hour continuous
infusion of 200mg for 5 days, 100mg for Day 6 & 7, 50mg on Day 8 &
9 and 25mg on Day 10 & 11
• The continuous infusion was preferred to prevent unwanted undulation in
blood glucose concentrations

23. Control
• The placebo was lyophilized mannitol which was indistinguishable
from the hydrocortisone (133mg mannitol – a tiny dose compared
with therapeutic mannitol for raised ICP = 1g/kg)

24. End point
• Primary End point: development of septic shock within 14 days, or
discharge from ICU

26. Outcome
• Primary outcome: the occurrence of septic shock within 14 days,
which was assessed daily until day 14 or discharge from ICU
• The intention to treat analysis excluded 27 patients – consent issues, septic
shock at inclusion, or did not receive study medication
• In the ITT population: shock occurred in 36/170 (21.2%) patients in the
hydrocortisone group vs 39/170 (22.9%) patients in the placebo group
(p=0.70, Difference= -1.8% 95% CI -10.7% to 7.2%)
• In the per-protocol analysis there was no difference in development of septic
shock
• Subgroup analysis: medical vs surgical patients, pneumonia, those receiving
study medication for> 48hrs did not reveal any benefit for shock prevention

27. Outcome
• Secondary outcome: No differences between groups:
• Time until development of septic shock or death
• Mortality in ICU and hospital
• Vital status at Day 28, 90 & 180
• Duration of ICU and hospital stay
• SOFA score
• Duration of mechanical ventilation
• Renal replacement therapy

28. Outcome
• In 206 patients, baseline cortisol concentration was checked and the level
rechecked following administration of 250ug corticotropin. The primary and
secondary outcomes in this subgroup were evaluated – 33.5% of these
patients had CIRCI (Critical Illness Related Corticosteroid Insufficiency). No
difference in primary or secondary endpoints between patients with or
without CIRCI

29. Outcome
• Adverse events assessed included muscle strength scores, secondary
infection, hyperglycaemia, gastrointestinal bleeding, delirium and weaning
failure. There were more episodes of hyperglycaemia in the hydrocortisone
group but the total amount of insulin delivered was not significantly different.
Delirium was less common in the hydrocortisone group (placebo group 24.5%
vs hydrocortisone group 11.2%, p=0.01). The other adverse events did not
differ between groups.

30. Discussion
Patient Population or Problem:
Intervention (or Exposure): Which medical event or therapy do you
need to study the effect of?
Comparison (if known): With what will you compare the
intervention's results?
Outcomes: What are the relevant effects (outcomes) you'll be
monitoring?

31. Strengths
• An important question: the use of steroids in sepsis and septic shock
is one of the longest running debates in critical care. This trial
uniquely examines the use of steroids to prevent shock in patients
with established sepsis.
• Allocation concealment
• Blinding
• Intention to treat analysis
• <5% lost to follow-up

32. Weaknesses
• Patients who developed septic shock early may have been missed
because informed consent was necessary before randomisation
• The mortality rate in this trial was relatively low (8.5% at Day 28) so
this was a relatively well cohort compared to other sepsis trials
(reflecting the haemodynamic stability of the patients at the time of
randomization)
• Not all patients had baseline adrenal function assessed. Only certain
sites did this test and it needed to be done before randomization
occurred.

33. Weaknesses
• Etomidate was used in 6.3% (placebo group) and 6.8%
(hydrocortisone group) of patients pre-randomization. Etomidate
selectively inhibits adrenal corticosteroid synthesis which may impact
the overall result
• Patients in the placebo arm were more likely to have received
glucocorticoids pre-randomization and at higher doses (3.4% vs 1.7%,
600mg vs 200mg), but the number of patients involved was small.

34. Conclusions
• Among adults with severe sepsis not in septic shock, the use of
hydrocortisone compared with placebo did not reduce the risk of
septic shock within 14 days.
• These findings do not support the use of hydrocortisone in these
patients.