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Scientific Letter to the Editor: Need for a Definitive Study of Global Longitudinal Strain for Prognostication in Septic Cardiomyopathy

2019; Elsevier BV; Volume: 32; Issue: 4 Linguagem: Inglês

10.1016/j.echo.2018.12.005

1097-6795

Robert R. Ehrman, Steven C. Moore, Mark Favot, Katherine G. Akers, John Gallien, Robert D. Welch, Aiden Abidov, Robert Sherwin, Phillip D. Levy,

Cardiovascular Function and Risk Factors

While the care of septic patients has improved over the last decade, there is a lack of a thorough understanding of the role that cardiac dysfunction plays in the pathophysiologic cascade of sepsis, the response to treatment, and overall outcomes. Cardiac dysfunction in sepsis has been recognized for more than 40 years,1Weisel R.D. Vito L. Dennis R.C. Valeri C.R. Hechtman H.B. Myocardial depression during sepsis.Am J Surg. 1977; 133: 512-521Abstract Full Text PDF PubMed Scopus (119) Google Scholar but the natural history of septic cardiomyopathy is poorly understood. This may be due to the complex interactions among host factors, pathogen factors, and therapeutic interventions and that their ultimate effect on cardiac performance likely exists across a spectrum of severity. Determination of left ventricular ejection fraction (LVEF) by echocardiography is commonly used to determine global LV performance.2Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of echocardiography and the European association of Cardiovascular imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4274) Google Scholar Early studies reported reduced LVEF in survivors when compared with nonsurvivors,3Parker M.M. Shelhamer J.H. Bacharach S.L. Green M.V. Natanson C. Frederick T.M. et al.Profound but reversible myocardial depression in patients with septic shock.Ann Intern Med. 1984; 100: 483-490Crossref PubMed Scopus (1010) Google Scholar but subsequent meta-analyses, with over 1,300 patients, failed to detect any meaningful relationship between LVEF and survival from sepsis or septic shock.4Huang S.J. Nalos M. McLean A.S. Is early ventricular dysfunction or dilatation associated with lower mortality rate in adult severe sepsis and septic shock? A meta-analysis.Crit Care. 2013; 17: R96Crossref PubMed Scopus (114) Google Scholar, 5Sevilla Berrios R.A. O'Horo J.C. Velagapudi V. Pulido J.N. Correlation of left ventricular systolic dysfunction determined by low ejection fraction and 30-day mortality in patients with severe sepsis and septic shock: a systematic review and meta-analysis.J Crit Care. 2014; 29: 495-499Crossref PubMed Scopus (84) Google Scholar Another method for quantifying LV performance is through the use of speckle-tracking echocardiography (STE).6Gorcsan 3rd, J. Tanaka H. Echocardiographic assessment of myocardial strain.J Am Coll Cardiol. 2011; 58: 1401-1413Crossref PubMed Scopus (343) Google Scholar The most commonly used strain parameter is global longitudinal strain (GLS), which represents the mean of the peak longitudinal systolic strain values from each segment of the LV.7Smiseth O.A. Torp H. Opdahl A. Haugaa K.H. Urheim S. Myocardial strain imaging: how useful is it in clinical decision making?.Eur Heart J. 2016; 37: 1196-1207Crossref PubMed Scopus (476) Google Scholar Assessment of the longitudinally orientated subendocardial fibers—the first to demonstrate impaired function—by STE is potentially advantageous compared with LVEF, which is strictly a volumetric measurement. In some instances, subtle perturbations in LV systolic performance have been detected using STE prior to decline in EF.8Liu Y.W. Tsai W.C. Su C.T. Lin C.C. Chen J.H. Evidence of left ventricular systolic dysfunction detected by automated function imaging in patients with heart failure and preserved left ventricular ejection fraction.J Card Fail. 2009; 15: 782-789Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 9Basu S. Frank L.H. Fenton K.E. Sable C.A. Levy R.J. Berger J.T. Two-dimensional speckle tracking imaging detects impaired myocardial performance in children with septic shock, not recognized by conventional echocardiography.Pediatric Crit Care Med. 2012; 13: 259-264Crossref PubMed Scopus (77) Google Scholar Impaired GLS has been associated with increased mortality in sepsis,10Chang W.T. Lee W.H. Lee W.T. Chen P.S. Su Y.R. Liu P.Y. et al.Left ventricular global longitudinal strain is independently associated with mortality in septic shock patients.Intensive Care Med. 2015; 41: 1791-1799Crossref PubMed Scopus (58) Google Scholar, 11Innocenti F. Palmieri V. Guzzo A. Stefanone V.T. Donnini C. Pini R. SOFA score and left ventricular systolic function as predictors of short-term outcome in patients with sepsis.Intern Emerg Med. 2018; 13: 51-58Google Scholar although the studies are heterogeneous and report varying results.12De Geer L. Engvall J. Oscarsson A. Strain echocardiography in septic shock—a comparison with systolic and diastolic function parameters, cardiac biomarkers and outcome.Crit Care. 2015; 19: 122Crossref PubMed Scopus (69) Google Scholar, 13Orde S.R. Pulido J.N. Masaki M. Gillespie S. Spoon J.N. Kane G.C. et al.Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function.Crit Care. 2014; 18: R149Crossref PubMed Scopus (114) Google Scholar, 14Zaky A. Gill E.A. Lin C.P. Paul C.P. Bendjelid K. Treggiari M.M. Characteristics of sepsis-induced cardiac dysfunction using speckle-tracking echocardiography: a feasibility study.Anaesth Intensive Care. 2016; 44: 65-76PubMed Google Scholar It is unknown whether GLS is a better predictor of mortality in sepsis than LVEF. We therefore performed a systematic review and meta-analysis to evaluate differences in GLS and LVEF between survivors and nonsurvivors with sepsis, severe sepsis, or septic shock. Our review was registered with the international prospective register of systematic reviews (PROSPERO), registry number CRD42018091302. We searched PubMed, EMBASE, CINAHL, Web of Science, Cochrane Library, and Google Scholar from inception through March 2018. Full details of the search strategy and article selection process, data extraction, and quality assessment are available in the Supplemental Appendix. Studies were included if they used a prospective study design, included adult patients with sepsis (by any definition) measured by GLS and LVEF, and reported all-cause mortality as an outcome. Echocardiograms were performed within 24 hours of hospital admission or diagnosis of sepsis. For LVEF, measurement per American Society for Echocardiography (ASE) Guidelines was required. For GLS, studies were eligible for inclusion only if strain was calculated from all three apical windows using STE. The primary outcome for this analysis was a difference in means of GLS and LVEF measured on echocardiographic diagnostic tests performed within 24 hours of hospitalization, among survivors, compared with those who died within 30 days. From the initial database search, 65 studies were identified as being potentially eligible (Figure 1). After title/abstract and full-text screening, five journal articles were included. Supplemental Table 1 (available at www.onlinejase.com) contains further details of study designs. A total of five studies, with 385 patients, were included in the quantitative analysis.10Chang W.T. Lee W.H. Lee W.T. Chen P.S. Su Y.R. Liu P.Y. et al.Left ventricular global longitudinal strain is independently associated with mortality in septic shock patients.Intensive Care Med. 2015; 41: 1791-1799Crossref PubMed Scopus (58) Google Scholar, 11Innocenti F. Palmieri V. Guzzo A. Stefanone V.T. Donnini C. Pini R. SOFA score and left ventricular systolic function as predictors of short-term outcome in patients with sepsis.Intern Emerg Med. 2018; 13: 51-58Google Scholar, 12De Geer L. Engvall J. Oscarsson A. Strain echocardiography in septic shock—a comparison with systolic and diastolic function parameters, cardiac biomarkers and outcome.Crit Care. 2015; 19: 122Crossref PubMed Scopus (69) Google Scholar, 13Orde S.R. Pulido J.N. Masaki M. Gillespie S. Spoon J.N. Kane G.C. et al.Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function.Crit Care. 2014; 18: R149Crossref PubMed Scopus (114) Google Scholar, 15Ricarte-Bratti J.P. Brizuela N.Y. Urinovsky M. Moreyra E. Paredes S.G. Vogliotti I. et al.Prognostic value of ventricular function assessed by speckle tracking echocardiography in patients with sepsis.Insufic Card. 2017; 12: 2-8Google Scholar There was heterogeneity in the inclusion criteria of enrollment, particularly patient acuity and hospital location. Patient populations varied (sepsis/severe sepsis/septic shock) as did admission location (ICU vs non-ICU). Mortality ranged from 27% to 35%. Acuity and associated risk factors could not be directly compared across studies due to heterogeneity and/or nonreporting of acuity indices and patient comorbidities (Supplemental Appendix, available at www.onlinejase.com). Pooled EF and GLS data were evaluated using random and fixed effects modeling to compare mean differences between survivors and nonsurvivors. Statistically significant differences in GLS and LVEF among the compared groups were seen on random effects modeling (−1.67 [95% CI, −6.67, −0.48] and 2.53 [95% CI, −0.86, 5.91], respectively; Figure 2), but not with fixed effects. Statistical heterogeneity was low for GLS (I2 = 30%) and LVEF (I2 = 23%). All studies had high risk of bias in patient flow and timing of the reference standard domains; there was varied risk in the remaining domains (Supplemental Figure 1, available at www.onlinejase.com). Chang et al10Chang W.T. Lee W.H. Lee W.T. Chen P.S. Su Y.R. Liu P.Y. et al.Left ventricular global longitudinal strain is independently associated with mortality in septic shock patients.Intensive Care Med. 2015; 41: 1791-1799Crossref PubMed Scopus (58) Google Scholar reported in-hospital rather than 30-day mortality; sensitivity analysis using the random effects model, with this study excluded, found a mean difference in GLS of −1.33 (95% CI, −2.89, 0.24), and 2.13 (95% CI, −1.32, 5.58) for LVEF. In individual studies, point estimates for GLS were better in survivors in four of five studies, with only Orde et al13Orde S.R. Pulido J.N. Masaki M. Gillespie S. Spoon J.N. Kane G.C. et al.Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function.Crit Care. 2014; 18: R149Crossref PubMed Scopus (114) Google Scholar reporting the reverse; the reasons for this small difference (−13.9 vs −14.6) are unclear given the marked clinical variation between studies. Exclusion of the Chang et al study10Chang W.T. Lee W.H. Lee W.T. Chen P.S. Su Y.R. Liu P.Y. et al.Left ventricular global longitudinal strain is independently associated with mortality in septic shock patients.Intensive Care Med. 2015; 41: 1791-1799Crossref PubMed Scopus (58) Google Scholar caused loss of statistical significance in the random effects model for GLS, but we feel that given the acuity of sepsis, in-hospital mortality likely approximates 30-day morality and therefore results of the full model represent the true relationship between GLS and mortality. Future studies should consider GLS as a more reliable modality for the echocardiographic evaluation of septic cardiomyopathy. While commonly used, LVEF has important limitations, including the geometric assumptions that are used when EF is calculated by Simpson's method, beat-to-beat variability, and dependency on loading conditions of the LV.2Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of echocardiography and the European association of Cardiovascular imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4274) Google Scholar GLS is advantageous in that it provides more granular detail of myocardial performance; subtle changes in LV function not evident by LVEF assessment are detectable by STE analysis, likely owing to the fact that STE is a myocardial imaging technique as opposed to the volumetric nature of LVEF. This is consistent with prior data that identified impaired LV performance via STE prior to changes in LVEF in patients with both sepsis and heart failure (HF).8Liu Y.W. Tsai W.C. Su C.T. Lin C.C. Chen J.H. Evidence of left ventricular systolic dysfunction detected by automated function imaging in patients with heart failure and preserved left ventricular ejection fraction.J Card Fail. 2009; 15: 782-789Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 9Basu S. Frank L.H. Fenton K.E. Sable C.A. Levy R.J. Berger J.T. Two-dimensional speckle tracking imaging detects impaired myocardial performance in children with septic shock, not recognized by conventional echocardiography.Pediatric Crit Care Med. 2012; 13: 259-264Crossref PubMed Scopus (77) Google Scholar While LVEF was relatively preserved in the included studies, our finding of no association between LVEF and mortality is consistent with two prior meta-analyses of 1,367 patients that found no significant differences in LVEF between survivors and nonsurvivors of severe sepsis and septic shock,4Huang S.J. Nalos M. McLean A.S. Is early ventricular dysfunction or dilatation associated with lower mortality rate in adult severe sepsis and septic shock? A meta-analysis.Crit Care. 2013; 17: R96Crossref PubMed Scopus (114) Google Scholar, 5Sevilla Berrios R.A. O'Horo J.C. Velagapudi V. Pulido J.N. Correlation of left ventricular systolic dysfunction determined by low ejection fraction and 30-day mortality in patients with severe sepsis and septic shock: a systematic review and meta-analysis.J Crit Care. 2014; 29: 495-499Crossref PubMed Scopus (84) Google Scholar one of which included patients with more severely reduced LVEF. Our results, added to extant data, indicate that LVEF is insufficiently sensitive to be the primary echocardiographic parameter for the study of septic cardiomyopathy. With its superior ability to detect subtle dysfunction, GLS is likely a better tool for this purpose. A 2014 meta-analysis found impaired GLS was more strongly associated with mortality than reduced LVEF in HF patients16Kalam K. Otahal P. Marwick T.H. Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction.Heart. 2014; 100: 1673-1680Crossref PubMed Scopus (671) Google Scholar; while the pathophysiology differs, the putative benefit of STE is similar in both HF and sepsis, and thus these results bolster our findings. We pooled all GLS measurements uniformly, despite STE algorithms being vendor specific (as are resultant "normal" values)—with three analysis packages used across the five studies—which is a source of confounding.17Farsalinos K.E. Daraban A.M. Unlu S. Thomas J.D. Badano L.P. Voigt J.U. Head-to-head comparison of global longitudinal strain measurements among nine different vendors: the EACVI/ASE Inter-Vendor Comparison Study.J Am Soc Echocardiogr. 2015; 28: 1171-1181, e1172Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar Vendor-neutral analysis platforms may minimize these effects, but this approach has limited feasibility owing to the associated costs of these workstations. Perhaps the most significant source of confounding within individual studies is the timing of echocardiograms. All included studies reported that echocardiograms were performed within the first 24 hours of admission or diagnosis of sepsis, but specific timing data were only reported in a single study.15Ricarte-Bratti J.P. Brizuela N.Y. Urinovsky M. Moreyra E. Paredes S.G. Vogliotti I. et al.Prognostic value of ventricular function assessed by speckle tracking echocardiography in patients with sepsis.Insufic Card. 2017; 12: 2-8Google Scholar This is problematic for two reasons. First, a great deal of resuscitation takes place within the first 24 hours of a diagnosis of sepsis (up to 5 L of IV fluid, according to a recent meta-analysis18Angus D.C. Barnato A.E. Bell D. Bellomo R. Chong C.R. Coats T.J. et al.A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators.Intensive Care Med. 2015; 41: 1549-1560Crossref PubMed Scopus (261) Google Scholar) such that echocardiographic findings on arrival are likely significantly different from those at hour 23, owing to worsening of disease, response to treatment, or both. There is also potential for spectrum bias if, for example, more severely ill patients had resuscitative interventions prioritized and thus echocardiograms performed later, compared with more stable patients whose echocardiograms could be performed immediately. There was a high degree of inter- and intrastudy variability in this realm, both of which encourage cautious interpretation of our results. There was marked variation in reported illness severity, baseline comorbidities (including cardiac conditions such as dysrhythmias, valvular abnormalities, and chronic HF), and treatment approaches, all of which potentially impact echocardiographic findings. In other cases, lack of patient-level data in these areas hampers interpretation of pooled results, owing to the inability to determine whether patients were clinically similar across included studies. Sanfilippo et al19Sanfilippo F. Corredor C. Fletcher N. Tritapepe L. Lorini F.L. Arcadipane A. et al.Left ventricular systolic function evaluated by strain echocardiography and relationship with mortality in patients with severe sepsis or septic shock: a systematic review and meta-analysis.Crit Care. 2018; 22: 183Crossref PubMed Scopus (72) Google Scholar recently published a similar meta-analysis, including eight studies with 794 patients. They reported a standard mean difference in GLS between survivors and nonsurvivors of −0.26 (95% CI, −0.47, −.0.04; P = .02), a smaller effect than we report. However, our analysis differs from theirs in a critical way: we only included studies that reported true GLS—that is, strain measurements from all segments of the LV, obtained from all three apical views. Their analysis, however, included two studies where strain was only measured in the apical four-chamber view20Lanspa M.J. Shahul S. Hersh A. Wilson E.L. Olsen T.D. Hirshberg E.L. et al.Associations among left ventricular systolic function, tachycardia, and cardiac preload in septic patients.Ann Intensive Care. 2017; 7: 17Google Scholar, 21Shahul S. Gulati G. Hacker M.R. Mahmood F. Canelli R. Nizamuddin J. et al.Detection of myocardial dysfunction in septic shock: a speckle-tracking echocardiography study.Anesth Analg. 2015; 121: 1547-1554Crossref PubMed Scopus (41) Google Scholar and two where it was measured in the apical four- and two-chamber views.22Boissier F. Razazi K. Seemann A. Bedet A. Thille A.W. de Prost N. et al.Left ventricular systolic dysfunction during septic shock: the role of loading conditions.Intensive Care Med. 2017; 43: 633-642Crossref PubMed Scopus (73) Google Scholar, 23Landesberg G. Jaffe A.S. Gilon D. Levin P.D. Goodman S. Abu-Baih A. et al.Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation.Crit Care Med. 2014; 42: 790-800Crossref PubMed Scopus (154) Google Scholar These four studies leave a significant portion of the LV unmeasured and thus do not represent true GLS, the definition of which, according to the ASE, requires measurements from all three apical views2Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of echocardiography and the European association of Cardiovascular imaging.Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4274) Google Scholar; these studies were discovered as part of our search but were excluded for this reason. Pooling the results of these studies with those that truly measure GLS is problematic as they are not actually measuring the same parameter. Alternatively, it may be that the myocardial depression in sepsis is diffuse enough that meaningful dysfunction could be detected from the apical four-chamber view alone. This would increase the feasibility of STE analysis in this critically ill population and reduce the time needed to complete the examination. Lanspa et al20Lanspa M.J. Shahul S. Hersh A. Wilson E.L. Olsen T.D. Hirshberg E.L. et al.Associations among left ventricular systolic function, tachycardia, and cardiac preload in septic patients.Ann Intensive Care. 2017; 7: 17Google Scholar adopted a similar approach, using e' velocity alone to identify diastolic dysfunction in septic patients, and found increased feasibility without significant change in the correct identification thereof using full ASE criteria. The emergency department is the ideal setting in which to perform the clarifying investigations in this area as initial echocardiograms could be performed within a fixed, early, and narrow time period after presentation. Capturing patients upon arrival would allow differentiation between native function and response to resuscitative interventions. In addition to mortality and GLS, thorough reporting of clinical data (including cardiac and other comorbidities, markers of disease severity, use and duration of vasopressors and mechanical ventilation, volume of IV fluid administered, and hospital/ICU length of stay) is needed to minimize confounding and maximize generalizability of results. Serial examinations—from presentation through recovery or death—would also provide valuable data and help elucidate the currently unknown natural history of the disease. A more thorough understanding thereof is needed to determine whether current therapeutic paradigms are appropriate. Alteration of treatment strategies, based on this improved knowledge, has the potential to positively impact patient outcomes. In summary, we believe that the results presented in this letter suggest that GLS is the preferred modality for investigating the relationship between LV systolic function and outcomes in patients with septic cardiomyopathy. Existing primary studies are limited by substantial biases and clinical heterogeneity. A large-scale prospective study is needed to provide a definitive answer to this question. Search terms related to the heart ("left ventricle" or "left ventricular" or "LV" or "myocardial" or "cardiac"), GLS (strain or "speckle tracking"), LVEF ("ejection fraction"), sepsis ("sepsis" or "septic"), and mortality ("mortality" or "death" or "died") were combined to identify relevant published journal articles and conference abstracts. Keywords and their variants, MeSH terms, and/or Emtree terms were used as appropriate for each database. Search results were limited to human studies in the PubMed and EMBASE databases; no limits related to language or publication dates were imposed. The reference lists of relevant studies were screened to identify additional articles. The search strategy was designed and conducted by a medical research librarian (K.G.A.). A flowchart of the article screening process is shown in Supplemental Figure 1. After deduplicating the search results from different databases, studies underwent two rounds of screening based on their (1) title/abstract and (2) full text. For each round, studies were screened by two independent reviewers (R.R.E, S.C.M.), and consensus was reached through discussion with input from a third author (M.J.F.) in cases of disagreement. Interrater reliability for study inclusion was assessed using Cohen's kappa for qualitative agreement. Kappa for title/abstract screening was 0.88 (95% CI, 0.79, 0.97) and 0.88 (95% CI, 0.75, 1.0) for full-text screening, indicating excellent agreement. Both phases of study review were conducted using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia.) Primary study authors were contacted in cases where reported data were missing or insufficient to meet the requirements for inclusion in this review. Data were independently extracted into a standardized data collection form by two investigators (R.R.E., J.Z.G) and compared; disagreements were discussed and adjudicated by a third investigator (M.J.F.). We extracted the following data (when available): study design, study size, mortality (30-day or nearest equivalent), age, sex, LVEF, GLS, vasopressor use (medication, duration), use and duration of mechanical ventilation, admission location, ultrasound system used, ICU, and hospital length-of-stay. Data were stratified by survivor/nonsurvivor status for each clinical variable. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to assess for risk of bias and applicability of the included studies. Two reviewers (R.R.E., S.C.M.) independently assessed each included study for risk of bias in the following domains: patient selection, index test (GLS), reference standard (EF), and patient flow/timing. Signaling questions for the last three domains were altered, per Quality Assessment of Diagnostic Accuracy Studies guidelines (https://www.bristol.ac.uk/population-health-sciences/projects/quadas/resources/), to address issues in our review not addressed by the core questions. Explicit criteria for "low risk of bias" were determined by consensus of three authors (R.R.E., M.J.F., S.C.M.) prior to study assessment; the modified tool was piloted by two authors (R.R.E., S.C.M.) to ensure adequate agreement prior to completion of full review. Disagreements between primary quality assessors were discussed and adjudicated by a third author (M.J.F.). The modified signaling questions for each domain are listed below: Could the selection of patients have introduced bias? (Signaling questions: Was a consecutive or random sample of patients enrolled? Was a case-control design avoided? Did the study avoid inappropriate exclusions? (If all questions can be answered "yes," risk of bias is "low.") Could the conduct or interpretation of the index text have introduced bias? (Signaling questions: Were the same index test methodology and type of equipment used for all patients? Were the index test and reference standard obtained/interpreted by different people? Was the person who obtained/interpreted the index test blind to clinical/lab data? If all questions can be answered "yes," risk of bias is "low.") Could the reference standard, its conduct, or its interpretation have introduced bias? (Signaling questions: Was the method of assessing the reference standard clearly defined (e.g., visual estimation of EF, Simpson's method)? Was the person who obtained/interpreted the reference standard blind to clinical/lab data? If all questions can be answered "yes," risk of bias is "low.") Could the patient flow have introduced bias? (Signaling questions: Was the timing of echocardiography clearly defined? Was the timing of echochardiography consistently applied for all patients in the study? Was feasibility of the index test and/or the number of patients excluded due to lack of feasibility reported? If all questions can be answered "yes," risk of bias is "low.") Are there concerns that the included patients and setting do not match the review question? Are there concerns that the index test, its conduct, or interpretation differ from the review question? Are there concerns that the target condition as defined by the reference standard does not match the review question?Supplemental Table 1Characteristics of studies included in quantitative analysisStudyYearnPopulationOutcomeFirst echocardiogramEcho feasibilityUltrasound system typeChang et al2015111ICU patients with septic shockICU and in- hospital mortalityWithin 24 hours of admission to ICU9 excluded due to lack of image quality3.5 MHz Probe GE Vivid-i or GE Vivid-QDe Geer et al201550ICU patients with septic shockICU/30-/90-day mortalityWithin 24 hours of admission to ICU4 excluded due to lack of image quality (3) or recording failure (1)GE Vivid E9Innocenti et al2015146Emergency department patients with sepsis or septic shock7- and 28-day mortalityWithin 24 hours of admission to hospital27 excluded due to lack of image qualityPhillips iE33Orde et al201460Inpatients with severe sepsis or septic shock30- and 180-day mortalityWithin 24 hours of meeting severe sepsis criteria14 excluded due to lack of image qualityGE Vivid 7Ricarte-Bratti et al201718ICU patients with sepsis or septic shock30-day mortalityWithin 24 hours of meeting sepsis diagnosisNone reported2.5 MHZ Probe GE Vivid 9All studies were prospective observational trials. Open table in a new tab Supplemental Table 2Clinical Characteristics of patients from included studiesStudyOutcomeNumberAverage ageMale, n (%)Mean LVEF, % (SD)Mean GLS, % (range/SD)MV Percentage, mean hoursNE use Percentage, mean μg/kg/minDobutamine Percentage, mean μg/kg/minComorbidities Cardiac∗Includes coronary artery disease, hypertension, HF. (%), Respiratory (%), CKD (%)Apache II, SAPS 3, SOFAChang et alSurvivor7271.842 (58.3)65 (60–72)–14.9 (3.4)45, NANA, .28NA, NA13, 18, NA19.0NANonsurvivor3968.727 (69.2)64.5 (51–71)–12.4 (4.9)28, NANA, .22NA, NA6, 6, NA24.3NANADe Geer et alSurvivor356524 (69)50 (42–57)−17.2 (–20 to −13)NA, 70NA, .09NA, 5.515, NA, NANA70NANonsurvivor15757 (47)53 (37–59)−15 (−20 to −11)NA, 45NA, .11NA, 5.49, NA, NANA81NAInnocenti et alSurvivor1077159 (56)51 (15)−12 (3)NA, NANA, NANA, NANA, NA, NANANANANonsurvivor407924 (59)44 (18)–10 (4)NA, NANA, NANA, NANA, NA, NANANANAOrde et alSurvivor406021 (70)56 (17)–13.92 (4.2)21, NANA, .15NA, NA7, 12, 5NANA10Nonsurvivor206516 (80)30 (13)–14.6 (4.3)18, NANA, .225NA, NA1, 6, 2NANA13Ricarte-Bratti et alSurvivor136310 (77)59 (6)–17 (2)23, NA31, NA0, NANA, NA, NA13NANANonsurvivor5583 (60)57 (5)−14 (4)100, NA100, NA80, NANA, NA, NA15NANABazalgette et alSurvivor10NANA53−17NA, NANA, NANA, NANA, NA, NANANANANonsurvivor3NANA28−6NA, NANA, NANA, NANA, NA, NANANANADaiki et alSurvivor1363NANA−18NA, NANA, NANA, NANA, NA, NANANANANonsurvivor55858NA−14NA, NANA, NANA, NANA, NA, NANANANAAPACHE II, Acute physiology and chronic health evaluation; MV, mechanical ventilation; NA, not available; NE, norepinephrine; SAPS 3, simplified acute physiology score; SOFA, Sequential organ failure assessment.The Bazalgette et al. and Daiki et al. studies were included in the systematic review but excluded from the quantitative analysis.∗ Includes coronary artery disease, hypertension, HF. Open table in a new tab All studies were prospective observational trials. APACHE II, Acute physiology and chronic health evaluation; MV, mechanical ventilation; NA, not available; NE, norepinephrine; SAPS 3, simplified acute physiology score; SOFA, Sequential organ failure assessment. The Bazalgette et al. and Daiki et al. studies were included in the systematic review but excluded from the quantitative analysis.