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INDEX SUPPLEMENTAL MATERIAL:

Figure S1 Flow diagram of retrieved trials.

Figure S2 Bias risk assessment.

Figure S3 All steroid trials evaluating mortality at longest follow up; forrest plot with

subgroups according to risk of bias (a. fixed-effect model); trial sequential

analyses (b. 10% relative risk reduction, and c. 20% relative risk

reduction).

Figure S4 All steroid trials evaluating mortality at longest follow up, stratified on

short versus long course steroid treatment; forrest plots (a. fixed effect; b.

random effect); trial sequential analyses (c-d. short course and e-f. long

course treatment).

Figure S5 All steroid trials evaluating mortality at longest follow up, stratified on

disease severity; forrest plots (a. fixed effect; b: random effect); trial

sequential analyses (c-d SIRS and sepsis and e-f severe sepsis and septic

shock).

Figure S6 Serious adverse events of all trials evaluating steroids for sepsis; forrest

plot with subgroups according to risk of bias (a. fixed-effects model); trial

sequential analysis (b.).

Figure S7 All steroid trials evaluating mortality at 30 days follow up; forrest plots (a.

fixed effect; b. random effect); trial sequential analyses (c. power 90%

anticipated RRR 10%; d. power 80% anticipated RRR 20%).

Figure S8 All steroid trials evaluating mortality at 90 days follow up: forrest plots

(a. fixed effect; b. random effect); trial sequential analysis (c. power 90%

anticipated RRR 10%).

Figure S9 High dose steroid trials evaluating mortality at longest available follow up:

forest plots (a. fixed effect; b. random effect); trial sequential analysis (c.

power 90% anticipated RRR 10%).

Figure S10 High dose steroid trials evaluating mortality at longest follow up; stratified

on disease severity; forrest plots (a. fixed-effect; b: random-effects); trial

sequential analyses (c-d. SIRS and sepsis and e. severe sepsis and septic

shock).

Figure S11 High dose steroid trials evaluating serious adverse events; forrest plot (a.

random-effects model); trial sequential analysis (b. power 90% anticipated

RRR 90%).

Figure S12 Low dose steroid trials evaluating mortality at longest follow-up; forrest

plot (a. fixed-effects model); trial sequential analyses of all low dose

steroid trials (b. 10% relative risk reduction, c. 20% relative risk

reduction); trial sequential analyses of lower risk of bias trials (d. power

90% anticipated RRR 90%; e. power 80% anticipated RRR 80%).

Figure S13 Low dose steroid trials evaluating mortality at longest follow up, stratified

on short versus long course steroid treatment; forrest plot random-effects.

Figure S14 Low dose steroid trials evaluating mortality at longest follow up, stratified

on disease severity; forrest plots (a. fixed-effect; b: random-effects); trial

sequential analyses (c-d SIRS and sepsis and e-f severe sepsis and septic

shock).

Figure S15 Low dose steroid trials evaluating serious adverse events; forrest plot (a.

random-effects model; trial sequential analysis (b. power 90%, anticipated

RRR 10%).

Figure S16 Low dose steroid trials evaluating mortality at 30 days follow-up; forrest

plot (a. random-effects model); trial sequential analyses (b. power 90%

anticipated RRR 10%; c. power 80% anticipated RRR 80%).

Figure S17 Error matrix plot (a. benefit of high dose steroids; b. harm of high dose

steroids).

Figure S18 Error matrix plot (a. benefit of low dose steroids; b. harm of low dose

steroids).

Table S1 Definition of SIRS, sepsis, severe sepsis, and septic shock

Table S2 Search strategy

Table S3 Outcome measures according to GRADE

Table S4 Excluded trials

Table S5 Baseline characteristics included trials – extended version

Table S6 Serious adverse events

Table S7 GRADE assessment of outcomes of both high and low dose steroid trials

Table S8 GRADE assessment of outcomes of high dose steroid trials

Table S9 GRADE assessment of outcomes of low dose steroid trials

Identification

Screening

Eligibility

Included

Excluded based on abstract (n = 397)

Full-text articles excluded (n = 36);Reasons for exclusion listed in table S4

Abstract not found (n=2)*

Excluded based on title (n = 3610)

Duplicates removed (n = 1266)

Records identified through database searching(n = 5366)

Records screened(n = 480)

Full-text articles assessed for eligibility(n = 83)

48 records describing 35 trials (3 trials: only abstract available)

Trials identified through cross reference search (n=1)

Screening

Eligibility

Included

Identification

Figure S1: Flow of papers through review. Abstract not found:* [e1,e2]

Figure S2: Risk of bias summary of all included

randomised clinical trials. The bias risk criteria are on the x-axis and the names of the first authors and year of the trial are on the y-axis. Green + = adequate. Red - =

c.

Figure S3 All steroid trials evaluating mortality at longest follow up. a. Forrest plot with

subgroups according to risk of bias (fixed-effect model). b+c. Trial Sequential Analyses.

b. A diversity-adjusted information size (DIS) of 21,755 patients was calculated based on

an anticipated relative risk reduction (RRR) of 10% (Diversity 73%, event proportion of

41% in the control arm, α=0.05 (two-sided), β=0.10 (power 90%)). The blue cumulative

z-curve was constructed using a random-effects model and did not cross any of the

boundaries when all trials were analysed. c. A DIS of 3,977 patients was calculated based

on an anticipated RRR of 20% (Diversity 73%, event proportion of 41% in the control

arm, α=0.05 (two-sided), β=0.20 (power 80%)). The blue cumulative z-curve was

constructed using a random-effects model and crossed the boundary for futility.

f.

Figure S4 All steroid trials evaluating mortality at longest follow up stratified on

treatment duration (short < 4 days and long ≥ 4 days) versus placebo. a.+b. Forrest plots

(a: fixed-effect model; b: random-effects model). c+d Trial sequential analyses of all

trials evaluating short course steroids for sepsis: c. A diversity-adjusted information size

(DIS) could not be calculated based on an anticipated relative risk reduction of 10%

(Diversity 71%, event proportion in the control arm 33.7%,α=0.05 (two sided), β 0.10

(power 90%)) . The blue cumulative z-curve was constructed using a random-effects

model. d. A DIS of 5118 patients was calculated based on an anticipated relative risk

reduction of 20% (Diversity 71%, event proportion in the control arm 33.7%, α=0.05

(two-sided), β=0.20 (power 80%)). The blue cumulative Z score did not cross any of the

boundaries. e+f. Trial sequential analyses of all trials evaluating long course steroids for

sepsis: e. A DIS of 19178 patients was calculated based on an anticipated relative risk


(two sided), β=0.10 (power 90%)). The blue cumulative z-curve was constructed using a

random-effects model and did not cross any of the boundaries after all trials were

analysed. f. A DIS of 3,722 patients was calculated based on an anticipated relative risk


(two-sided), β=0.20 (power 80%)). Nearly futility for an intervention effect of RRR 20%

was found.

f.

Figure S5 a+b Forrest plots (a. fixed effect, b. random effect) evaluating all trials

stratified based on disease severity: Severe Inflammatory Response Syndrome (SIRS)

and sepsis versus severe sepsis and septic shock. c+d: Trial sequential analysis based on

all trials evaluating SIRS and sepsis. c. A diversity-adjusted information size (DIS) of

30,895 patients was calculated based on an anticipated relative risk reduction of 10%

(Diversity 74%, event proportion in the control arm 34.2%, α=0.05 (two sided), β=0.10

(power 90%)). The blue cumulative z-curve was constructed using a random-effects

model. d. A DIS of 5,605 patients was calculated based on an anticipated relative risk


(two-sided), β=0.20 (power 80%)). The blue cumulative Z score did not cross any of the

boundaries. e+f Trial sequential analyses based on all trials evaluating severe sepsis and

septic shock e. A DIS of 14,808 patients was calculated based on an anticipated relative

risk reduction of 10% (Diversity 75%, event proportion of 53% in the control arm,

α=0.05 (two-sided), β=0.10 (power 90%)). The blue cumulative z-curve was constructed

using a random-effects model and did not cross any of the boundaries after all trials were

analysed. f. A DIS of 2,762 patients was calculated based on an anticipated relative risk

reduction of 20% (Diversity 75%, event proportion of 53% in the control arm, α=0.05

(two-sided), β=0.20 (power 80%)). The blue cumulative z-curve did not cross any of the

boundaries after all trials were analysed.

b.

Figure S6: Serious adverse events of all trials evaluating steroids for sepsis. a. Forrest

plot with subgroups according to risk of bias (fixed-effect model). b. Trial Sequential

Analysis of serious adverse events of all trials evaluating steroids for sepsis. A diversity-

adjusted information size (DIS) of 52,784 patients was calculated (Diversity 88%, event

proportion of 40.4 % in the control arm, anticipated relative risk reduction 10%, α=0.05

(two-sided), β=0.10 (power 90 %)). The blue cumulative z-curve was constructed using a

random-effects model and did not cross any of the boundaries when all trials were

analysed.

d.

Figure S7 a+b Forrest plots (a. fixed effect, b. random effect) evaluating mortality in all

steroid trials with 30 days follow up stratified on risk of bias. c.+d. TSA analysis

evaluating mortality in all steroid trials with 30 days follow up. c. A Diversity adjusted

information size (DIS) of 5,875 patients was calculated based on an anticipated relative

risk reduction of 10% (Diversity 0%, event proportion of 41.3% in the control arm,

α=0.05 (two-sided), β=0.10 (power 90%)). The blue cumulative z-curve was constructed

using a random-effects model and did not cross any of the boundaries after all trials were

analysed. d. A DIS of 1075 patients was calculated based on an anticipated relative risk

reduction of 20% (Diversity 0%, event proportion in the control arm 41.3%, α=0.05 (two-

sided), β=0.20 (power 80%)). The cumulative z-curve (blue line), constructed using a

random-effects model, crossed the boundary for futility (using an anticipated intervention

effect of 20% relative risk reduction).

a.

b.

c.

Figure S8 a+b Forrest plots of all trials with 90 days mortality data (a. fixed effect, b.

random effects). Only two low dose steroid trials provided 90 days mortality data. c.

TSA analysis of all trials evaluating mortality with 90 days follow up. Insufficient data

was available to perform a trial sequential analyses.

a.

b.

c.

Figure S9: All-cause mortality at longest follow-up in high dose steroids (>500 mg

hydrocortisone or equivalent) versus placebo. a+b Forest plots of with subgroups

according to the risk of bias in the trials (a. fixed-effect model, b. random-effects model);

c. Trial sequential analysis of lower risk of bias trials. A diversity adjusted information

size of 31,163 patients was calculated based on an anticipated relative risk reduction of

10% (Diversity 78%, event proportion of 37.3% in the control arm, α=0.05 (two-sided),

β=0.10 (power 90%)). The blue cumulative z-curve was constructed using a random-

effects model and did not cross any of the borders.

a.

b.

e.

Figure S10 a+b. Forrest plots (a. fixed effect, b. random effect) evaluating all high dose

steroid trials (>500 mg hydrocortisone or equivalent) stratified based on disease severity:

Severe Inflammatory Response Syndrome (SIRS) and sepsis versus severe sepsis and

septic shock. c+d. Trial sequential analyses based on all high dose steroid trials

evaluating SIRS and sepsis. c. A diversity-adjusted information size (DIS) of 28,497

patients was calculated based on an anticipated relative risk reduction of 10%

(Diversity=75%, event proportion of 36.2 % in the control arm, α=0.05 (two-sided),


effects model and did not cross any of the boundaries after all trials were analysed. d. A

DIS of 5,182 patients was calculated based on an anticipated relative risk reduction of

20% (Diversity 20%, event proportion of 36.2% in the control arm, α=0.05 (two-sided),

β=0.20 (power 80%)). The cumulative z-curve (blue line) was constructed using a

random-effects model and did not cross any of the boundaries after all trials were

analysed. e. Trial sequential analysis based on all high dose steroid trials evaluating

severe sepsis and septic shock could not be performed because of lack of data, also to less

data was available when an analysis anticipating a RRR of 20% was attempted.

b.

Figure S11. a. Forest plot on serious adverse events in the trials with high dose steroids

(>500 mg hydrocortisone or equivalent) with subgroup according to bias risk. b. Trial

sequential analysis of serious adverse events. A diversity adjusted information size (DIS)

of 9,665 patients was calculated based on an anticipated relative risk reduction of 10%

(Diversity=44%, event proportion of 43.4% in the control arm, α=0.05 (two-sided),


effects model and did not cross any of the boundaries.

e.

Figure S12: Low dose steroid trials (≤500 mg hydrocortisone or equivalent) mortality at

longest available follow-up a. forest plot according to risk of bias subgroups (fixed-effect

model). b+c. Trial sequential analyses (TSA) of the effect of low dose steroid use on

mortality at longest follow-up. b. A diversity-adjusted information size (DIS) of 16,044

patients was calculated based on an anticipated relative risk reduction (RRR) of 10%

(Diversity 70%, event proportion of 46% in the control arm, α=0.05 (two-sided), β=0.10

(power 90%)). The blue cumulative z-curve was constructed using a random-effects

model and did not cross any of the borders after all trials were analysed. c. A DIS of

2,951 patients was calculated based on an anticipated RRR of 20% (Diversity 70%, event

proportion of 46% in the control arm, α=0.05 (two-sided), β=0.20 (power 80%)). The

blue cumulative z-curve was constructed using a random-effects model and did not cross

any of the boundaries when all trials were analysed.

d+e. Trial sequential analyses of low dose steroid trials with lower risk of bias. d. A

diversity-adjusted information size (DIS) of 9,226 patients was calculated based on an

anticipated relative risk reduction of 10% (Diversity=59%, event proportion of 52.4% in

the control arm). The blue cumulative z-curve was constructed using a random-effects

model and did not cross any of the boundaries. e. A DIS of 1,718 patients was calculated

based on an anticipated relative risk reduction of 20% (Diversity 59%, event proportion

in the control arm 52.4%, α=0.05 (two-sided), β=0.20 (power 80%)). The cumulative z-

curve (blue line), constructed using a random-effects model, crossed the boundary for

futility (using an anticipated intervention effect of 20% relative risk reduction).

Figure S13: Forrest plot of mortality at longest follow-up of all trials evaluating low dose

steroid (≤500 mg hydrocortisone or equivalent) use with subgroups according to short

(<4 days) or long (≥4 days) course low dose steroid use (random-effects model).

f.

Figure S14 a+b Forrest plots (a. fixed effect, b. random effect) evaluating all low dose

trials (≤500 mg hydrocortisone or equivalent) stratified based on disease severity: Severe

Inflammatory Response Syndrome (SIRS) and sepsis versus severe sepsis and septic

shock. c+d. Trial sequential analyses based on all low dose trials evaluating SIRS and

sepsis. c. A diversity-adjusted information size (DIS) could not be calculated based on an

anticipated relative risk reduction of 10% (Diversity=63%, event proportion in the control

arm 24.8%,α=0.05 (two sided), β=0.10 (power 90%)) d. A DIS of 6,034 patients was

calculated based on an anticipated relative risk reduction of 20% (Diversity=63%, event

proportion in the control arm 24.8%,α=0.05 (two sided), β=0.20 (power 80%)). The blue

cumulative z-curve was constructed using a random effects model and did not cross any

of the boundaries. e+f. Trial sequential analyses based on all low dose trials evaluating

severe sepsis and septic shock e. A DIS of 8,070 patients was calculated based on an

anticipated relative risk reduction of 10% (Diversity 56%, event proportion of 54.6% in

the control arm, α=0.05 (two-sided), β=0.10 (power 90%)). The blue cumulative z-curve

was constructed using a random-effects model and did not cross any of the boundaries

after all trials were analysed. f. A DIS of 1,510 patients was calculated based on an

anticipated relative risk reduction of20% (Diversity 56%, event proportion in the control

arm 54.6%, α=0.05 (two-sided), β=0.20 (power 80%)). The cumulative z-curve (blue

line), constructed using a random-effects model, crossed the boundary for futility (using

an anticipated intervention effect of 20% relative risk reduction).

b.

Figure S15: Serious adverse events of low dose steroid (≤500 mg hydrocortisone or

equivalent) use a. forest plot with subgroups according to the risk of bias in the trials. b.

trial sequential analysis including all trials. A diversity adjusted information size could

not be calculated due to insufficient data.

Figure S16: a. Forrest plot of mortality (random effects model) at 30 days follow-up of

low dose steroids (≤500 mg hydrocortisone or equivalent) use according to risk of bias

subgroups. b+c. Trial sequential analyses of mortality at 30 days including all trials

evaluating low dose steroids versus placebo. b. A diversity-adjusted information size

(DIS) of 8734 patients was calculated based on an anticipated relative risk reduction of

10% (Diversity 27%, event proportion of 39.2% in the control arm, α=0.05 (two sided),


effects model and did not cross any of the boundaries after all trials were analysed. c. A

DIS of 1,594 patients was calculated based on an anticipated relative risk reduction of

20% (Diversity 27%, event proportion of 39.2% in the control arm, α=0.05 (two sided),

β=0.20 (power 80%) The blue cumulative z-curve was constructed using a random

effects model and crossed the inner border after all trials were analysed, indicating futility

for an intervention effect with 20% relative risk reduction.

b.

Figure S17 The Manhattan error matrix plot for overview of benefit and harm of all trials

evaluating high dose steroids (>500 mg hydrocortisone or equivalent) use. Trials and

their outcomes with a. benefit and b. harm according to the three dimensions of

systematic error (bias, measured by level of evidence), random error (measured by

standard error (SE)), and design error (measured by grading the outcome measures from a

patients’ perspective). Two trials had standard errors larger than 80 and were therefore

not shown.

b.

Figure S18 The Manhattan error matrix plot for overview of benefit and harm of all trials

evaluating low dose steroids (≤500 mg hydrocortisone ore equivalent) use. Trials and

their outcomes with a. benefit and b. harm according to the three dimensions of

systematic error (bias, measured by level of evidence), random error (measured by

standard error (SE)), and design error (measured by grading the outcome measures from a

patients’ perspective). Three trials had standard errors larger than 80 and were therefore

not shown.

Condition Definition

Systemic inflammatory

response syndrome (SIRS)

The presence of two or more of the following: temperature

> 38°C or < 36°C, heart rate > 90 beats/minute, respiratory

rate > 20 breaths/minute or PaCO2 < 4.3 kPa , and white

blood cell count > 12 cells/mm3 or < 4 cells/mm3 or > 10%

immature (band) forms.

Sepsis SIRS in response to an infectious process.

Severe sepsis Sepsis associated with organ dysfunction, hypoperfusion, or

hypotension. Hypoperfusion and perfusion abnormalities

may include, but are not limited to lactic acidosis, oliguria,

or an acute alteration in mental status.

Septic shock Sepsis with hypotension, despite adequate fluid

resuscitation, along with presence of perfusion

abnormalities that may include, but are not limited to lactic

acidosis, oliguria, or an acute alteration in mental status.

Table S1 Definitions for sepsis and organ failure as stated by the American College of Chest Physicians/Society of Critical Care Medicine in 1992 [e3].

Database Search strategy

Pubmed 1. exp steroid/2. exp corticosteroid/3. (steroid* or glucocorticoid* or corticosteroid* or cortisone* or hydrocortisone* or prednisolon* or methylprednisolon* or prednison* or dexamethason* or triamcinolon*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]4. 1 or 2 or 35. exp sepsis/6. (seps* or septic*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]7. 5 or 68. 4 and 79. (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]10. 8 and 9

Cochrane

Central

#1 MeSH descriptor: [Steroids] explode all trees#2 MeSH descriptor: [Adrenal Cortex Hormones] explode all trees#3 (steroid* or glucocorticoid* or corticosteroid* or cortisone* or hydrocortisone* or prednisolon* or methylprednisolon* or prednison* or dexamethason* or triamcinolon*) #4 #1 or #2 or #3 #5 MeSH descriptor: [Sepsis] explode all trees#6 seps* or septic* #7 #5 or #6 #8 #4 and #7

Embase 1. exp steroid/2. exp corticosteroid/3. (steroid* or glucocorticoid* or corticosteroid* or cortisone* or hydrocortisone* or prednisolon* or methylprednisolon* or prednison* or dexamethason* or triamcinolon*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]4. 1 or 2 or 35. exp sepsis/6. (seps* or septic*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]7. 5 or 68. 4 and 79. (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]10. 8 and 9

Science

Citation

Index

Expanded

#5 #4 AND #3#4 TS=(random* or blind* or placebo* or meta-analys*)#3 #2 AND #1#2 TS=(seps* or septic*)#1 TS=(steroid* or glucocorticoid* or corticosteroid* or cortisone* or hydrocortisone* or prednisolon* or methylprednisolon* or prednison* or dexamethason* or triamcinolon*)

Table S2 Summary of search strategy

The importance of outcomes

All-cause mortality within longest

follow-up

9 Critical for decision making

Serious adverse events 8

All-cause mortality at 30 days 7 Important, but not critical for decision making

All-cause mortality at 90 days 6

Persistent dependence on

haemodialysis

5

Duration of mechanical

ventilation

4

3

2 Not important for decision making - of lower

importance to patients1

Table S3: Hierarchy of outcomes according to importance to patients for steroid use for sepsis (GRADE [26]). Some outcome measures may be correlated (e.g. all-cause mortality at 30 days and all-cause mortality within longest follow-up).

Trial Reason for exclusionAjao 1984 [e4] Pediatric trialAnnane 1996 [e5] CommentAnnane 2010 [e6] All study groups receive steroidsAsehnoune 2014 [e7] Steroids for prevention of development of

hospital acquired pneumoniaBergkvist 1997 [e8] No SIRS SIRS/Sepsis/severe sepsis/septic shockGrumme 1995 [e9] Steroids to improve outcome after traumatic brain

injury. SIRS criteria not explicitly describedJaeschke 2009 [e10] EditorialJama 1975 [e11] No RCT Huh 2011 [e12] All study groups receive steroidsHoffman 1984 [e13] Same trial as the included trial by Hoffman [37] Keh 2003 [e14] Crossover designKurugundla 2008 [e2] Abstract unretrievableLevine 1978 [e15] Steroids used for the treatment of inhalation

injuryLucas 1984 [e16] Quasi randomisedMeduri 1998 [e17] SIRS/Sepsis/severe sepsis/septic shock criteria

not explicitly described Meduri 2002 [e18] Subanalyses Meduri 1998 [e17] Meduri 2005 [e19] Observational ARDS trialMeduri 2007 [e20] SIRS/Sepsis/severe sepsis/septic shock criteria

not explicitly describedMentzelopous 2009 [e21] Steroids during cardiopulmonary resuscitation.

SIRS criteria not explicitly describedMentzelopoulos 2013 [e22]

Steroids during cardiopulmonary resuscitation. SIRS criteria not explicitly described

Meijvis 2011 [e23] SIRS criteria not explicitly described. Exclusion of patients needing ICU admission at study start

Mikami 2007 [e24] SIRS criteria not explicitly described. Patients with sepsis were excluded.

Phillips 2006 [e25] Sepsis is listed in the exclusion criteria Payen 2012 [e26] No SIRS/Sepsis/severe sepsis/septic shockRamirez Acosta 1975 [e27]

All study groups receive steroids

Remmelts 2012 [e28] Subanalyses Meijvis 2011 [e23] Roquilly 2011 [e29] Steroids for prevention for development of

pneumonia in trauma patients. SIRS criteria not explicitly described.

Russell 2009 [e30] Subanalyses Vasopressin trial [e31]Steinberg 2006 [e32] SIRS/Sepsis/severe sepsis/septic shock criteria

not explicitly describedTam 2012 [e33] Viral infection

Theodossi 1982 [e34] Steroids in alcoholic hepatitis, sepsis in minority. SIRS criteria not explicitly described

Tandan 2005 [e1] Abstract irretrievableTolaj 2010 [e35] Pediatric trialWagner 1956 [e36] Quasi randomisedYamamura 1992 [e37] No RCTZagara 1987 [e38] Effect of steroids in traumatic brain injury

Trial Subanalyses of included steroid trials:Annane 2006 [e39] Annane 2002 [46]Arabi 2009 [e40] Preliminary results of CMAJ 2010 trial [47]Bone 1987 [e41] Bone NEJM 1987 [41]Bone 1989 [e42] Bone NEJM 1987 [41]Briegel 2001 [e43] Briegel 1999 [49]Klastersky 1970 [e44] Likely prelimary results of NEJM 1971 trial [29]Laviolle 2012 [e45] Annane 2002 [46]Marks 1990 [e46] Luce 1988 [42]Mirea 2014 [e47] Mirea 2014 [55] Moreno 2011 [e48] Sprung 2008 [60]Mussack 2005 [e49] Briegel 1999 [49]Mussack 2005 [e50] Briegel 1999 [49]Schelling 2001 [e51] Briegel 1999 [49]

Table S4: List of excluded trials and reasons for exclusion.

Trial

Num

ber of study sites

Num

ber of patients

Inclusion criteria

Exclusion criteria

Experim

ental Intervention

Control intervention

Follow up

Duration

Primary outcom

e

Secondary outcomes

Undefined outcom

es

High dose steroids (> 500 mg hydrocortisone or equivalent dose) in experimental intervention groupBernard 1987 [35]

7 99 1. Illness associated with ARDS

2. All of the following:a. PaO2 ≤ 70 mmHg with ≥

40% O2 or partial pressure of arterial O2/partial pressure of alveolar oxygen ≤ 0.3

b. Bilateral infiltrates diffuse infiltrates on chest X-ray

c. Pulmonary artery wedge pressure ≤ 18 mmHg

1. Age < 18 years2. Pregnancy3. Life threatening burns4. Untreated fungal or

mycobacterial disease5. Active herpes zoster6. Disease requiring CS7. Hypersensitivity to CS8. Mean arterial pressure <

60 mmHg9. Immunization < 28 days

MP 30 mg/kg every 6 hours for a total of 4 doses

Placebo containing mannitol every 6 hours for a total of 4 doses

45 days Mortality 1. ARDS reversal

2. Infectious compli-cations

3. Serum glucose levels

Bone 1987 [41]

19 382 1. Clinical evidence of infection,

2. Fever or hypothermia3. Tachycardia (>90

beats/min)4. Tachypnea (>20

breaths/min)5. Inadequate organ perfusion

or organ dysfunction

1. Age >752. Prior CST or steroid

allergy3. Uncontrolled diabetes4. Vaccination <28 days5. Burns 6. Pregnancy 7. Peptic ulcer < 6 months8. TBC or fungal infection9. Participation in another

trial10. Administration of N

MP bolus 30mg/kg repeated every 6 hours up to a total of 4 doses

Placebo Maximal 14 days (or until discharge or death)

1. Mortality2. Develop-

ment of septic shock

3. Reversal of septic shock

Not defined

Gans 2002 [36]

301 53 Suspected meningitis in combination with cloudy CSF, bacteria in CSF on Gram’s staining, or a CSF leukocyte count > 1000/mm3

1. Hypersensitivity to b-lactam AB or CS

2. Pregnancy3. Cerebrospinal shunt4. AB treatment < 48 hours 5. History of active

tuberculosis or fungal infection

6. Recent TBI, neurosurgery, or peptic ulcer disease

7. Enrolment in another trial.

D 10 mg every 6 hours for 4 days

Placebo identical in appearanceto the active drug every 6 hours for 4 days

8 weeks GCS 8 weeks after randomization

1. Mortality2. Focal

neurologic abnormalities

3. Adverse events

Hoffman 1984 [37]

38 1 All admitted patients with febrile illnesses

NM D 3 mg/kg, followed by 1 mg/kg every 6 hours for 8 times

Placebo indistinguish-able from D

16 months Mortality Complications

Hughes 1984 [28]

1 57 1. Systolic BP <90 mm Hg2. Fever3. Oliguria (< 15

ml/hour/l.73m2

4. Positive blood cultures

NM Group A (n=14): bolus N 10 ug/kg and a single dose of 30 mg/kg MP and 30 minutes later, a second dose of l00 ug/kg NGroup B (GOI): (n=15) single bolus of 30 mg/kg MP Group I (n=7): 30 ug/kg bolus of N, followed by 30 ug/kg/hr for 1 hour plus a single dose of 30 mg/kg MPGroup II (n=7), bolus 30 ug/kg N, followed by 30 ug/kg/hr for 1 hour without MPGroup III (n=7) (GOI): MP, 30 mg/kg

Group IV (n=7): conventional therapy alone.

NM Effect of various dosing regimens of naloxone and MP upon hemo-dynamics and plasmacatecholamines

If plasma catecholamines are increased: relationship between catecholamine levels and hemodynamics

Klastersky 1 85 1. Disseminated cancer Not mentioned B 0,5 mg/kg q 12 IS q 12 hours 30 days Mortality ND

1971 [29] 2. Life threatening infection hours, during 3 consecutive days

during 3 consecutive days

Luce 1988 [42]

1 87 For already hospitalized patients:1. T rise ≥ 1.5° C 2. Decrease in systolic BP ≥

20 mm Hg

For newly admitted patients 1. T > 38.5°C or < 35.5°C 2. Systolic BP < 90 mm Hg

1. Pregnancy2. Age < 76 years3. Active peptic ulcer

disease < 6 months4. Allergy to CS5. Burns6. HIV7. Active or prior fungal or

TBC infection8. CST < 24 hours ago 9. Diffuse pulmonary

infiltrates

MP 30 mg/kg per dose q 6 hours, four timesMP diluted in 50ml of 5% dextrose in water

Mannitol (600 mg mannitol, 12.8mg sodiumphosphate, 133.6mg benzyl alcohol, andsterile water) q 6 hours ,four timesplacebo diluted in 50ml of 5% dextrose in water

7 days or until final course was clear at the hospital-ward

1. Mortality2. ARDS

1. Effect of MP on respiratory and hemody-namic variables

2. Adverse events

Marik 1993 [38]

1 30 1. Admission to the intensive care unit prior to start antibiotic therapy

2. Community-acquired pneumonia with ≥ 3 of the following:

a. Respiratory rate >30/minute

b. Diastolic BP <60 mm Hgc. confusiond. Pa02 <55 mm Hg (on room

air)e. WBC count <4 or

>30*106/lf. Serum urea >7 mmol/lg. Platelet count < 140*106/Lh. Radiographic evidence of

multilobar involvement.

1. Age <18 or >70 years 2. Allergic to beta-lactam

antibiotics3. Malignancy4. Immunosuppressive-

therapy5. Active tuberculosis6. Humane immuno-

deficiency virus-positive patients

Once HC 10mg/kg i.v. 30 minutes prior to start antibiotic therapy

Once normal saline solution i.v. 30 minutes prior to start antibiotic therapy

NM TNF alpha levels

1. Mortality2. Duration of

ICU stay

Scar-borough 2007 [30]

1 465 Clinical suspicion of bacterial meningitis with either positive CSF on microscopy (organisms on Gram’s stain or > 100 white cells/ mm3, of which: > 50% neutrophils) or cloudy CSF

1. Age < 16 years2. CS received in the

previous 48 hours3. Cryptococcus detected in

CSF4. Contraindications to study

D 16 mg in 4 ml of sterile water twice daily at a dose of 4 mltwice daily intravenously for 4

Placebo(buffered sterile water) at a dose of 4 mltwice daily intravenously

10 days, 40 days, 6 months

Mortality 1. Disability2. Adverse

events

when immediate microscopy was unavailable

drugs days for 4 days

Schumer 1976 [43]

1 1721. ‘Septic history’2. ’Falling BP’3. Positive (an)aerobic blood

cultures

ND Single bolus infusion of either:3mg/kg D in 100 ml ISOr:30 mg/kg of MP in 100 ml ISIf ‘necessary’ repeated once after 4 hours

Single bolus infusion of 100 ml ISIf ‘necessary’ repeated once after 4 hours.

ND Mortality Adverse events

Sprung 1984 [44]

2 59 1. Systolic BP < 90 mmHg or decrease ≥ 50 mmHg

2. Decreased organ perfusion as evidenced as: altered mental status or oliguria < 20 ml/hour urine production

3. Persistent hypotension despite infusion ≥ 500 ml normal saline.

4. Bacteremia or an identified source of infection

1. Improvement of blood pressure after 500 ml IS

2. Hypotension secondary to: hemorrhage, AMI, cardiopulmonary arrest, acute pulmonary aspiration

Group 1 (n=21): MP 30 mg/kgGroup 2 (n=22): D 6 mg/kg Dose was repeated once in both groups after 4 hours if shock persisted

No control intervention (n=16)

ND 1. Shock reversal

2. Survival

Difference in incidence of the primary endpoint between Group 1 and Group 2

Thwaites 2004 [20]

2 545 1. Age > 14 years of age with clinical evidence of meningitis (defined as the combination of nuchal rigidity and CSF abnormalities)

1. Contraindication for CS2. Prior > 1 dose CS the

patient 3. > 30 days of

antituberculosis therapy before entry

D week 1: 0.4 mg/kg/day, week 2: 0.3 mg/kg/day, week 3:0.2 mg/ kg/day, week 4: 0.1 mg/kg/day, week 5: fixed dose 4 mg/day, decreased by 1 mg each week in following weeks***

Placebo 9 months Mortality 1. Adverse events

2. Disability3. Time to:a. GCS im-

provement b. fever

clearancec. Hospital

discharged. relapse4. Focal

neurologic deficit after 9

months

VASSC 1987 [45]

10 223 Clinical suspicion of sepsis and 4 of the following 7 signs within 8-hour period: 1. Shaking chills or fever2. Tachypneu or hypocapnia3. Tachycardia4. Hypotension5. Abnormal white-cell count6. Thrombocytopenia7. Surgical or invasive

procedure performed (<48 hours)

1. CST <2 weeks2. Cushing disease3. LE <2 weeks4. Allergy for CS 5. Body weight >132kg6. N treatment <4 hours

MP 30 mg/kg bolus followed by 5mg/kg/hour for 9 hours. Maximal dose: 10gram

Placebo 14 days 14-day all-cause mortality

Adverse events

Wan 2011[31]

1 81 1. Severe acute pancreatitis based on the combination of:

a. Atlanta criteria for acute pancreatitis: history of typical abdominal pain associated with ≥ 2 fold increase in serum lipase and confirmed with contrast enhanced computer tomography.

b. Ransons’s signs ≥ 3c. Balthazar computer

tomography severity index ≥ 5

d. SIRS as defined in table S1

1. Aged < 18 years 2. Steroid use prior to

admission3. Recurrent acute

pancreatitis with existent local complications

4. Pregnancy5. Malignancy6. Rheumatism disease7. Mental disorders. 8. Admission > 48 hours

after onset of pain9. Expected to die < 48

hours after admission

1. Modified Dachengqi Decoction# 50 mL enteral every 2 hours; or 200 mL by enema every 6–8 hours for 7 days.

2. D i.v. 1 mg/kg 3 times/day for 3 days.

Modified Dachengqi Decoction# 50 mL enteral every 2 hours; or 200 mL by enema every 6–8 hours for 7 days.

30 days Mortality Incidence rates of: 1. ARDS2. Renal failure 3. Hemorrhage4. Sepsis5. Pancreatic

pseudocyst6. Abscess7. Overall

surgery8. Days of

hospitaliza-tion

Low dose steroids (≤ 500 mg hydrocortisone or equivalent dose) in experimental intervention groupAnnane 2002 [46]

19 300 1. Documented site or at least strong suspicion of infection

2. T > 38.3°C or < 35.6°C 3. HR < 90 beats per minute4. Systolic BP < 90 mm Hg5. Urinary output of less than

0.5 mL/kg of body weight

1. Pregnancy2. Acute myocardial

infarction 3. Pulmonary embolism 4. AIDS5. Contraindication for CST

HC 50 mg q 6 hours and FC 50 µgram q 24 hoursTreatment duration 6 days

Placebo 1 year Mortality 1. 28 day, ICU, hospital and 1 year mortality rates

2. Time to vaso-pressor withdrawal

for at least 1 hour or PaO2/FIO2 < 280 mm Hg

6. Arterial lactate > 2 mmol/L7. Need for MV8. Duration of shock < 3

hoursArabi 2010 [47]

1 75 1. Cirrhosis2. Septic shock as defined in

table S1 3. Hypotension duration < 72

hours

Not mentioned 5 ml IS with 50 mg HC q 6 hours After shock resolution, defined as a MAP > 65 mm Hg without vasopressorsfor 24 hours: dose reduction by 1 mL every two days until discontinuation

5 ml IS q 6 hoursAfter shock resolution, defined as a MAP > 65 mm Hg without vasopressorsfor 24 hours: dose reduction by 1 mL every two days until discontinuation

28 days All cause mortality

1. ICU and hospital-mortality

2. MAP3. Vasopressor

doses 4. Shock-

reversal5. Vasopressor

free days6. Mechanical

ventilation free days

7. Renal replacement free days

Bollaert 1998 [48]

2 41 1. Septic shock as defined in table S1

2. MV 3. Vasopressor therapy for >

48 hours

1. TI LE < 1 week2. Considered to withhold

therapy3. Gastroduodenal ulcer or

GB4. Prior CST 5. Post corticotropine

[cortisol] <18 ugram/kg

HC 75 mg q 6 hours for 5 or more daysIn case of shock reversal after 5 days: for 3 days 150 mg HC, then 75 mg for the next 3 days Treatment was stopped after 5 days in the absence of shock reversal

2 ml of IS q 6 hours

28 days Shock reversal 1. 28 days all cause mortality

2. Changes in hemodynamics

Briegel 1999 [49]

NM 40 1. Septic shock as defined in table S1

2. Vasopressor support3. Cardiac output > 4.0

l/min/m2

1. Age >752. Pregnancy 3. TI4. Treatment with

vasopressors for >72 hrs5. Prior CST

HC bolus of 100 mg, followed by a continuous infusion of 0.18 mg/kg/hr after shock reversal

IS administrated in the same manor as in the intervention group

ND Time to cessation of vasopressor support

1. Evolution of hemodynamics and the multiple organ dysfunction syndrome (MODS)

6. Organ transplant recipients

7. Burns8. Hemorrhagic shock9. AMI < 6 months

dose reductionto 0.08 mg/kg/hr Dose was kept constant for 6 days. HC was tapered in steps of 24 mg/day after successful treatment of infection or serum [sodium] >155 mmol/l

2. Mortality

Chawla 1999 [50]

NM 44 1. Septic shock, exact definition not specified

2. Vasopressor support in order to reach a MAP ≥ 60 mmHg for > 72 hours

NM HC 100 mg q 8 hours for 72 hours, followed by tapering over 4 days

IS infusion NM Shock reversal

Cicarelli 2006 [32]

1 29 SIRS or sepsis as defined in table S1

1. IST2. Prior CST3. Active pancreatitis4. TI LE < 3 months5. Recent GB

D 0.2 mg/kg (in a single dose)

0.9% IS 7 days or till discharge from ICU

Blocking of progression of SIRS

1. Mortality2. Duration of

vasopressor support

3. Cardiovascular SOFA score ≥ 2

4. MV Cicarelli 2007 [51]

1 29 Septic shock exact definition not specified

1. IST 2. Prior CST3. active pancreatitis4. TI LE < 3 months5. Recent GB

D 0.2 mg/kg given three times at intervalsof 36 hours

Placebo 28 days Mortality 1. Duration of MV

2. Days of vaso-pressor use

Confalo-nieri, 2005 [33]

6 46 1. At least two of the following: systolic BP < 90 mm Hg, diastolic BP < 60 mm Hg.rr > 30 breaths / minute, PaO2:FiO2 < 250, chest radiograph with multiple infiltrates

2. At least one of the following: requirement of vasopressors > 4 hours, serum creatinine ≥ 2 mg/dl,

1. Nosocomial pneumonia 2. IST3. Acute burn injury4. TI LE < 3 months 5. Pregnancy6. Recent major GB 7. Prior CST therapy > 0.5

mg/kg/day of P equivalent

HC bolus 200 mg, followed by an infusion rate of 10 mg/hour for 7 days

IS in a volume equal to the study drug

ND 1. improve-ment in PaO2:FiO2

ratio2. Improve-

ment in MODS

3. Reduction in delayed septic shock

1. Duration of MV

2. Length of ICU/RIU and hospital stay

3. Survival to hospital discharge and to 60 days

requirement of mv, increase of ≥ 50% opacities on chest radiograph at 48 hours

Gordon 2014 [52]

4 61 Septic shock as defined in table S1

1. Prior IV vasopressor 2. Adrenal insufficiency3. CST < 3 months4. ESRD5. MI, RP, SS 6. AMI 7. LE < 24 hours 8. Pregnancy9. Enrolment in another trial

that might interact with the study drugs, or hypersensitivity to any of the study drugs

HC 50 mg q 6 hours for the first 5 days, 50 mg q 12 hours for the next 3 days, 50 mg q 24 hours for the last 3 daysHC was weaned quicker if shock had resolvedVP (titrated upto 0.06 U/min)

IS 0.5 ml q 6 hours for the first 5 days, 0.5 ml q 12 hours for the next 3 days, 0.5 ml q 24 hours for the last 3 days. IS was weaned quicker if shock had resolved.VP (titrated up to 0.06 U/min)

28 Interaction between vasopressinand CS in regard to:-plasma VP levels

1. Interaction between VP and CS in regard to: VP dose require-ments, 28-day, ICU and hospital mortality, organ failure free days

2. Feasibility of VP as initial vaso-pressor

3. Adverse events

Hu 2009 [53]

1 77 1. Septic shock definition not specified

2. Shock refractory to noradrenalin

NM HC 50 mg q 6 hours for the first 7 days, 50 mg q 8 hours for the next 3 days, 50 mg q 12 hours for the next 2 days50 mg q 24 hours for the next 2 days

NM 14 days Mortality

Kaufmann 2008 [54]

1 30 Septic shock as defined in table S1

1. Pregnancy2. IST3. Hemorrhage4. Transplantation5. Burns

HC bolus of 100 mg followed by a continuous infusion of 10 mg/h) for 24 hours

Infusion of placebo for 24 hours

24 hours Effects ofstress doses of HC on clinical parameters and laboratory parameters

Mirea 2014 [55]

NM 171 Septic shock definition not specified

NM Group A: bolus 200 mg HC q 24 hours during 4 daysGroup B: continuous HC 200

Group C:No intervention

7 days Risk of development of hyper-natriemia

mg/day during 4 days

Meduri 2009 [56]

1 80 Severe sepsis definition not specified divided in 2 groups:Group A:No shock and MODS <2Group B:Shock orMODS >3

NM HC infusion (10 mg/hr) for 7 days

NM 7 days Group A improvement in MODS;Group B resolution of shock by day 7.

1. Day 7 CRP2. Duration of:a. MV b. ICU stayc. Hospital stay3. Mortalitya. ICU4. Hospital

Nafae 2013 [39]

1 80 1. Age ≥ 18 years 2. Clinical and radiographic

evidence of community acquired pneumonia:

a. Cough with or without sputum

b. Temperature > 38.5c. Dyspnead. Pleuritic chest pain or

abnormal breath soundse. New radiographic

pulmonary abnormalities at least segmental and not due to other known causes

f. Either community acquired or ≥ 48 hours of hospitalization

1. Nosocomial pneumonia 2. Severe immune-

suppression 3. Acute burn injury4. Life expectancy < 3

months5. Pregnancy6. Major gastro-intestinal

bleeding < 3 months of hospitalization.

7. Condition requiring more than 0.5 mg/kg/day of P equivalent

8. Hepatic cirrhosis

1. 60 patients2. 200 mg HCloading bolus dose followed by a continuous infusion of 240 mg/24 hours for 7 days

1. 20 patients2. Sterile normal salinein a volume equal to the study drug

7 days Attenuation of systemic inflammation

1. “Sepsis related compli-cations”

2. Mortality

Oppert 2005 [57]

1 48 1. Two or more of the following: hr > 90 bpm, T ≥38.5°C or < 36°C, leukocytosis of ≥12 /nL or >10% immature cells, rr > 20 per minute, mv

2. evidence or strong clinical suspicion of infection.

3. arterial systolic BP <90 mm Hg for ≥1 hr despite adequate fluid resuscitation

4. CI ≥ 3.5 L/min/m2;5. need for vasopressor

support

1. Pregnancy2. HIV positive3. organ transplant

receipients 4. CS contra-indicated5. CST

HC (500 mg/50 ml) bolus 50 mg, followed by continuous infusion of 0.18 mg/kg/hr1 hour after cessation of vasopressor support: 0.06 mg/kg/hr for 24 hours, followed by a reduction of 0.02 mg/kg/hour every

IS bolus 10 ml, followed by an equal volume of continuous saline infusion

28 days Time to cessation of vasopressor support

Cytokine response28 days survivalSequential Organ Failure Assessment (SOFA) score

6. duration of septic shock < 24 hrs.

day

Rinaldi 2006 [58]

1 40 Severe sepsis according to definition in table S1

1. Prior illness associated with chronic microalbuminuria

2. Prior or preexisting renal failure

3. CST < 3 months 4. IST5. Chronic hematologic

diseases6. Pregnancy7. Septic shock8. Therapy with endothelial

active drugs

Standard therapy and HC 300 mg/day dilutedin 50 mL of IS for 6 days via continuous intravenousinfusion After the study period HCtherapy was tapered

Standard therapy

7 days Effect of steroids on urinary albumin/creatinin ratio

1. Duration of MV

2. Duration of ICU stay

3. Hospital mortality

4. Several laboratory data

Ruolan 2014 [59]

NM 60 Sepsis definition not specified 1. Age > 80 years 2. CST or alternative 3. IST < 3 months 4. Pregnancy 5. Primary adrenal

insufficiency6. Autoimmune diseases7. Prior postpartum

hemorrhage8. Adrenal tumors9. End-stage chronic

diseases10. Participation in another

trial

Chinese herb group:100 ml Sini decoction** q 24 hours for 7 daysHC group (GOI):200 mg HC q 24 hours for 7 days

Standard therapy

28 days Effect of Sini decoction on function of HPA-axis in sepsis

1. APACHE II score

2. day 3 shock reversal

3. 28 days mortality

Snijders 2010 [40]

1 213 1. Clinical symptoms suggestive of CAP: cough (with or without sputum), fever (38.5°C), pleuritic chest pain, or dyspnea

2. New consolidations on chest radiograph.

3. Age ≥ 18 years

1. Presence of severe immune-suppression (HIV infection,use of immune-suppressants)

2. Malignancy3. Pregnancy or

breastfeeding4. Use of macrolides for

more than 24 hours5. P ≥15 mg for > 24 hours6. Any condition requiring

CS

P 40 mg once daily for a total of 7 days, administered in thesame way as the antibiotics (intravenous or oral)

placebo once daily for a total of 7 days, administered in thesame way as the antibiotics (intravenous or oral)

30 days Day 7 clinical outcome

1. 30-day mortality

2. Adverse events

3. Clinical outcome on day 30

4. Length of stay

5. Time to clinical stability

7. Any likely infection other than CAP

8. Obstruction pneumonia9. Pneumonia < 8 days after

hospital discharge10. Indications that patients

wereunable and/or unlikely to comprehend and/or follow the protocol.

6. Subsidence of fever

7. Serum CRP

Sprung 2008 [60]

52 499 1. Clinical evidence of infection < 72 hours

2. Systemic response to infection defined by ≥2 of the following < 24 hours: T >38.3°C or < 35.6°C); HR >90 beats/min; RR > 20 breaths/min or PaCO2<32 mmHg or need for invasive mv; white cell count >12 cells/mm3 or <4 cells/mm3 or >10% immature neutrophils.

3. Evidence of shock within the previous 72 hours defined by (both a + b required):

a. Systolic BP < 90 mmHg or decrease in systolic bp > 50 mmHg for ≥1 hour despite adequate fluid replacement OR need for vasopressors ≥1 hour

b. Hypoperfusion or organ dysfunction attributable to sepsis

1. TI2. LE < 24 hours 3. IST4. Long-term CST < 6

months5. Short-term CST < 4

weeks.

HC 50 mg iv bolusq 6 hours for 5 days, then tapered to 50 mgiv q 12 hours for days 6 to 8, 50 mgq 24 hours for days 9 to 11, and then stopped

Placebo 28 days and death at 1 year

28 days mortality rate in patients who did not have RC

1. ICU mortality, hospital mortality, 1 year mortality

2. Reversal of organ system failure (including shock)

3. Duration of ICU and hospital stay

4. Adverse events

5. 28 days mortality rate in patients who had RC

Yildiz 2002 [61]

1 40 Sepsis according to definition in table S1

1. Pre-existing adrenal disease or adrenalectomy

2. Known malignancies3. TBC with possible

involvement of the

P IV at 06.00 (5 mg) and 18.00 (2.5 mg) for 10 days

IS at 06.00 and 18.00 for 10 days in identical manner

28 days and 1 month after dis-charge

28 days all cause mortality

1. Adverse events

2. comparing survivors and non survivors

adrenal gland4. CST < 3 months5. Burns6. Hemorrhagic shock 7. AMI

in regard to: average basal cortisol values; peak cortisol; cortisol responses to ACTH on the first day

Yildiz 2011 [62]

1 55 Sepsis according to definition in table S1

1. Pre-existing adrenal disease or adrenalectomy

2. Known malignancies3. TBC with possible

involvement of the adrenal gland

4. CST < 3 months5. Burns6. Hemorrhagic shock 7. AMI

P IV3 times a day at 06.00 (10 mg),14.00 (5 mg), and 22.00 (5 mg) for 10 days

IS in an identical manner

28 days 28 days all cause mortality

1. Adverse events

2. All medi-cations given

3. Reversal of organ system failure

4. Duration of hospitalization

5. Mortality6. Causes of

death7. Comparing

survivors and non survivors in regard to: average basal cortisol values; peak cortisol; cortisol responses to ACTH on the first day

Table S5: Characteristics of included trials – extended version.

Abbreviations: AB: antibiotics. B: betamethasone, BP: blood pressure, CI: cardiac index, CS: corticosteroids, CSF: cerebrospinal

fluid, CST: corticosteroid treatment, D: dexamethasone, ESRD: end stage renal disease, FC: fludrocortisone, MP: methylprenisolone,

AMI: acute myocardial infarction, GB: gastrointestinal bleeding, GCS: Glasgow Coma Scale, GOI: group of interest for this analysis,

HR: heart rate, HC: hydrocortisone, HPA-axis: hypothalamic-pituitary-adrenal-axis, IV: intravenous, IS: isotonic saline, IST:

immunosuppressive therapy, LI: life expectancy, MAP: mean arterial pressure, MI: mesenteric ischemia, MV: mechanical ventilation,

N: naloxone, ND: not defined, NM: not mentioned, P: prednisolone, RC: response to corticotrophin, RP: Raynaud’s phenomenon, RR:

respiratory rate, SS: systemic sclerosis, T: temperature, TBI: traumatic brain injury, TI: terminal illness, VP: vasopressin ** Sini decoction: decoction of monkshood 15 g, dried ginger 15g, honey-fried licorice 10g.

# modified Dachengqi Decoction: Radix et Rhizoma Rhei 12 g, Natrii sulfas 9 g, Cortex Magnoliae officinalis 10 g, Fructus Aurantii

Immaturus 10 g, Radix Bupleuri 12 g, Radix Aucklandiae 9 g, Radix Scutellariae 9 g, Fructus Gardeniae 12 g, Radix Paeoniae Alba

10 g, Radix Salviae Miltiorrhizae 15 g, and decocted with water to 300 mL.*** ⅓ of patients received a lower dose of dexamethasone, but still a high dose.

All steroid trials High dose trials Low dose trials

Study group

Number of

patients

Steroids

1453

Control

1362

Steroids

1001

Control

948

Steroids

452

Control

414

Total Serious

Adverse Events 619 550 444 411 175 139

ICU acquired

bacteriemia 43 48 17 23 26 25

Nosocomial

pneumonia 17 20 NR NR 17 20

Urinary tract

infection 3 1 NR NR 3 1

Surgical wound

infection 0 7 NR NR 0 7

Infections not

otherwise

specified

110 149 100 141 10 8

Gastrointestinal

bleeding 36 30 9 15 27 15

Shock relapse/

Shock

development 14 15 NR NR 14 15

Arrhythmia 15 10 NR NR 15 10

Table S6: Serious adverse events in both high and low dose steroid trials. Only the most

important subcategories are shown. Only data of trials reporting SAE’s are displayed.

SAE’s of the 2008 trial by Sprung [60] were excluded, since in this trial there were more

SAE’s then patients. NR = Not reported.

Quality assessment No of patients Effect

Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Steroids for sepsis high

and low doseControl Relative

(95% CI) Absolute

mortality - longest follow-up

31 randomised trials

very serious1

very serious2 no serious indirectness

very serious3

none 829/2204 (37.6%)

855/2086

(41%)

TSA-adjusted RR 0.89 (0.74

to 1.08)4

45 fewer per 1000 (from 107 fewer to

33 more)

VERY LOW

CRITICAL

39.1%43 fewer per 1000 (from 102 fewer to

31 more)

Serious Adverse Events


very serious1

serious2 no serious indirectness

very serious3

reporting bias5 619/1453 (42.6%)

550/1362

(40.4%)


to 1.48)

8 more per 1000 (from 121 fewer to

194 more)

VERY LOW

CRITICAL

30.2%6 more per 1000 (from 91 fewer to

145 more)

mortality 30 days


very serious6

no serious inconsistency

no serious indirectness

very serious3

none 417/1053 (39.6%)

432/1046

(41.3%)


to 1.17)


70 more)

VERY LOW

CRITICAL

47%


80 more)

mortality 90 days

2 randomised trials

no serious risk of bias



very serious7

reporting bias8 6/43 (14%)

15/43 (34.9%)

RR 0.36 (0.04 to 2.9)9

223 fewer per 1000 (from 335

fewer to 663 more)

VERY LOW

IMPORTANT

34.6%


fewer to 657 more)

persistent dependence on haemodialysis - not reported

0 - - - - - none - - - - IMPORTANT

duration of mechanical ventilation - not reported

0 - - - - - none - - - - IMPORTANT

Table S7: GRADE assessment of outcomes of both high and low dose steroid trials1 Only two trials scored low risk of bias on all domains2 Substantial heterogeneity in results was found in between trials3 Total information is smaller than the calculated optimal information size.4 TSA = trial sequential analysis5 Many trials included in this systematic review do not report data on serious adverse events.6 Only one trial scored low risk of bias on all domains7 No explanation was provided8 Only two trials assessed mortality at 90 days9 Insufficient data was available to calculate TSA-adjusted RR


Quality Importance



High dose steroids for

sepsisControl Relative

(95% CI) Absolute



very serious1


very serious3

none 449/1297 (34.6%)

463/1240

(37.3%)


to 1.99)4


370 more)

VERY LOW

CRITICAL


409 more)


8 randomised trials

very serious1



very serious3

reporting bias5 444/1001 (44.4%)

411/948 (43.4%)


to 1.37)


160 more)

VERY LOW

CRITICAL


99 more)

mortality 30 days

3 randomised trials

very serious6



very serious3

none 151/314 (48.1%)

142/306 (46.4%)

OR 1.07 (0.77 to 1.49)


99 more)

VERY LOW

CRITICAL


99 more)

mortality 90 days - not measured

0 - - - - - none - - - - IMPORTANT

persistent dependence on haemodialysis

0 No evidence available

none - - - - IMPORTANT

0% -

duration of mechanical ventilation



0% -

Table S8: GRADE assessment of outcomes of high dose (> 500 mg hydrocortisone or equivalent) steroid trials1 Only one trial scored low risk of bias on all domains2 Substantial heterogeneity in results was found between trials3 Total information size was smaller than the calculated optimal information size.4 TSA = trial sequential analysis5 Many trials included in this systematic review do not report data on serious adverse events.6 Only trials with high risk of bias reported 30 days mortality


Quality Importance



Low dose steroids for

sepsisControl Relative

(95% CI) Absolute



very serious1


very serious3

none 380/907 (41.9%)

392/846

(46.3%)

TSA-adjusted RR 0.9 (0.49 to

1.67)4


310 more)

VERY LOW

CRITICAL


249 more)


9 randomised trials

very serious1


very serious3

none 175/452 (38.7%)

139/414

(33.6%)

RR 0.98 (0.83 to 1.15)5


50 more)

VERY LOW

CRITICAL


45 more)

mortality 30 days


very serious1


very serious3

none 266/739 (36%)

290/740

(39.2%)


to 1.62)


243 more)

VERY LOW

CRITICAL


296 more)

mortality 90 days

2 randomised trials

no serious risk of bias



very serious3

reporting bias6 6/43 (14%)

15/43 (34.9%)

RR 0.36 (0.04 to 2.9)5


fewer to 663 more)

VERY LOW

IMPORTANT

34.6%221 fewer per

1000 (from 332 fewer to 657 more)

persistent dependence on haemodialysis



0% -

duration of mechanical ventilation



0% -

Table S9: GRADE assessment of outcomes of low dose (≤ 500 mg hydrocortisone or equivalent) steroid trials1 Only one trial scored low risk of bias on all domains2 Substantial heterogeneity in results was found between trials.3 Total information is smaller than the calculated optimal information size.4 TSA = Trial sequential analysis5 Insufficient data was available to calculate TSA-adjusted RR.6 Only two trials assessed mortality at 90 days.

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