Full search strategy Additional statistical analyses...
Transcript of 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
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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).
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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.
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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.
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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).
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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.
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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).
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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
Acute respiratory distress syndrome
Increased Poor methodology
Glucocorticoids8-9
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
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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.
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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 therapy
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
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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
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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
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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 therapy
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
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
13
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
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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
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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%
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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%
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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.
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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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