Association of Corticosteroid Treatment With

Outcomes
in Adult Patients With Sepsis

A Systematic Review and Meta-analysis

Authors-FangFang,MD;YuZhang,MD;JingjingTang,BS et al.
Published in JAMADecember21,2018.

• CHAIR PERSON- DR.ASHOK SIR

• CO CHAIR PERSON-DR.ARAVIND SIR
• ASSISTANT PROFESSOR-DR.SURESH SIR
• SENIOR RESIDENT-DR.KARTHIK SIR
• SPEAKER-DR.SHASHANK
 SEPSIS
• Definition- Sepsis is defined as a life-threatening organ
dysfunction caused by a dysregulated host response to
infection
• Sepsis-1, was developed at a 1991 in which SIRS(Systemic inflammatory response syndrome)
criteria were established. Four SIRS criteria were defined, namely

1. tachycardia (heart rate >90 beats/min)

2. tachypnea (respiratory rate >20 breaths/min)

3. fever or hypothermia (temperature >38 or <36 °C)

4. leukocytosis, leukopenia, or bandemia (white blood cells >1,200/mm3, <4,000/mm3 or bandemia

≥10%)
• Sepsis-1 was defined as infection or suspected infection leading to the onset of SIRS.

• Sepsis complicated by organ dysfunction was termed severe sepsis, which could progress to septic
shock.

• Septic shock is defined as “sepsis-induced hypotension persisting despite adequate fluid

resuscitation.”

• Sepsis-2 introduced in 2001 and stated an individual must have at least 2 SIRS criteria and a
confirmed or suspected infection
• In 2016 SCCM/ESICM compared SIRS and SOFA scores

• Sofa score was found to have a higher mortality predictive value than the sirs score.

• Individuals having an initial score of 2 or more having a predictive mortality rate of 10% and
individuals with a score of >14 have a mortality rate of 95.2%

• Recognizing the practical limitations, the 2016 SCCM/ESICM task force described a simplified
method termed

• The “quick SOFA” to facilitate easier identification of patients potentially at risk of dying from
sepsis.
• The qSOFA score consists of 3 parameters

• Respiratory rate ≥22/min - 1point

• Change in mental status – 1point

• Systolic blood pressure ≤100 mmHg – 1point

• A qSOFA score of 2 or more indicates organ dysfunction

• qSOFA was specific but poorly sensitive for organ dysfunction (96.1%, 29.7% respectively)
 Corticosteroid therapy
• Corticosteroid insufficiency has been associated with severe illness.

• American College of Critical Care Medicine (ACCCM) uses the term “critical illness-related corticosteroid
insufficiency” (CIRCI)

• Cortisol deficiency in sepsis is likely multifactorial, usually reversible and results in an inadequate amount
of cortisol at the tissue level.

• Hypothalamic-pituitary-adrenal (HPA) axis dysfunction in critically ill patient

• May be due to alteration in the number or function of glucocorticoid receptors, cortisol metabolism or
access to tissues.

• This may cause unregulated activation of the inflammatory cascade leading to end-organ dysfunction.
• NEED FOR THE STUDY - Although corticosteroids are widely used for adults with sepsis, both the
overall benefit and potential risks remain unclear.

• OBJECTIVE - To conduct a systematic review and meta-analysis of the efficacy and safety of
corticosteroids in patients with sepsis.

• SOURCE-MEDLINE, ENBASE and COCHRANE CENTRAL REGISTER

• INCLUSION CRITERIA –

1. Adults (age ≥18 years)who were diagnosedwith sepsis, severe sepsis, or septic shock, or any
combinations thereof

2. The intervention included any type of corticosteroid administered orally or parenterally

compared with placebo or standard supportive care
• EXCLUSION CRITERIA :-

1. Studies were excluded if they were case reports case series or observational studies

2. The intervention included inhaled or topical corticosteroids

3. All the patients received corticosteroids.

• METHODOLOGY :-

 Followed the Preferred Reporting Items For Systemic Review And Meta Analysis Protocol(PRISMA-
P).

 Randomized clinical trials (RCTs) were selected from the source according to the inclusion criteria.

 9939 studies were selected initially and finally 37 were selected for the meta-analysis after
screening.

 From these 37 studies information on primary and secondary outcomes were obtained and
compared.
• PRIMARY OUTCOME- 28 day mortality rate

• SECONDARY OUTCOME:-
1. 90 day mortality
2. ICU length of stay
3. SOFA score at day 7
4. Time to shock reversal and vasopressor free days
5. In hospital mortality rate
STUDY SAMPLE SIZE TYPE OF Experimental Outcome
PATIENT intervention studied
POPULATION
Annane et 1241 Septic shock Hydrocortison 90 day
al,2018 e 50mg q6h mortality
and oral
fludrocortison
rate
e 50mcg every
24hrs for a
total of 7 days
Venkateshet 3800 Septic shock Hydrocortison 90 day
al,2018 e(200mg)IV mortality
everyday for a
maximum of
rate
7d or until ICU
discharge or
death
Tongyoo et 206 Severe sepsis Hydrocortisone(5 28 day
al,2016 or septic 0mg)q6h for 7d mortality rate
shock
and ARDS

Key et al,2016 380 Severe sepsis Hydrocortisone 14 day shock

bolus(50mg) reversal
followed by a
continuous
infusion of
200mg daily for
3d
Meijvis et 304 CAP and Dexamethasone( Length of
al,2011 sepsis 5mg) hospital stay
intravenously for
4d
 RESULTS

• In this meta-analysis of 37RCTs (including 9564 patients), corticosteroid treatment was significantly
associated with:

• Reduced 28-day mortality

• Reduced ICU mortality

• Reduced in-hospital mortality among patients with sepsis

• Reduced SOFA score at 7 days

• Increase in shock reversal

• Decrease in ICU length of stay

• This meta-analysis also showed no association between significant adverse effects and
corticosteroid treatment

• Corticosteroid administration was associated with an increased risk of hypernatremia and

hyperglycemia.
• STRENGTHS OF THE STUDY:-

1. Explicit eligibility criteria that enhanced generalizability

2. Use of the GRADE approach to rate quality of evidence

3. The meta analysis included more than 8000 patients

4. This study included the 2 largest RCTs available in the literature.

• LIMITATIONS OF THE STUDY

1. Clinical heterogeneity

2. Study might not be powered enough to study adverse events.

• CLINICAL IMPLICATIONS:-

 If fluids and vasopressors are not adequate to maintain BP guidelines suggest the administration of
IV hydrocortisone at a dose of 200 mg per day

 This recommendation was weak recommendation, low quality of evidence

 The findings of the study provide compelling reasons to include corticosteroids as one of the
mainstay treatments

 However, the optimal strategy for the administration of corticosteroids in patients with sepsis is
uncertain.

 Future studies are needed to associate personalized medicine with treatment of sepsis for the
selection of suitable patients who are more likely to show a benefit.
 Comparison with similar studies

• 2009,Annane et al, identified 12 eligible trials and found no significant association of corticosteroid
treatment with 28-day mortality, hospital mortality,or or ICU mortality in severe sepsis or septic
shock

• 2015,Annane et al, published a Cochrane systematic review including a total of 33 trials showed
that cortico-steroid treatment was associated with reduced 28-day mortality
• Volbeda et al, included 35 trials and 4682 patients showed corticosteroids were not sta-tistically
significantly associated with mortality.

• Reygards et al,compared low dose corticosteroids with placebo in adults with septic shock but
found that both short-term and longer-term and longer-term mortality were unaffected by low-
dose cortico
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