Supplementary Appendix Table of contents

1 Supplementary Appendix

Table of contents

 Full search strategy

 The consensus process and major exclusions

 Additional statistical analyses

 Results of the second web poll

 Figures

Figure S1 - Flow chart on the selection of the topics with an effect on mortality in critically ill adult

Figure S2 - Journals where the trials were published

Figure S3 - Trial size distribution graph. Panel A. Number of centers enrolling patients in trials reporting a positive survival effect in critically ill patients. Panel B. Number of patients randomized in trials reporting a negative survival effect in critically ill patients

Figure S4 - Correlation between trial size and size effect. Interventions that increase survival are presented in green, interventions that increase mortality are presented in red.

Panel A, correlation between trial size and ARR/ARI. Panel B, correlation between trial size and RRR/RRI. Panel C, correlation between trial size and NNT/NNH.

Figure S5 – Correlation between the year of publication and the percentage of use among clinicians.

Figure S6 – Graphic visualization of the percentage of agreement with the validity of selected intervention (red) and of use among those who agreed (blue).

 Tables

Table S1 - Trials excluded during the Consensus Conference

2 Table S2 -Trails excluded after the web survey.

Table S3 – Characteristics of the populations and the interventions studied in the trials excluded by the Consensus Conference and the web vote.

Table S4 – Characteristic of excluded trials, details on trial size, size effect, follow-up, end of enrollment, and blinding.

Table S5 – Complete statistical analysis of selected trials

Table S6 - Complete statistical analysis of all trials identified by the systematic literature search

Table S7– Comparison of the selected and excluded trials

Table S8 Agreement and use in practice scores for interventions that increase survival Table S9 - Agreement and use in practice score for interventions that increase mortality Table S10 – Nationality of web survey clinicians

 Supplemental References

3 Full search strategy

The literature was searched systematically on MEDLINE/PubMed and updated to June 20^th 3013 to identify all multicenter randomized published papers concerning any intervention influencing mortality in critically ill patients. We used the following search strategy:

(dead[tiab] or death[tiab] or die[tiab] or died[tiab] or mortality[tiab] or fatalit*[tiab] or exitus[tiab]

or surviv*[tiab]) and ("anesthesia"[tiab] OR "cardiac arrest"[tiab] or "critical care"[tiab] or sepsis[tiab] or "critical illness"[tiab] or "critically ill" [tiab] or "ARDS"[TIAB] or "acute respiratory distress syndrome"[tiab] OR "ecmo"[tiab] OR "intensive care"[tiab] or emergen[tiab]) AND ((randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized controlled trials[mh] OR random allocation[mh] OR double-blind method[mh] OR single-blind method[mh]

OR clinical trial[pt] OR clinical trials[mh] OR (clinical trial[tw] OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND (mask*[tw] OR blind[tw])) OR (latin square[tw]) OR placebos[mh] OR placebo*[tw] OR random*[tw] OR research design[mh:noexp] OR comparative study[tw] OR follow-up studies[mh] OR prospective studies[mh] OR cross-over studies[mh] OR control*[tw] OR prospectiv*[tw] OR volunteer*[tw]) NOT (animal[mh] NOT human[mh]))

This search strategy yielded 36,435 results. These papers were screened according to the inclusion and exclusion criteria reported in the main article and we identified 63 papers that were discussed in the Consensus Meeting (Figure S1).

4 The Consensus process and major exclusions

The 63 papers identified with the search strategy detailed in the appendix (see above) and well explained in supplemental figure 1 (see below) were further discussed during the Consensus meeting and 24 papers were finally selected to be voted online.

During the consensus meeting 19 papers were considered screening failures and excluded while 16 studies were considered to have major exclusions (Table S1), because of poor methodology, preliminary evidence, lack of biological plausibility, reproducibility, or generalizability. Poor methodology identified those papers with statistical pitfalls (e.g.: low power, inhomogeneity between case and control groups) or design defects (e.g.: inadequacy of the control treatment).

Biological plausibility represents information and studies previous to the considered one, the reproducibility refers to finding consistency in subsequent trials and in diverse populations, settings, and across time, and generalizability is the applicability of the study findings, their external validity.

We also considered excluded four papers which only achieved an agreement of less than 50% at the interactive web questionnaire published online after the consensus meeting (Table S2).

The characteristics of these trials are reported in Table S3 and S4.

5 Additional statistical analyses

The results of the statistical analyses carried out on the selected papers and mentioned in the main article are fully reported in Table S5. Figure S4 showed the correlation between the trial size and the effect size. The diameter of the balloons represents the number of patients enrolled in each trial, while the number of centers involved is represented in the ordinate. As shown, the greater the trial size is the smaller the absolute risk reduction/increase (panel A) or the relative risk reduction/increase (panel B). Due to mathematical reasons, trial size shows a direct

correlation with the number needed to treat/harm (panel C). This correlation was expected, because all selected the trials were statistically significant, therefore interventions testes on few patients need to have a great effect in order to impact mortality in a significant way.

In addition, we repeated the same analysis on all the papers identified by the systematic literature search. We use non parametric Mann-Whitney U test to assess if there was a correlation between trial size and effect on mortality, trial size and blinding, effect size and effect on survival, and effect size and blinding. The correlation between trial size and the size of the effect was tested using Spearman’s correlation test, and that between blinding and effect on survival with the chi- square test. The results are presented in Table S6.

As observed also in the selected papers, trials size correlated with both outcome and blinding.

Smaller trials were more likely to show an improvement in survival (p < 0.01) and to be un-blinded (p = 0.01). Also the correlation between effect size and trial size was preserved. Trials that showed a positive effect on survival had a smaller NNT (6 vs 10, p = 0.02) and a larger ARR (0.177 vs 0.107, p = 0.04). This correlation was lost in the selected paper.

Finally, we compared trial size, effect size, the percentage of blinding, and effect on survival

6 between excluded and selected papers, using Mann-Whitney U test, Kruskal-Wallis test, and Chi- square test as appropriate (Table S7).

There were significantly more blinded trials among the excluded papers (30% vs 60%, p = 0.04) and papers showing an increase in mortality were significantly less common among those trials excluded from final selection by the consensus conference (33% vs 0%, p = 0.01).

7 Results of the web survey

555 colleagues from 61 different countries indicated whether they agreed or disagreed with the validity of each intervention identified by the systematic review and the consensus meeting in affecting mortality in critically ill patients.

The web survey was made up of two questions for each intervention, the first being “Do you consider this evidence convincing enough to adopt it as standard clinical practice?”, and the second being “Do you routinely use this evidence to guide your practice?”

Both questions admitted three answers: “yes”, “no” and “don’t know”. Since methodological research suggests that there is no difference in response rate depending on the inclusion or exclusion of the "don't know" option (if less than 40%) we considered only the "yes" and "no"

responses.

The degree of agreement and use in practice score is shown in Tables S8 and S9. We investigated the possible correlation between the percentage of use and year of publication, but we found no correlation (Figure S5). The difference between agreement and use is presented in Figure S6. The countries with the most respondents were the United States of America [11%], Australia [11%]

and Italy [11%]) (Table S10).

Throughout the process, all participants were asked to disclose any potential conflicts of interest.

Excluding the vote of those who declared any conflict of interest, the percentage of agreement and avoidance did not change significantly.

8 Figure Legend

Figure S1 - Flow chart on the selection of the topics with an effect on mortality in critically ill adult patients.

Figure S2 – Journals where the trials were published.

Figure S3 - Trial size distribution graph. Panel A. Number of centers enrolling patients in trials reporting a positive survival effect in critically ill patients. Panel B. Number of patients randomized in trials reporting a negative survival effect in critically ill patients.

Figure S4 – Correlation between trial size and size effect. Interventions that increase survival are presented in green, interventions that increase mortality are presented in red. Panel A.

Correlation between trial size and ARR/ARI. Panel B. Correlation between trial size and RRR/RRI.

Panel C. Correlation between trial size and NNT/NNH.

Figure S5 – Correlation between the year of publication and the percentage of use among clinicians.

Figure S6 – Graphic visualization of the percentage of agreement with the validity of selected intervention (red) and of use among those who agreed (blue).

9 Supplemental Tables

Table S1 - Trials excluded during the Consensus Conference

Drug/technique/bundle of care Setting Effect on survival Reason for exclusion during conference

Antioxidant disodium edetate in propofol infusion (vs propofol alone)¹

Critically ill patients Increased Lack of reproducibility, poor methodology

Intermittent dialysis vs continuous renal replacement therapy²

Acute Kidney Failure Increased Lack of reproducibility, lack of balance at randomization

Drotrecogin alfa activated (Xigris)³ Sepsis/

Septic Shock

Increased Contradicted by subsequent studies

Immuno-enhancing enteral diets⁴ Critically ill patients Increased Lack of reproducibility

Early percutaneous dilational tracheotomy⁵ Critically ill patients Increased Lack of reproducibility. Contradicted by subsequent large trials

Pressure vs Volume controlled ventilation⁶ Acute respiratory distress syndrome

Increased Lack of biological plausibility, reproducibility and poor methodology

Recruitment maneuver⁷ Acute respiratory distress syndrome

Increased Poor methodology

Glucocorticoids^8-9 Acute respiratory distress

syndrome

Increased Lack of reproducibility. Contradicted by subsequent larger trial

Ofloxacin prophylaxis¹⁰ Mechanically ventilated COPD patients

Increased Lack of generalizability

High-volume hemofiltration¹¹ Cardiac arrest Increased Lack of biological plausibility and reproducibility

Hydrocortisone¹² Severe community acquired

pneumonia

Increased Preliminary evidence. Contradicted by trials of steroids in sepsis

External cooling¹³ Sepsis/

Septic shock

Increased Preliminary evidence. Lack of reproducibility

Hydrocortisone and fludrocortisone¹⁴ Sepsis/Septic shock Increased Lack of reproducibility, poor methodology. Difference only after adjustments

Talactoferrin¹⁵ Sepsis/Septic Shock Increased Preliminary evidence. Modified intention to treat analysis used

Parenteral branch-chain amino acids¹⁶ Sepsis/Septic Shock Increased Lack of reproducibility, poor methodology

10 Table S2 -Trials excluded after the web survey.

Treatment Reference Agreement (%) Use (%)

Antimicrobial therapy¹⁷ Crit Care, Nseir, 2008 46% 41%

Enteral antioxidant supplementation¹⁸ Anesth Analg, Crimi, 2004 18% 17%

Non invasive ventilation¹⁹ N Engl J Med, Esteban, 2004 49% 42%

Nitric oxide synthase inhibitor (546C88)²⁰ Crit Care Med, Lopez, 2004 49% 37%

We excluded the interventions that collect an agreement of less than 50% at the interactive web questionnaire published online after the consensus meeting.

11 Table S3 – Characteristics of the populations and the interventions studied in the trials excluded by the Consensus Conference and the web vote.

Treatment Population Intervention Comparator Effect on

survival Antioxidant disodium edetate in propofol

infusion (vs propofol alone)¹

Intubated stable patients Propofol EDTA Propofol increased

Intermittent dialysis vs continuous renal replacement therapy²

Adult ICU patients with ARF Intermittent hemodialysis Continuous hemodiafiltration increased

Drotrecogin alfa activated (Xigris)³ Severe sepsis Drotrecogin alfa activated Placebo increased

Immuno-enhancing enteral diets⁴ Septic patients, older than 14 years Impact (Novartis Nutrition) Precitene Hiperproteico (PH) (Novartis Nutrition, Bern, Switzerland)

increased

Early percutaneous dilational tracheotomy⁵

Intubated patients with ARF, expected to need ventilatory support for at least 14 days

Percutaneous tracheotomy within 48 hours

Percutaneous tracheotomy at days 14–16 day

increased

Pressure vs Volume controlled ventilation⁶ ARDS Pressure controlled ventilation Volume controlled ventilation increased

Recruitment maneuver⁷ ARDS Protective mechanical ventilation +

Recruitment maneuver

Protective mechanical ventilation

increased

Glucocorticoids⁸ ARDS Methylprednisolone iv, than orally Placebo iv, than orally increased

Glucocorticoids⁹ ARDS Methylprednisolone iv, than orally Placebo iv, than orally increased

Ofloxacin prophylaxis¹⁰ Exacerbation of COPD requiring mechanical ventilation

Ofloxacin Placebo increased

High-volume hemofiltration¹¹ Patients with ROSC after cardiac arrest

Standard supportive care + isovolumic high volume hemofiltration

Standard supportive care increased

High-volume hemofiltration¹¹ Patients with ROSC after cardiac arrest

Standard supportive care + isovolumic high volume hemofiltration +

hypothermia

Standard supportive care increased

Hydrocortisone¹² Severe pneumonia Hydrocortisone iv Placebo increased

12

External cooling¹³ Septic shock External cooling + standard supportive

care

Standard supportive care increased

Hydrocortisone and fludrocortisone¹⁴ Septic shock Hydrocortisone iv + fludrocortisone orally

Placebo increased

Talactoferrin¹⁵ Severe sepsis Talactoferrin Placebo increased

Parenteral branch-chain amino acids¹⁶ Septic patients unable to receive enteral nutrition

Branch-chain amino acids-rich formulas (45%) PNT

Standard PNT increased

Antimicrobial therapy¹⁷ ICU patients expected to need enteral feeding for at least 10 days

Enteral nutrition + vitamins E and C Enteral nutrition increased

Enteral antioxidant supplementation¹⁸ Intubated patients with VAT Antimicrobial treatment iv No antimicrobial treatment increased

Non invasive ventilation¹⁹ Successfully extubated patients NIV Standard medical therapy decreased

Nitric oxide synthase inhibitor (546C88)²⁰ Septic shock Hydrochloride salt of NG -methyl-L- arginine (546C88) iv

Placebo decreased

ARF = acute respiratory failure, ARDS = acute respiratory distress syndrome, COPD = chronic obstructive pulmonary disease, EDTA =

ethylenediaminetetraacetic acid, ICU- intensive care unit, iv = intravenously, NIV- non invasive ventilation, PNT = parenteral nutrition, VAT = ventilator associated tracheobronchitis

13 Table S4 – Characteristic of excluded trials, details on trial size, size effect, follow-up, end of enrollment, and blinding.

Treatment Centers Patient ARR RRR NNT p-value Follow-up (*significant) Stopped at

interim

Blind

Antioxidant disodium edetate in propofol infusion (vs propofol alone)¹

7 126 0.158 0.905 6 <0.05 7 days*; 28 days* no yes

Intermittent dialysis vs continuous renal replacement therapy²

4 166 0.179 0.273 6 <0.02 Hospital discharge*; 28 days* no no

Drotrecogin alfa activated (Xigris)³ 164 1690 0.061 0.198 16 0.005 28 days* no yes

Immuno-enhancing enteral diets⁴ 6 176 0.131 0.407 8 <0.05 ICU discharge* no no

Early percutaneous dilational tracheotomy⁵ 2 120 0.3 0.486 3 <0.005 28 days* no no

Pressure vs Volume controlled ventilation⁶ 12 79 0.204 0.295 5 0.02 ICU and hospital discharge* no no

Recruitment maneuver⁷ 14 110 0.2 0.379 5 0.03 ICU* and hospital discharge,

28 days

no yes

Glucocorticoids⁸ 5 91 0.222 0.518 5 0.03 ICU* and hospital discharge no yes

Glucocorticoids⁹ 4 24 0.625 1 2 0.002 ICU* and hospital discharge* no yes

Ofloxacin prophylaxis¹⁰ 2 93 0.175 0.805 6 0.01 ICU* and hospital discharge* no yes

High-volume hemofiltration¹¹ 2 61 0.239 0.303 4 0.026 Hospital discharge*; 6

months

yes no

0.108 0.137 9 0.018

Hydrocortisone¹² 6 46 0.304 0.999 3 0.009 ICU* and hospital discharge*,

60 days*

no yes

External cooling¹³ 7 200 0.155 0.451 6 0.013 ICU and hospital discharge,

14 days*

no no

Hydrocortisone and fludrocortisone¹⁴ 19 300 0.064 0.105 16 0.09 ICU and hospital discharge, 28 days, and one year

no yes

Talactoferrin¹⁵ 24 190 0.138 0.401 7 0.039 28 and 90 days, 6 months* no yes

14

Parenteral branch-chain amino acids¹⁶ 7 69 0.26 0.636 4 <0.03 ICU* and hospital discharge no no

Antimicrobial therapy¹⁷ 3 224 0.241 0.355 4 <0.05 28 days* no yes

Enteral antioxidant supplementation¹⁸ 12 58 0.29 0.614 3 0.047 ICU discharge* yes no

Non invasive ventilation¹⁹ 37 221 0.105 0.749 10 0.048 ICU discharge* yes no

Nitric oxide synthase inhibitor (546C88)²⁰ 124 797 0.104 0.214 10 0.001 28 days*; 60 days*; 90 days* yes yes

ARR = absolute risk reduction, ICU = intensive care unit, NNT = number need to treat to save one life, RRR = relative risk reduction

15 Table S5 – Complete statistical analysis of selected trials

Outcome Blinding

Increase mortality Improve Survival p Unblind Blind p

Trail size Number of patients 540 (219-1013.5) 116(87.5-305.5) 0.0433 106(90-336) 532(126-1223) 0.0390

Number of centres 32.5(18-41) 6(3-10.5) 0.0166 5(3-11) 26(18-46) 0.0082

Effect Size ARR/ARI 0.113(0.0635-0.2105) 0.115(0.121-0.1985) 0.3743 0.142(0.12-0.238) 0.109(0.052-0.221) 0.3568 RRR/RRI 0.4(0.1852-0.7845) 0.53(0.3495-0.6954) 0.5815 0.521(0.332-0.675) 0.468(0.174-0.902) 0.7250

NNT/NNH 9(5-16) 6.5(5-8) 0.2003 7(5-8) 9(5-19) 0.2850

Number of patients ARR/ARI RRR/RRI NNT/NNH Number of centers Number of patients 1.0000

ARR/ARI -0.5203 1.0000

0.0091

RRR/RRI -0.4316 0.5674 1.0000

0.0352 0.0038

NNT/NNH -0.9628 -0.6843 -0.5368 1.0000

0.0000 0.0002 0.0068

Number of centres 0.9615 -0.5300 -0.4190 0.9134 1.0000 0.0000 0.0077 0.0416 0.0000

16 Table S6 - Complete statistical analysis of all trials identified by the systematic literature search

Outcome Blinding

Increase mortality Improve Survival p Unblind Blind p

Trail size Number of patients 540(221-804) 115(82-224) 0.0039 120(85-236) 190(93-797) 0.2505

Number of centres 38(18-42) 6.5(3-12) 0.0014 6(3-11) 18(6-40) 0.0144

Effect Size ARR/ARI 0.107(0.075-0.2) 0.177(0.134-0.222) 0.0409 0.168(0.122-0.2) 0.175(0.075-0.221) 0.8210 RRR/RRI 0.4(0.191-0.749) 0.492(0.191-0.749) 0.5565 0.486(0.273-0.64) 0.401(0.191-0.902) 0.9528

NNT/NNH 9.5(5-13) 6(5-7) 0.0236 6(5-8) 6(5-13) 0.7017

Number of patients ARR/ARI RRR/RRI NNT/NNH Number of centers Number of patients 1.0000

ARR/ARI -0.3486 1.0000

0.0204

RRR/RRI -0.3346 0.5313 1.0000

0.0264 0.0002

NNT/NNH 0.9464 0.5420 -0.4608 1.0000

0.0000 0.0001 0.0016

Number of centres 0.7910 -0.4312 -0.3977 0.7841 1.0000 0.0000 0.0035 0.0075 0.0000

17 Table S7– Comparison of the selected and excluded trials

Selected Papers

Excluded Papers

Papers excluded by consensus conference

Papers excluded by

web vote

Comparison

1 2+3 2 3 1 vs 2 vs 3 1 vs 2+3 1 vs 2 1 vs 3 2 vs 3

N of patients median 199 123 115 222.5 NS NS NS NS NS

IQR 101.5-540 74-210.5 74-183 139.5-510.5

N of centres median 9.5 7 6.5 24.5 NS NS NS NS NS

IQR 3-26.5 4-16.5 4-13 7.5-80.5

ARR/ARI median 0.142 0.177 0.177 0.173 NS NS NS NS NS

IQR 0.105-0.2 0.1345-0.2505 0.1465-0.241 0.1045-0.2655

RRR/RRI median 0.505 0.429 0.429 0.4845 NS NS NS NS NS

IQR 0.245-0.6954 0.284-0.6925 0.284-0.7205 0.2845-0.6815

NNT/NNH median 7 6 6 7 NS NS NS NS NS

IQR 7-9.5 4-7.5 4.5-6.5 3.5-10

Blinding 7/24 12/20 10/16 2/4 NS 0.040 0.037 NS NS

% 29.17% 60% 62.5% 50%

Save life 16/24 18/20 16/16 2/4 0.019 NS 0.010 NS 0.003

% 66.67% 90% 100% 50%

18 Table S8 Agreement and use in practice scores for interventions that increase survival

Treatment Agreement (%) Use (%)

Albumin in hepatorenal syndrome²¹ 75% 65%

Daily interruption of sedatives²² 70% 60%

Mild hypotermia²³ 92% 88%

Non invasive ventilation^24-31 94% 90%

Prone position³² 77% 56%

Protective ventilation^33-35 86% 85%

Tranexamic acid³⁶ 75% 55%

19 Table S9 - Agreement and use in practice score for interventions that increase mortality

Treatment Agreement (%) Avoidance (%)

Supranormal elevation of systemic oxygen delivery³⁷ 84% 73%

Diaspirin cross-linked hemoglobin³⁸ 86% NA*

Growth hormone³⁹ 86% 70%

Tight glucose control⁴⁰ 89% 84%

IV Salbutamol⁴¹ 76% 64%

Hydroxyethyl starch⁴² 88% 84%

High frequencies oscillation ventilation⁴³ 73% 63%

Glutamine supplementation⁴⁴ 71% 59%

* NA = not applicable. Diaspirin cross-linked hemoglobin was not commercialized, therefore we could not investigate if the clinicians use this evidence to guide their clinical practice.

20 Table S10 – Nationality of web survey clinicians

Country Frequency Percent

Australia 60 10.8

Italy 60 10.8

USA 58 10.5

France 34 6.1

South America 40 7.2

Africa 12 2.2

Asia 54 9.7

Europe 142 25.6

Russia 13 2.3

Canada 11 2.0

Others 71 12.8

total 555 100

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