full search strategy additional statistical analyses...

1

Supplementary Appendix

Table of contents

Full search strategy

The consensus process and major exclusions

Additional statistical analyses

Figure legends

Tables

Supplemental References

2

Full search strategy

The literature was searched systematically on MEDLINE/PubMed and updated to June 20th 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 (Fig. S1, Supplemental Digital Content 2,

http://links.lww.com/CCM/B244).

3

The Consensus process and major exclusions The 63 papers identified with the search strategy detailed above and well explained in Figure S1

(Supplemental Digital Content 2, http://links.lww.com/CCM/B244) were further discussed during

the Consensus meeting and 24 papers were finally selected to be voted online.

During the consensus meeting 21 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 Tables S3 and S4.

4

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 (Supplemental Digital Content 5,

http://links.lww.com/CCM/B247) 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.

5

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

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).

6

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 (Fig. S5, Supplemental Digital Content 6, http://links.lww.com/CCM/B248). The

difference between agreement and use is presented in Figure S6 (Supplemental Digital Content 7,

http://links.lww.com/CCM/B249). 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.

7

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).

8

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 therapy

2

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


Increased Poor methodology

Glucocorticoids8-9


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

9

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.

10

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


1

Intubated stable patients Propofol EDTA Propofol increased


2

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 tracheotomy

5

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


Exacerbation of COPD requiring mechanical ventilation

Ofloxacin Placebo increased


Patients with ROSC after cardiac arrest

Standard supportive care + isovolumic high volume hemofiltration

Standard supportive care increased


Patients with ROSC after cardiac arrest

Standard supportive care + isovolumic high volume hemofiltration + hypothermia


Hydrocortisone12

Severe pneumonia Hydrocortisone iv Placebo increased

11

External cooling13

Septic shock External cooling + standard supportive care



Septic shock Hydrocortisone iv + fludrocortisone orally

Placebo increased

Talactoferrin15

Severe sepsis Talactoferrin Placebo increased


Septic patients unable to receive enteral nutrition

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

Standard PNT increased


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

Enteral nutrition + vitamins E and C Enteral nutrition increased


Intubated patients with VAT Antimicrobial treatment iv No antimicrobial treatment increased


Successfully extubated patients NIV Standard medical therapy decreased


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

12

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


1

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


2

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


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


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


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

13


7 69 0.26 0.636 4 <0.03 ICU* and hospital discharge no no


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


12 58 0.29 0.614 3 0.047 ICU discharge* yes no


37 221 0.105 0.749 10 0.048 ICU discharge* yes no


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

14

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

15

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

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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%

17

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 ventilation24-31

94% 90%

Prone position32

77% 56%

Protective ventilation33-35

86% 85%

Tranexamic acid36

75% 55%

18

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 hemoglobin

38 86% NA*

Growth hormone39

86% 70%

Tight glucose control40

89% 84%

IV Salbutamol41

76% 64%

Hydroxyethyl starch42

88% 84% High frequencies oscillation ventilation

43 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.

19

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

20

Supplemental References

1. Herr DL, Kelly K, Hall JB, Ulatowski J, Fulda GJ, Cason B, Hickey R, Nejman AM, Zaloga GP, Teres

D. Safety and efficacy of propofol with EDTA when used for sedation of surgical intensive care unit

patients. Intensive Care Med 2000;26 Suppl 4:S452-62.

2. Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, Kaplan RM; Collaborative

Group for Treatment of ARF in the ICU. A randomized clinical trial of continuous versus

intermittent dialysis for acute renal failure. Kidney Int 2001;60:1154-63.

3. Bernard GR1, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS,

Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide

Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human

activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.

4. Galbán C, Montejo JC, Mesejo A, Marco P, Celaya S, Sánchez-Segura JM, Farré M, Bryg DJ. An

immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic

intensive care unit patients. Crit Care Med 2000;28:643-8.

5. Rumbak MJ, Newton M, Truncale T, Schwartz SW, Adams JW, Hazard PB. A prospective,

randomized, study comparing early percutaneous dilational tracheotomy to prolonged

translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. Crit Care Med

2004;32:1689-94.

21

6. Esteban A, Alía I, Gordo F, de Pablo R, Suarez J, González G, Blanco J. For the Spanish Lung

Failure Collaborative Group. Prospective randomized trial comparing pressure-controlled

ventilation and volume-controlled ventilation in ARDS. Chest 2000;117:1690-6.

7. Xi XM, Jiang L, Zhu B. Clinical efficacy and safety of recruitment maneuver in patients with acute

respiratory distress syndrome using low tidal volume ventilation: a multicenter randomized

controlled clinical trial. Chin Med J 2010;123:3100-5.

8. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R.

Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest

2007;131:954-63.

9. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of

prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a

randomized controlled trial. JAMA 1998;280:159-65.

10. Nouira S, Marghli S, Belghith M, Besbes L, Elatrous S, Abroug F. Once daily oral ofloxacin in

chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a

randomised placebo-controlled trial. Lancet 2001;358:2020-5.

11. Laurent I, Adrie C, Vinsonneau C, Cariou A, Chiche JD, Ohanessian A, Spaulding C, Carli P,

Dhainaut JF, Monchi M. High-volume hemofiltration after out-of-hospital cardiac arrest: a

randomized study. J Am Coll Cardiol 2005;46:432-7.

22

12. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C,

Blasi F, Umberger R, Meduri GU. Hydrocortisone infusion for severe community-acquired

pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-8.

13. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, Dellamonica J, Bouadma L,

Cook F, Beji O, Brun-Buisson C, Lemaire F, Brochard L. Fever control using external cooling in septic

shock: a randomized controlled trial. Am J Respir Crit Care Med 2012;185:1088-95.

14. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y,

Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of

hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA

2002;288:862-71.

15. Guntupalli K, Dean N, Morris PE, Bandi V, Margolis B, Rivers E, Levy M, Lodato RF, Ismail PM,

Reese A, Schaumberg JP, Malik R, Dellinger RP; TLF LF-0801 Investigator Group. A phase 2

randomized, double-blind, placebo-controlled study of the safety and efficacy of talactoferrin in

patients with severe sepsis. Crit Care Med 2013;4:706-16.

16. García-de-Lorenzo A, Ortíz-Leyba C, Planas M, Montejo JC, Núñez R, Ordóñez FJ, Aragón C,

Jiménez FJ. Parenteral administration of different amounts of branch-chain amino acids in septic

patients: clinical and metabolic aspects. Crit Care Med 1997;25:418-24.

23

17. Nseir S, Favory R, Jozefowicz E, Decamps F, Dewavrin F, Brunin G, Di Pompeo C, Mathieu D,

Durocher A; VAT Study Group. Antimicrobial treatment for ventilator-associated

tracheobronchitis: a randomized, controlled, multicenter study. Crit Care 2008; 12:R62.

18. Crimi E, Liguori A, Condorelli M, Cioffi M, Astuto M, Bontempo P, Pignalosa O, Vietri MT,

Molinari AM, Sica V, Della Corte F, Napoli C. The beneficial effects of antioxidant supplementation

in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-

controlled trial. Anesth Analg 2004; 99:857-63.

19. Esteban A, Frutos-Vivar F, Ferguson ND, Arabi Y, Apezteguía C, González M, Epstein SK, Hill NS,

Nava S, Soares MA, D'Empaire G, Alía I, Anzueto A. Noninvasive positive-pressure ventilation for

respiratory failure after extubation. N Engl J Med 2004; 350:2452-60.

20. López A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A,

Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S,

Grover R. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide

synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 2004;

32:21-30.

21. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, Castells L, Vargas V, Soriano

G, Guevara M, Ginès P, Rodés J. Effect of intravenous albumin on renal impairment and mortality

in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-9.

24

22.Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG,

Pohlman AS, Kinniry PA, Jackson JC, Canonico AE, Light RW, Shintani AK, Thompson JL, Gordon SM,

Hall JB, Dittus RS, Bernard GR, Ely EW. Efficacy and safety of a paired sedation and ventilator

weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing

Controlled trial): a randomised controlled trial. Lancet 2008;371:126-34.

23. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the

neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56.

24. Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, Simonneau G, Benito S,

Gasparetto A, Lemaire F, et al. Noninvasive ventilation for acute exacerbations of chronic

obstructive pulmonary disease. N Engl J Med 1995;333:817-22.

25. Nava S, Ambrosino N, Clini E, Prato M, Orlando G, Vitacca M, Brigada P, Fracchia C, Rubini F.

Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to

chronic obstructive pulmonary disease. A randomized, controlled trial. Ann Intern Med

1998;128:721-8.

26. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of

chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised

controlled trial. Lancet 2000;355:1931-5.

25

27. Ferrer M, Esquinas A, Leon M, Gonzalez G, Alarcon A, Torres A. Noninvasive ventilation in

severe hypoxemic respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med

2003;168:1438-44.

28. Ferrer M, Valencia M, Nicolas JM, Bernadich O, Badia JR, Torres A. Early noninvasive

ventilation averts extubation failure in patients at risk: a randomized trial. Am J Respir Crit Care

Med. 2006;173:164-70.

29. Collaborating Research Group for Noninvasive Mechanical Ventilation of Chinese Respiratory

Society. Pulmonary infection control window in treatment of severe respiratory failure of chronic

obstructive pulmonary diseases: a prospective, randomized controlled, multi-centred study. Chin

Med J (Engl) 2005;118:1589-94.

30. Ferrer M, Sellarés J, Valencia M, Carrillo A, Gonzalez G, Badia JR, Nicolas JM, Torres A. Non-

invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders:

randomised controlled trial. Lancet 2009;374:1082-8.

31. Nava S, Grassi M, Fanfulla F, Domenighetti G, Carlucci A, Perren A, Dell'Orso D, Vitacca M,

Ceriana P, Karakurt Z, Clini E. Non-invasive ventilation in elderly patients with acute hypercapnic

respiratory failure: a randomised controlled trial. Age Ageing 2011;40:444-50.

32. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A,

Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C,

Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study

26

Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med

2013;368:2159-68.

33. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA,

Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. Effect of a protective-ventilation

strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-54.

34. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung

injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome

Network. N Engl J Med 2000;342:1301-8.

35.Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A. A high positive end-expiratory

pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory

distress syndrome: a randomized, controlled trial. Crit Care Med 2006;34:1311-8.

36. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-

Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe

E, Marrero MA, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R,

Ramana PV, Ravi RR, Yutthakasemsunt S. Effects of tranexamic acid on death, vascular occlusive

events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a

randomised, placebo-controlled trial. Lancet 2010;376:23-32.

37. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen

delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-22.

27

38. Sloan EP, Koenigsberg M, Gens D, Cipolle M, Runge J, Mallory MN, Rodman G Jr. Diaspirin

cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock: a

randomized controlled efficacy trial. JAMA 1999;282:1857-64.

39. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ.

Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med

1999;341:785-92.

40. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V,

Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C,

McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus

conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283-97.

41. Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE; BALTI-

2 study investigators. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute

respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet

2012;379:229-35.

42. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller

MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P,

Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB,

Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S

Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's

acetate in severe sepsis. N Engl J Med 2012;367:124-34.

28

43. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD,

Lamontagne F, Granton JT, Arabi YM, Arroliga AC, Stewart TE, Slutsky AS, Meade MO; OSCILLATE

Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute

respiratory distress syndrome. N Engl J Med 2013;368:795-805.

44. Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day

AG; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in

critically ill patients. N Engl J Med 2013;368:1489-97.

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