Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

Journal of Critical Care (2013) 28, 532.e1–532.e10

Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis☆ Aristine Cheng MD a,b , Hsin-Yun Sun MD b , Ching-Wen Lee MS c , Wen-Je Ko MD d , Pi-Ru Tsai BSc d , Yu-Chung Chuang MD b , Fu-Chang Hu ScD e , Shan-Chwen Chang MD b , Yee-Chun Chen MD b,⁎ a

Department of Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan Department of Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan c Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, PA 15213, USA d Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan e International Harvard Statistical Consulting Company, Taipei, Taiwan b

Keywords: Extracorporeal life support; Sepsis; Adults; ECMO

Abstract Purpose: Limited data on the outcomes of adults with active sepsis undergoing extracorporeal membrane oxygenation (ECMO) exist. Materials and Methods: We analyzed our prospective database for adults undergoing their first ECMO from 2001 to 2009. Patients with preexisting sepsis had newly emerging or uncontrolled infections precipitating refractory respiratory and/or circulatory failure within 7 days preceding ECMO. Propensity score matching was performed to equalize potential prognostic factors between patients with and patients without sepsis. Results: Of the 514 adults receiving their first ECMO, 108 with preexisting sepsis were matched with 108 without sepsis by propensity score. Overall survival to discharge did not differ between those with (28.7%) and those without sepsis (37.0%; P = .192). When venovenous ECMO and venoarterial ECMO were considered separately, survival tended to be worse for septic patients on venoarterial ECMO (24.4%) compared with nonseptic adults on venoarterial ECMO (34.9%; P = .147). After adjustments for age, stroke, acute myocarditis, inter-extracorporeal cardiopulmonary resuscitation, and post-ECMO renal and neurologic deficits by multivariate analysis, the increased risk of mortality persisted for septic adults receiving venoarterial ECMO (hazard ratio, 2.54; 95% confidence intervals, 1.75-3.70; P b .01). Patients on venovenous ECMO had similar outcomes regardless of preexisting sepsis. Conclusions: Preexisting sepsis is not a contraindication for ECMO. However, venoarterial ECMO should be used with caution, given active sepsis. © 2013 Elsevier Inc. All rights reserved.

☆

Preliminary analyses of these data were presented as abstract in the poster session K-1469 at the 51st Interscience Conference for Antimicrobial Agents and Chemotherapy, September 9-12, 2011, in Chicago and at the 1st EURO Extracorporeal Life Support Organization Meeting, May 11-13, 2012, in Rome. ⁎ Corresponding author. Department of Internal Medicine, Division of Infectious Diseases, National Taiwan University Hospital, Taipei 100, Taiwan. Tel.: +886 2 2312 3456x65908; fax: +886 2 2397 1412. E-mail address: [email protected] (Y.-C. Chen). 0883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2012.11.021

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A. Cheng et al.

Extracorporeal membrane oxygenation (ECMO) was first used successfully for life-threatening respiratory failure in an adult in 1971 and in a neonate with meconium aspiration in 1975 [1,2]. Since then, ECMO use in pediatrics has become well established [3]. Guidelines recommending the use of ECMO in the setting of pediatric septic shock [4] were based on observations that neonates (~ 80% survival) and children (~ 50% survival) have the same outcomes whether the indication for ECMO is refractory respiratory failure or refractory shock from sepsis or not [5,6]. Similar observations have not been confirmed for adults, although ECMO has supported more than 4300 adults in 132 centers worldwide [7]. Indeed, published data on the impact of sepsis on adult ECMO use have been limited to case reports or small series subject to publication bias [8–13]. At our center, some experts refuse to initiate ECMO in patients with suspicion of preexisting sepsis, even if they were experiencing postcardiotomy cardiogenic shock, mostly from personal experiences of worse outcomes for this subset of patients. Indeed “old” wisdom considered sepsis as a relative contraindication to ECMO; the main purported reasons were the continuous presence of central vascular catheters, foreign membranes and heparin in ECMO circuitry, perpetuated bacteremia, inflammation, and bleeding diathesis in septic patients with disseminated intravascular coagulopathy, respectively [14]. However, other surgeons rationalize that the recent advances in extracorporeal technology and clinical practice might minimize these complications and that potential benefits may outweigh potential risks [15]. Worldwide, encouraged by the anecdotal case reports of successful application of ECMO for adult staphylococcal or meningococcal sepsis [9,13,16], some centers consider adult sepsis in their expanding list of indications for ECMO. To address the lack of evidence to substantiate or refute these views, particularly in adults with profound shock requiring venoarterial (VA) ECMO, we asked the hypothetical question that given all else being equal, are adults with refractory respiratory or circulatory failure in the setting of active sepsis as likely to survive ECMO as those with refractory respiratory or circulatory failure without sepsis? If outcomes were equivalent, akin to that observed for children, perhaps preexisting sepsis need not contraindicate this lifesustaining technology for critically ill adults.

collated prospectively into our database and reported to the Extracorporeal Life Support Organization [7]. Patients were identified from the NTUH-ECMO Registry if they were 16 years or older, underwent ECMO between 1st January 2001 and 31st December 2009, and required ECMO for respiratory or circulatory failure, refractory to maximal conventional therapy. Inhaled nitric oxide, high-frequency oscillatory ventilation, and intra-aortic balloon counterpulsation were available as adjunctive supportive therapies at this center. The decision to initiate ECMO was made by the institution's specialist team based on standard parameters of insufficient gaseous exchange or organ perfusion [20]. At this center, respiratory failure was defined as the sustained need for 100% fractional inspired oxygen under which the PaO2 was 40 mm Hg or less, the oxygenation index was 40 or greater, or the arterial-alveolar gradient was greater than 600; circulatory failure was defined by the requirement for sustained cardiopulmonary resuscitation (CPR), inability to maintain mean arterial pressure greater than 60 mm Hg, or progressive lactic acidosis and end-organ dysfunction despite 2 or more continuous infusions of high-dose inotropes. Dopamine or dobutamine infusions greater than 20 μg kg− 1 min− 1 and norepinephrine and epinephrine infusions greater than 0.5 μg kg− 1 min− 1 were typically considered high doses. The ECMO mode was categorized as VA or venovenous (VV). Septic patients with acute respiratory distress syndrome and concomitant shock not meeting the criteria for VA-ECMO received VV-ECMO. Patients were excluded if this was not their first-time ECMO or if ECMO was initiated offsite to minimize underestimation of infections secondary to incomplete surveillance. Patients routinely received septic workup at ECMO onset, including 2 sets of blood cultures, chest radiograph, and culture of sites as indicated [18]. Preexisting sepsis was defined as newly emerging or uncontrolled infections occurring within 7 days before ECMO initiation and directly contributing to the refractory respiratory or circulatory failure precipitating rescue therapy [18]. Infections not present at ECMO onset but occurring during ECMO use and caused by pathogens different from those of infections within 7 days before ECMO initiation were considered post-ECMO infections [18]. The Centers for Disease Control and Prevention/ National Health Surveillance Network criteria for infections in the acute care settings were followed (Supplement Table 1) [21]. Two infectious disease clinicians independently reviewed and discussed the medical records to reach an agreement in cases of dispute. The institutional review board approved the study and waived the need for informed consent.

2. Methods

2.1. Statistical analysis

National Taiwan University Hospital (NTUH) has provided ECMO since 1994, with current cases exceeding 100 annually [17–19]. The equipment and standardized management of cases have been detailed previously [17,19,20]. The data of all patients receiving ECMO were

Analysis was performed using the R 2.11.1 software (R Foundation for Statistical Computing, Vienna, Austria). Two-sided P values of .05 or less was considered significant. To reduce the selection bias caused by the differences in the baseline risks for mortality between the sepsis and the

1. Introduction

Extracorporeal life support in septic adults nonsepsis groups, propensity score analysis was conducted. First, the probability for receiving ECMO for sepsis was estimated for each of the 514 subjects using a multivariable logistic regression model with demographics and pre-ECMO characteristics listed in Supplement Tables 2 and 3. Then, each subject in the sepsis group was 1:1 matched with the nearest neighbor in the nonsepsis group by the logit of the estimated propensity score using the nearest available Mahalanobis metric matching method. The chosenpsize of the caliper was 0.2438 based on ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ^ ½logit ðestimated propensity scoreÞ Var CaliperL ¼ , where the 4 sample variance of the logit (estimated propensity score) was 0.9508. After pairing all available subjects, we rechecked the distributions of the risk factors for mortality between matched septic and nonseptic subjects. Finally, we examined the effect of preexisting sepsis on post-ECMO survival by fitting multivariable Cox proportional hazards model on the matched cohort using all the univariate significant and nonsignificant relevant covariates and some of their interactions (eg, preexisting sepsis × VA mode). The significance levels for entry and for stay were set to 0.15 or larger. Specifically, the stepwise variable selection procedure (with iterations between the forward and the backward steps) was applied to obtain the candidate final regression model. Then, with the aid of substantive knowledge, the best final regression model was identified manually by dropping the covariates with P values greater than .05 one at a time, until all regression coefficients were significantly different from 0. The generalized additive model was applied to detect nonlinear effects of continuous covariates or to discretize them.

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Fig. 1 Flow diagram of patient selection. With propensity score matching, patients for whom appropriately similar “controls” could not be found in our original cohort were excluded from analysis.

primary bloodstream infections (BSIs) in 19% of 108 septic patients. Most infections (93%) were monomicrobial, but 10 patients had more than 1 pathogen. From the 21 patients with BSI, a total of 28 pathogens were isolated; Staphylococcus aureus (18%), Streptococcus species (14%), and Klebsiella pneumoniae (14%) were the 3 most predominant isolates. From the 43 patients with respiratory tract infection, influenza (7%) was the most common viral respiratory pathogen detected, whereas Pseudomonas aeruginosa (21%), K. pneumoniae (12%), and Acinetobacter baumannii complex (9%) were the 3 most common bacterial isolates.

3.2. Univariate analysis of survival

3. Results During the 9-year study period, 514 adult patients underwent ECMO for the first time (Fig. 1), and 135 (26.3%) harbored sepsis at ECMO initiation. A total of 108 septic adults were matched with 108 nonseptic patients by propensity analysis. The baseline characteristics and clinical outcomes of the 216 paired patients are shown in Tables 1 and 2 (and of the unmatched cohort of 514 patients in the Supplement Tables 2 and 3).

3.1. Propensity score matching After matching, the distributions of the logit (estimated propensity scores) were well balanced (Supplement Fig 1), and no significant differences in baseline characteristics between septic and nonseptic subjects remained (Tables 1 and 2). Thus, the remaining difference between the 2 groups was the presence or absence of active sepsis. Table 1 shows the types of infections of preexisting sepsis: pneumonia in 40%, acute myocarditis in 25%, and

Overall survival to discharge did not differ between those with (28.7%) and those without sepsis (37.0%; P = .192). Table 3 shows that nonsurvivors were more likely to have poor host factors (older age, higher Charlson score, and stroke history), advanced disease (higher Acute Physiology and Chronic Health Evaluation II [APACHE II] scores, inotropic demand, serum lactate levels, VA use, concurrent CPR, and longer pre-ECMO hospitalization), and postECMO neurologic and renal complications compared with survivors, whereas more survivors had myocarditis and thrombotic complications. Of note, the percentage of patients with preexisting sepsis was not different between survivors and nonsurvivors (43.7% vs 53.1%, P = .247). However, there was a trend for fewer survivors with sepsis on VA-ECMO (29.6% vs 44.8%, P = .045). The percentages of survivors in ascending order for septic adults on VA-ECMO, nonseptic adults on VA-ECMO, nonseptic adults on VV-ECMO, and septic adults on VV-ECMO were as follows: 24.4% (21/86), 34.9% (30/86), 45.5% (10/22), and 45.5% (10/22), respectively (data not shown). Crude observations from the Kaplan-Meier

532.e4 Table 1

A. Cheng et al. Baseline characteristics of propensity score–matched 108 septic and 108 nonseptic adults undergoing ECMO

Variables

Septic (n = 108)

Nonseptic (n = 108)

P

Age (y), mean (SD) 16-30, % (n) 31-45, % (n) 46-65, % (n) N 65, % (n) Male, % (n) Initial body mass index (kg/m2), mean (SD) Underlying diseases Charlson comorbidity index, mean (SD) Hypertension, % (n) Diabetes mellitus, % (n) Congestive heart failure, NYHA II-IV, % (n) Coronary artery disease, % (n) Remote ischemic stroke, % (n) Remote intracranial hemorrhage, % (n) Cirrhosis of the liver, % (n) End-stage renal disease under dialysis, % (n) Types of preexisting infections, % (n) Pneumonia Acute myocarditis Primary BSIs Intra-abdominal infections Infective endocarditis Mediastinitis Necrotizing fasciitis Posttransrectal prostate biopsy urosepsis Initial disease severity, mean (SD) APACHE II Inotropic equivalent score a Indications for ECMO b, % (n) Acute respiratory failure Mechanical circulatory support Septic shock (no cardiopulmonary disease) Sepsis exacerbating chronic heart disease Sepsis exacerbating chronic lung disease Acute myocardial infarction Cardiomyopathy Postcardiotomy stunning Trauma Acute heart transplant rejection Electrocution Phaeochromocytoma Miscellaneous ECMO for primary admission diagnosis, % (n) ECMO for secondary complication, % (n) Clinical course (d), mean (SD) Admission to ECMO interval ECMO start to death Mechanical ventilation to ECMO use Duration of ECMO use Total duration of mechanical ventilation

52.0 (17) 13.0 (14) 20.4 (22) 42.6 (46) 24.1 (26) 68.5 (74) 23.6 (3.9)

49.0 16.7 25.0 39.8 18.5 74.1 24.4

(17) (18) (27) (43) (20) (80) (4.6)

.156 .595

2.6 (2.7) 25.9 (28) 24.1 (26) 37.0 (40) 13.0 (14) 3.7 (4) 3.7 (4) 2.8 (3) 4.6 (5)

3.0 (2.5) 25.9 (28) 17.6 (19) 39.8 (30) 21.3 (23) 5.6 (6) 4.6 (5) 2.8 (3) 4.6 (5)

.299 .999 .241 .675 .104 .517 .999 .999 .999

40.0 (43) 25.0 (27) 19.4 (21) 6.5 (7) 3.7 (4) 2.8 (3) 1.9 (2) 1.0 (1)

– – – – – – – –

– – – – – – –

22.3 (9.8) 77.4 (151.9)

21.2 (8.7) 66.2 (178.3)

.386 .622

21.3 (23) 78.7 (85) 55.3 (47/85) 36.5 (31/85) 8.2 (7/85) – – – – – – – – 63.9 (69) 36.1 (39)

21.3 (23) 78.7 (85) – – – 25.9 (22/85) 18.8 (16/85) 16.5 (14/85) 3.5(3/85) 3.5 (3/85) 2.4 (2/85) 2.4 (2/85) 27.1 (23/85) 69.4 (75) 30.6 (33)

14.9 (21.2) 8.84 (1.20) 8.5 (35.7) 6.60 (7.16) 20.1 (37.1)

14.8 (35.0) 15.01 (2.58) 2.0 (5.1) 6.70 (10.7) 17.8 (26.0)

.367 .155

.996 .074 .060 .938 .510

Inotrope equivalent score was calculated from the dosages of dopamine + dobutamine (in μg kg−1 min−1) + [dosages of epinephrine + norepinephrine + isoproterenol (in μg kg−1 min−1)] × 100 + dosages of milrinone (in μg kg−1 min−1) × 15. The score here quantified the inotropes being infused when the ECMO was applied [22]. b Extracorporeal membrane oxygenation indications. At this center, respiratory failure was defined as the sustained need (N12 hours) for 100% fractional inspired oxygen under which the PaO2 was 40 mm Hg or less, the oxygenation index was 40 or greater, or the arterial-alveolar gradient was greater than 600, or by a lung Murray injury score of 3 or higher; circulatory failure was defined by the requirement for continuous CPR, inability to maintain mean arterial pressure above 60 mm Hg, or progressive lactic acidosis and end-organ dysfunction despite 2 or more continuous infusions of high-dose inotropes. a

Extracorporeal life support in septic adults Table 2

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Clinical outcomes of propensity score–matched 108 septic and 108 nonseptic adults undergoing ECMO

Variables

Septic (n = 108)

Nonseptic (n = 108)

P

79.6 (86) 20.4 (22)

79.6 (86) 20.4 (22)

1.000

28.7 (31) 25.9 (28) 19.0 (20)

35.2 (38) 37.0 (40) 25.3 (25)

.307 .079 .285

34.3 (37) 15.7 (17) 1.9 (2) 19.4 (21) 7.4 (8) 57.4 (62) 12.0 (13) 4.6 (5) 44.4 (48)

33.3 (36) 18.5 (20) 4.6 (5) 20.4 (22) 4.6 (5) 42.6 (46) 10.2 (11) 5.6 (6) 46.3 (50)

.886 .588 .445 .865 .391 .029 .665 .757 .785

0.31 (1.41) 5.75 (6.17) 2.23 (4.74) 8.66 (12.66)

0.68 (1.91) 6.44 (7.01) 2.43 (5.22) 8.48 (14.24)

.111 .438 .770 .924

71.3 (77) 35.1 (27/77) 58.4 (45/77) 12.0 (13) 0.9 (1) 3.7 (4) 44.4 (48) 28.7 (31)

63.0 (68) 39.7 (27/68) 52.9 (36/68) 18.5 (20) 0.9 (1) 4.6 (5) 56.5 (61) 37.0 (40)

.192 .564 .506 .424

a

ECMO mode , % (n) VA VV Cardiac events, % (n) CPR before ECMO CPR during ECMO IABP during ECMO Complications b on ECMO, % (n) ECMO circuit clot Major bleeding Post-ECMO neurologic deficit Survived with neurologic disability Pneumothorax Post-ECMO dialysis dependence Post-ECMO infection Hypoglycemia Peripheral limb ischemia Transfusion within first 72 h (units), mean (SD) Whole blood Packed red blood cells Fresh-frozen plasma Platelet Survival outcomes, % (n) Overall mortality Death b 3 d of ECMO use Death b 7 d of ECMO use Removal ECMO and ICU death Removal ECMO and ward death Bridge to definitive treatment Survived beyond ECMO Survived beyond discharge

.192

IABP indicates intra-aortic balloon counterpulsation. a Extracorporeal membrane oxygenation mode was categorized as VA or VV. Venoarterial mode with additional venous drainage (VA + V) and VV transition to VA mode (VV-A) were categorized as VA. Arterio-venous access for CO2 removal was classified as VV. b Complications on ECMO: ECMO circuit clot, clot of any component in the circuit resulting in mechanical malfunction; major bleeding, gastrointestinal, surgical site, and ECMO cannulation site hemorrhage with sufficient blood loss triggering blood transfusion; post-ECMO neurologic deficit, brain death or radiographic evidence of brain infarction or hemorrhage; Survived with neurologic disability, as indicated by Glasgow-Pittsburgh cerebral performance categories scores of 3 to 4 after discharge from hospital [35]; pneumothorax, radiologic or chest-tube evidence of any volume of pneumothorax; post-ECMO dialysis dependence, need for intermittent hemodialysis or continuous VV hemofiltration after ECMO removal; post-ECMO infection, infections occurring in the period from the initiation to the removal of ECMO and caused by pathogens different from those of infections within 7 days before ECMO initiation; hypoglycemia; serum glucose less than 40 mg/dL; peripheral limb ischemia, digital gangrene, application of distal reperfusion catheter, or fasciotomy for compartment syndrome.

survival curves of patients stratified by the presence of sepsis and ECMO modes also revealed septic patients on VAECMO to have the worst cumulative survival compared with the other 3 groups, namely, nonseptic patients undergoing VA-ECMO and patients with and without sepsis undergoing VV-ECMO (Fig. 2).

3.3. Multivariate analysis for in-hospital mortality of a matched cohort of 216 patients In-hospital mortality did not differ between those with and those without sepsis (71.3% vs 63%, P = .192; Table 2). All the univariate significant and nonsignificant relevant

covariates in Table 3 were put on the variable list to be selected for multivariate analysis model. After analysis as described in Methods, septic adults on VA-ECMO were at an increased risk for hospital mortality (hazard ratio [HR], 2.54; P b .001), compared with nonseptic adults on VA-ECMO, even after adjustment for the effects of the dominant covariates (Table 4). Patients with sepsis on VV-ECMO had outcomes equivalent to those without sepsis on VVECMO. The generalized additive model detected the nonlinear effect of age on mortality with a plateau of risk after 55 years. Hence, those older than 55 years were more likely to die in hospital compared with those 55 years and younger (HR, 1.56; P = .017).

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A. Cheng et al.

Table 3 Distinguishing characteristics of survivors and nonsurvivors among the matched 216 adult patients with and without sepsis preceding ECMO Variables

Survived to discharge (n = 71)

Died in hospital (n = 145)

P

Age (y), mean (SD) Charlson comorbidity index, mean (SD) Congestive heart failure NYHA II-IV, % (n) Ischemic stroke history, % (n) Preexisting sepsis, % (n) VA mode, % (n) Preexisting sepsis undergoing VA mode, % (n) Admission to ECMO (d), mean (SD) Initial disease severity APACHE II score, mean (SD) Inotropic equivalent score, mean (SD) Serum lactate a pre-ECMO, mean (SD) Serum lactate a 24 h post-ECMO, mean (SD) CPR before ECMO, % (n) CPR during ECMO, % (n) ECMO complications, % (n) ECMO circuit clot Major bleeding Post-ECMO neurologic deficit Post-ECMO dialysis dependence Post-ECMO infection Hypoglycemia Peripheral limb ischemia

44.8 (16.3) 2.4 (2.5) 29.6 (21) 0.0 (0) 43.7 (31) 71.8 (51) 29.6 (21) 11.0 (36.4)

53.5 3.0 42.8 6.9 53.1 84.1 44.8 16.7

(16.2) (2.66) (62) (10) (77) (122) (65) (24.3)

b .001 .023 .074 .033 .247 .052 .045 .001

18.2 (8.4) 59.2 (184.4) 6.0 (4.5) 6.3 (5.2) 29.6 (21) 22.5 (16)

23.6 77.0 7.6 8.2 33.1 35.9

(9.2) (154.3) (5.5) (6.0) (48) (52)

b .001 .024 .085 .046 .714 .068

43.7 (31) 18.3 (13) 5.6 (4) 29.6 (21) 39.4 (28) 1.4 (1) 36.7 (26)

29.0 16.6 26.2 60.0 24.1 6.9 49.7

(42) (24) (38) (87) (55) (10) (72)

.046 .897 b .001 b .001 .948 .106 .096

a

Serum lactate measured in millimoles per liter; data missing for 61 patients pre-ECMO and for 51 patients 24 h post-ECMO.

Fig. 2 Kaplan-Meier estimates for 216 matched adults stratified by ECMO mode and sepsis status. Septic adults on VA-ECMO had the worst cumulative survival compared with septic patients on VA-ECMO and patients with and without sepsis on VV-ECMO. P value was .006 among the 4 groups, .063 for sepsis and VA model vs nonsepsis and VA model, and .659 for sepsis and VV model vs nonsepsis and VV model.

Extracorporeal life support in septic adults

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Table 4 Multivariate (Cox proportional hazards regression) analysis of 108 matched pairs a for identifying the risk factors of time to hospital death using Cox proportional hazards model, stratified by the presence vs the absence of mechanical circuit clot b Covariate

HR

Lower 95% CI

Upper 95% CI

P

Logit of estimated propensity score a Age N 55 y vs ≤ 55 y History of ischemic stroke × survival time c Acute myocarditis CPR during ECMO Post-ECMO dialysis dependence × survival time c Post-ECMO neurologic deficit Sepsis and VA ECMO d

1.06

0.87

1.29

.580

1.56 1.12

1.08 1.04

2.24 1.20

.017 .002

0.23 2.18 1.03

0.11 1.48 1.01

0.48 3.21 1.05

b .001 b .001 .010

2.13

1.43

3.18

b .001

2.54

1.75

3.70

b .001

2

The goodness-of-fit measure, adjusted generalized R = 0.322, indicated a good fit because the value of that measure is usually low. a The 108 pairs of subjects were matched by the logit (estimated propensity score), and thus, the logit (estimated propensity score) was purposefully kept in the above regression model to reduce selection bias. b Although we performed multivariate analysis, mechanical circuit clot appeared to be protective with an HR less than 1, but its effect was neither time dependent nor constant so that the final model was stratified by the presence or absence of thrombotic complications. c History of ischemic stroke and post-ECMO dialysis dependence were nonproportional hazards risk factors for hospital mortality so that they were multiplied by survival time to indicate that their hazard risks increased as time passed. d The significant negative effect of the interaction between sepsis and VA mode was motivated by biological plausibility and endorsed by the differences in the crude Kaplan-Meir estimates of survival curves among the 4 subgroups classified by the sepsis and VA vs VV mode.

In summary, age greater than 55 years, history of stroke, CPR during ECMO, post-ECMO neurologic deficits, and dialysis dependence were independent predictors of hospital mortality. Myocarditis was a protective factor (HR, 0.23; P b .001). In the subgroup analysis excluding all myocarditis patients, the same set of covariates remained significant, and septic patients on VA still had excess mortality (HR, 2.91; 95% CI, 1.95-4.35; P b .001; data not shown).

3.4. Multivariate analysis for in-hospital mortality of matched 172 patients on VA-ECMO only In a further subgroup analysis excluding 68 patients on VV-ECMO from the original cohort of 514 patients, we applied the same methodology to match septic vs nonseptic patients on VA-ECMO. Of 446 adults on VA-ECMO, a total of 86 pairs of patients were analyzed; 67 of the 172 individuals were not included in the previous survival analysis, whereas 105 were among the matched cohort of

more than 216 patients. Multivariate analysis confirmed the robustness of the above findings (Supplement Table 4); preexisting sepsis became an independent predictor of hospital mortality among adults requiring VA-ECMO (HR, 2.38; P b .001), and myocarditis remained protective (HR, 0.29; P b .001).

4. Discussion This study is unique in terms of the relatively large adult population with life-threatening infections undergoing VAor VV-ECMO. We demonstrated that outcomes in the setting of sepsis were conditional on the ECMO mode. When patients had conditions necessitating VA-ECMO, those with sepsis had worse outcomes than did their counterparts with non–sepsis-related shock on VA-ECMO (Fig. 2 and Table 4). In contrast, when sepsis resulted in refractory respiratory failure, no excess mortality was observed for patients undergoing VV-ECMO. Consistent with these findings, noninferior outcomes for adults receiving VV-ECMO for respiratory failure caused by sepsis based on one center's retrospective review of 100 patients (14 of whom were septic), later accumulated to 255 patients (22 of whom were septic), were reported [22,23], whereas higher risks of death have been associated with VAECMO under conditions of sepsis in a single-center retrospective cohort of 607 adults and in 40 recipients undergoing heart transplant [24,25]. Hence, the view that primary sepsis does not contribute to increased mortality in adults receiving ECMO is supported by 2 series for adults with respiratory failure [22,23]. This view is reasonable because VV-ECMO comparators include patients with similar likelihoods and time courses for recovery, for example, aspiration or chemical pneumonitis, pulmonary vasculitides, pancreatitis, trauma, or obstetricsrelated acute respiratory distress syndrome [11]. There are no data suggesting that the same applies to adults with circulatory collapse. In fact, we showed that septic adults on VA-ECMO relative to their counterparts with surgically correctable diseases may not be weaned off VA-ECMO quickly enough (Supplement Table 2). Hence, the questions raised were as follows: first, why should sepsis result in greater mortality among adults on VAECMO but not on VV-ECMO? Second, why are VA mode outcomes equivalent for children irrespective of sepsis but not adults? Third, how do we fit these findings in the context of conflicting case reports of exemplary success? Some plausible explanations ensue (summarized in Supplement Table 5). Better outcomes are associated in general with VV-ECMO for reasons attributed both to the less moribund patients requiring only respiratory support and the more physiological circuit [26]. In other words, VA-ECMO was reserved for cases of septic shock that failed or was likely to fail VV mode. Our results do not refute the view that patients who were

532.e8 “more ill” required VA-ECMO and were more likely to die because we are not comparing the outcomes of patients on VA mode vs VV mode. Nevertheless, after adjusting for underlying disease severity by multivariate analysis, the lower benefit of VA-ECMO for septic patients compared with VA-ECMO for nonseptic patients was highlighted. Prolonged ECMO in septic adults on VA-ECMO increased the potential for morbidity and mortality related to subsequent complications and was indicative of delayed or diminished likelihoods of recovery. Our results showed a higher frequency of post-ECMO dialysis dependence among septic patients (Table 2). Septic patients experience not only shock-related ischemic insults but also the superimposed nephrotoxic effects of antimicrobial agents and endotoxins. Hence, sepsis by predisposing to irreversible kidney injury plausibly contributes excess mortality [27]. Venoarterial ECMO by femoral vascular access preferentially predisposes septic adults, with relative rather than absolute myocardial dysfunction to upper body hypoxemia (Supplement Fig 2). The best outcomes for children with septic shock have been reported using central (atrioaortic) rather than conventional VA-ECMO [28]. Selective upper body hypoxemia was observed clinically, but we are insufficiently experienced to know whether alternative approaches to return oxygenated blood to the proximal aorta can circumvent the flaw of the less physiological femoral access and improve outcomes for septic adults on VA-ECMO. Furthermore, VA-ECMO does not ameliorate adult septic shock that is predominantly vasoplegic rather than cardiogenic. In other words, the contribution of VA-ECMO in providing macrocirculatory hemodynamic support or adding flow to low-flow states is not the solution to the impaired microcirculation in developed sepsis and septic shock. The continuous flow provided by VA-ECMO may also affect the homeostatic adjustments of the microvasculature, giving rise to the lower benefit of VA-ECMO seen in septic patients. Indeed peripheral vascular failure is a major determinant of mortality in septic shock because patients with high cardiac output and low systemic vascular resistance experienced higher mortality [29]. In instances when VA-ECMO has been successfully used in adults with septic shock, the contribution of myocardial failure has been an important feature. This is interesting because myocardial dysfunction with sepsis is well described [30]. However, use of VA-ECMO for this indication in the adults is rare. Five such cases reports comprise a patient with prosthesis-related osteomyelitis, 2 with necrotizing fasciitis, 1 with novel H1N1 influenza, and one with sternal wound infection, all of them had left ventricular ejection fraction less than 35% [9,12,16,31]. The hemodynamic responses of these patients were similar to those seen in septic young children (Supplement Table 5). This may explain their favorable outcomes after VA-ECMO. Altogether, our results concur with the view that VAECMO should rarely be indicated for septic shock in adults.

A. Cheng et al. Perhaps, owing to the differences in the hemodynamic manifestations of sepsis, the VA circuitry (proximal aorta or internal carotid artery cannulation rather than femoral artery cannulation in children), timing of rescue (adults present later than children), and intrinsic capabilities to heal (which decline with age), VA-ECMO appears to rescue more septic children than septic adults. Overall survival to discharge of adults with preexisting sepsis is 29% in this study. This is comparable with the pooled survival rate of adults supported with extracorporeal circulation for cardiac failure in general (34%) and for extracorporeal CPR (ECPR; 27%) [7]. Importantly, this survival is not marred by significant disability, which may not be true for survivors of ECPR (namely, 94% of our patients were neurologically preserved in contrast to only 30% of patients on ECPR) [17]. However, it remains to be proven whether survival can be improved by fine-tuning patient selection.

4.1. Limitations This study was observational and retrospective. Despite an attempt to control for prognostic factors, our study is a poor substitute to efficacy trials. However, given the logistical and ethical concerns with conducting such trials, our findings offer relevant information for intensivists who cannot keep septic adults alive by conventional management and are considering ECMO. There may be occult confounders that were not matched. The chances of missing a significant confounder were not high based on the adjusted R2 of our final model (0.3224). We were unable to explicitly define maximal conventional therapy because of important secular changes over the last decade. However, because these changes applied to both septic and nonseptic patients, they should not subtract from our ability to compare the survival of these 2 groups of patients. We restricted enrollment to ensure standardized care to a single center. The suboptimal survival seen at this center reflects the suboptimal selection of candidates for ECMO. Owing to local customs and culture, intensivists are often under pressure from patients' families to initiate ECMO, despite informed low likelihoods of survival [32]. Our mostly male (71% vs 17%-58%) [33,34], leaner (body mass index, 23-24 kg/m2 vs 29-33 kg/m2) [8,34], and older (24% vs 0% older than 65 years) [33] patients may not be directly comparable with other published institutional experiences. Our center has a low trigger point to start ECMO as evidenced by the high proportion of very sick patients (29%35% CPR pre-ECMO and 26%-37% CPR during ECMO) with prolonged hypoxia (documented by high lactates 24 hours post-ECMO). Other centers, probably, would not use ECMO in such high-risk patients. Whether ECMO is appropriate therapy for septic adults is beyond the scope here. Subgroup analysis to define factors that may predict poorer outcomes for septic adults deserves urgent study to limit potential harm and futility.

Extracorporeal life support in septic adults

5. Conclusions We documented that ECMO rescued approximately 30% of septic adult patients with life-threatening cardiopulmonary failure. Although overall survival is low, ECMO represents a possible form of rescue therapy in adults when all other treatments have failed. We concur that VV-ECMO need not be withheld from patients with active sepsis. However, given the inferior outcomes for septic adult patients on VA mode, we would advocate careful risk-benefit assessment on an individual basis before VA-ECMO is initiated for adult refractory septic shock.

Acknowledgments Y.C. Chen received a grant (DOH100-TD-B-111-001) from the Department of Health, Taiwan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. The authors are indebted to Dr Victor L. Yu (University of Pittsburgh) and Dr Chi-Ming Lee (NTUH) for critical review of the manuscript.

Appendix A. Supplementary Data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcrc.2012.11.021.

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