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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 b 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 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 Journal of Critical Care (2013) 28, 532.e1532.e10

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Page 1: 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 adultsreceiving extracorporeal membrane oxygenation forcardiopulmonary failure: A propensity-matched analysis☆

Aristine Cheng MDa,b, Hsin-Yun Sun MDb, Ching-Wen Lee MS c, Wen-Je Ko MDd,Pi-Ru Tsai BSc d, Yu-Chung Chuang MDb, Fu-Chang Hu ScDe,Shan-Chwen Chang MDb, Yee-Chun Chen MDb,⁎

aDepartment of Medicine, Far Eastern Memorial Hospital, New Taipei City 220, TaiwanbDepartment of Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, TaiwancDepartment of Biostatistics, Graduate School of Public Health, University of Pittsburgh, PA 15213, USAdDepartment of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 100, TaiwaneInternational Harvard Statistical Consulting Company, Taipei, Taiwan

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0h

Keywords:Extracorporeal lifesupport;

Sepsis;Adults;ECMO

AbstractPurpose: Limited data on the outcomes of adults with active sepsis undergoing extracorporealmembrane oxygenation (ECMO) exist.Materials and Methods:Weanalyzed our prospective database for adults undergoing their first ECMO from2001 to 2009. Patients with preexisting sepsis had newly emerging or uncontrolled infections precipitatingrefractory respiratory and/or circulatory failure within 7 days preceding ECMO. Propensity score matchingwas 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 108without 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 wereconsidered 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 neurologicdeficits by multivariate analysis, the increased risk of mortality persisted for septic adults receivingvenoarterial ECMO (hazard ratio, 2.54; 95% confidence intervals, 1.75-3.70; P b .01). Patients onvenovenous ECMO had similar outcomes regardless of preexisting sepsis.Conclusions:Preexisting sepsis is not a contraindication for ECMO.However, venoarterial ECMO should beused 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).

883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved.ttp://dx.doi.org/10.1016/j.jcrc.2012.11.021

Page 2: Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

532.e2 A. Cheng et al.

1. Introduction

Extracorporeal membrane oxygenation (ECMO) was firstused successfully for life-threatening respiratory failure in anadult in 1971 and in a neonate with meconium aspiration in1975 [1,2]. Since then, ECMO use in pediatrics has becomewell established [3]. Guidelines recommending the use ofECMO in the setting of pediatric septic shock [4] were basedon observations that neonates (~80% survival) and children(~50% survival) have the same outcomes whether theindication for ECMO is refractory respiratory failure orrefractory shock from sepsis or not [5,6]. Similar observa-tions have not been confirmed for adults, although ECMOhas supported more than 4300 adults in 132 centersworldwide [7]. Indeed, published data on the impact ofsepsis on adult ECMO use have been limited to case reportsor small series subject to publication bias [8–13].

At our center, some experts refuse to initiate ECMO inpatients with suspicion of preexisting sepsis, even if theywere experiencing postcardiotomy cardiogenic shock, most-ly from personal experiences of worse outcomes for thissubset of patients. Indeed “old” wisdom considered sepsis asa relative contraindication to ECMO; the main purportedreasons were the continuous presence of central vascularcatheters, foreign membranes and heparin in ECMOcircuitry, perpetuated bacteremia, inflammation, and bleed-ing diathesis in septic patients with disseminated intravas-cular coagulopathy, respectively [14]. However, othersurgeons rationalize that the recent advances in extracorpo-real technology and clinical practice might minimize thesecomplications and that potential benefits may outweighpotential risks [15]. Worldwide, encouraged by the anecdotalcase reports of successful application of ECMO for adultstaphylococcal or meningococcal sepsis [9,13,16], somecenters consider adult sepsis in their expanding list ofindications for ECMO.

To address the lack of evidence to substantiate or refutethese views, particularly in adults with profound shockrequiring venoarterial (VA) ECMO, we asked the hypothet-ical question that given all else being equal, are adults withrefractory respiratory or circulatory failure in the setting ofactive sepsis as likely to survive ECMO as those withrefractory respiratory or circulatory failure without sepsis? Ifoutcomes were equivalent, akin to that observed for children,perhaps preexisting sepsis need not contraindicate this life-sustaining technology for critically ill adults.

2. Methods

National Taiwan University Hospital (NTUH) hasprovided ECMO since 1994, with current cases exceeding100 annually [17–19]. The equipment and standardizedmanagement of cases have been detailed previously[17,19,20]. The data of all patients receiving ECMO were

collated prospectively into our database and reported to theExtracorporeal Life Support Organization [7].

Patients were identified from the NTUH-ECMO Registry ifthey were 16 years or older, underwent ECMO between 1stJanuary 2001 and 31st December 2009, and required ECMOfor respiratory or circulatory failure, refractory to maximalconventional therapy. Inhaled nitric oxide, high-frequencyoscillatory ventilation, and intra-aortic balloon counterpulsationwere available as adjunctive supportive therapies at this center.

The decision to initiate ECMO was made by theinstitution's specialist team based on standard parametersof insufficient gaseous exchange or organ perfusion [20]. Atthis center, respiratory failure was defined as the sustainedneed for 100% fractional inspired oxygen under which thePaO2 was 40 mm Hg or less, the oxygenation index was 40 orgreater, or the arterial-alveolar gradient was greater than 600;circulatory failure was defined by the requirement forsustained cardiopulmonary resuscitation (CPR), inability tomaintain mean arterial pressure greater than 60 mm Hg, orprogressive lactic acidosis and end-organ dysfunctiondespite 2 or more continuous infusions of high-doseinotropes. Dopamine or dobutamine infusions greater than20 μg kg−1 min−1 and norepinephrine and epinephrineinfusions greater than 0.5 μg kg−1 min−1 were typicallyconsidered high doses. The ECMO mode was categorized asVA or venovenous (VV). Septic patients with acuterespiratory distress syndrome and concomitant shock notmeeting the criteria for VA-ECMO received VV-ECMO.

Patients were excluded if this was not their first-timeECMO or if ECMO was initiated offsite to minimizeunderestimation of infections secondary to incomplete sur-veillance. Patients routinely received septic workup at ECMOonset, including 2 sets of blood cultures, chest radiograph, andculture of sites as indicated [18]. Preexisting sepsis wasdefined as newly emerging or uncontrolled infectionsoccurring within 7 days before ECMO initiation and directlycontributing to the refractory respiratory or circulatory failureprecipitating rescue therapy [18]. Infections not present atECMO onset but occurring during ECMO use and caused bypathogens different from those of infections within 7 daysbefore ECMO initiation were considered post-ECMO in-fections [18]. The Centers for Disease Control and Prevention/National Health Surveillance Network criteria for infections inthe acute care settings were followed (Supplement Table 1)[21]. Two infectious disease clinicians independentlyreviewed and discussed the medical records to reach anagreement in cases of dispute. The institutional review boardapproved the study and waived the need for informed consent.

2.1. Statistical analysis

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 inthe baseline risks for mortality between the sepsis and the

Page 3: Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

Fig. 1 Flow diagram of patient selection. With propensity scorematching, patients for whom appropriately similar “controls” couldnot be found in our original cohort were excluded from analysis.

532.e3Extracorporeal life support in septic adults

nonsepsis groups, propensity score analysis was con-ducted. First, the probability for receiving ECMO forsepsis was estimated for each of the 514 subjects using amultivariable logistic regression model with demographicsand pre-ECMO characteristics listed in Supplement Tables2 and 3. Then, each subject in the sepsis group was 1:1matched with the nearest neighbor in the nonsepsis groupby the logit of the estimated propensity score using thenearest available Mahalanobis metric matching method.The chosen size of the caliper was 0.2438 based on

CaliperL ¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

^Var logit estimated propensity scoreð Þ½ �p

4 , where thesample variance of the logit (estimated propensity score)was 0.9508.

After pairing all available subjects, we rechecked thedistributions of the risk factors for mortality betweenmatched septic and nonseptic subjects.

Finally, we examined the effect of preexisting sepsis onpost-ECMO survival by fitting multivariable Cox propor-tional hazards model on the matched cohort using all theunivariate significant and nonsignificant relevant covariatesand some of their interactions (eg, preexisting sepsis × VAmode). The significance levels for entry and for stay were setto 0.15 or larger. Specifically, the stepwise variable selectionprocedure (with iterations between the forward and thebackward steps) was applied to obtain the candidate finalregression model. Then, with the aid of substantiveknowledge, the best final regression model was identifiedmanually by dropping the covariates with P values greaterthan .05 one at a time, until all regression coefficients weresignificantly different from 0. The generalized additivemodel was applied to detect nonlinear effects of continuouscovariates or to discretize them.

3. Results

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

3.1. Propensity score matching

After matching, the distributions of the logit (estimatedpropensity scores) were well balanced (Supplement Fig 1),and no significant differences in baseline characteristicsbetween septic and nonseptic subjects remained (Tables 1and 2). Thus, the remaining difference between the 2 groupswas the presence or absence of active sepsis.

Table 1 shows the types of infections of preexistingsepsis: pneumonia in 40%, acute myocarditis in 25%, and

primary bloodstream infections (BSIs) in 19% of 108 septicpatients. Most infections (93%) were monomicrobial, but 10patients had more than 1 pathogen.

From the 21 patients with BSI, a total of 28 pathogenswere isolated; Staphylococcus aureus (18%), Streptococcusspecies (14%), and Klebsiella pneumoniae (14%) were the 3most predominant isolates. From the 43 patients withrespiratory tract infection, influenza (7%) was the mostcommon viral respiratory pathogen detected, whereasPseudomonas aeruginosa (21%), K. pneumoniae (12%),and Acinetobacter baumannii complex (9%) were the 3 mostcommon bacterial isolates.

3.2. Univariate analysis of survival

Overall survival to discharge did not differ between thosewith (28.7%) and those without sepsis (37.0%; P = .192).Table 3 shows that nonsurvivors were more likely to havepoor host factors (older age, higher Charlson score, andstroke history), advanced disease (higher Acute Physiologyand Chronic Health Evaluation II [APACHE II] scores,inotropic demand, serum lactate levels, VA use, concurrentCPR, and longer pre-ECMO hospitalization), and post-ECMO neurologic and renal complications compared withsurvivors, whereas more survivors had myocarditis andthrombotic complications.

Of note, the percentage of patients with preexisting sepsiswas not different between survivors and nonsurvivors(43.7% vs 53.1%, P = .247). However, there was a trendfor fewer survivors with sepsis on VA-ECMO (29.6% vs44.8%, P = .045). The percentages of survivors in ascendingorder for septic adults on VA-ECMO, nonseptic adults onVA-ECMO, nonseptic adults on VV-ECMO, and septicadults on VV-ECMOwere 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

Page 4: Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

Table 1 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) 52.0 (17) 49.0 (17) .15616-30, % (n) 13.0 (14) 16.7 (18) .59531-45, % (n) 20.4 (22) 25.0 (27)46-65, % (n) 42.6 (46) 39.8 (43)N65, % (n) 24.1 (26) 18.5 (20)Male, % (n) 68.5 (74) 74.1 (80) .367Initial body mass index (kg/m2), mean (SD) 23.6 (3.9) 24.4 (4.6) .155Underlying diseasesCharlson comorbidity index, mean (SD) 2.6 (2.7) 3.0 (2.5) .299Hypertension, % (n) 25.9 (28) 25.9 (28) .999Diabetes mellitus, % (n) 24.1 (26) 17.6 (19) .241Congestive heart failure, NYHA II-IV, % (n) 37.0 (40) 39.8 (30) .675Coronary artery disease, % (n) 13.0 (14) 21.3 (23) .104Remote ischemic stroke, % (n) 3.7 (4) 5.6 (6) .517Remote intracranial hemorrhage, % (n) 3.7 (4) 4.6 (5) .999Cirrhosis of the liver, % (n) 2.8 (3) 2.8 (3) .999End-stage renal disease under dialysis, % (n) 4.6 (5) 4.6 (5) .999Types of preexisting infections, % (n)Pneumonia 40.0 (43) – –Acute myocarditis 25.0 (27) – –Primary BSIs 19.4 (21) – -Intra-abdominal infections 6.5 (7) – –Infective endocarditis 3.7 (4) – –Mediastinitis 2.8 (3) – –Necrotizing fasciitis 1.9 (2) – –Posttransrectal prostate biopsy urosepsis 1.0 (1) – –Initial disease severity, mean (SD)APACHE II 22.3 (9.8) 21.2 (8.7) .386Inotropic equivalent score a 77.4 (151.9) 66.2 (178.3) .622Indications for ECMO b, % (n)Acute respiratory failure 21.3 (23) 21.3 (23)Mechanical circulatory support 78.7 (85) 78.7 (85)Septic shock (no cardiopulmonary disease) 55.3 (47/85) –Sepsis exacerbating chronic heart disease 36.5 (31/85) –Sepsis exacerbating chronic lung disease 8.2 (7/85) –Acute myocardial infarction – 25.9 (22/85)Cardiomyopathy – 18.8 (16/85)Postcardiotomy stunning – 16.5 (14/85)Trauma – 3.5(3/85)Acute heart transplant rejection – 3.5 (3/85)Electrocution – 2.4 (2/85)Phaeochromocytoma – 2.4 (2/85)Miscellaneous – 27.1 (23/85)ECMO for primary admission diagnosis, % (n) 63.9 (69) 69.4 (75)ECMO for secondary complication, % (n) 36.1 (39) 30.6 (33)Clinical course (d), mean (SD)Admission to ECMO interval 14.9 (21.2) 14.8 (35.0) .996ECMO start to death 8.84 (1.20) 15.01 (2.58) .074Mechanical ventilation to ECMO use 8.5 (35.7) 2.0 (5.1) .060Duration of ECMO use 6.60 (7.16) 6.70 (10.7) .938Total duration of mechanical ventilation 20.1 (37.1) 17.8 (26.0) .510

a 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 theECMO was applied [22].

b Extracorporeal membrane oxygenation indications. At this center, respiratory failure was defined as the sustained need (N12 hours) for 100% fractionalinspired oxygen under which the PaO2was 40mmHg or less, the oxygenation indexwas 40 or greater, or the arterial-alveolar gradient was greater than 600, orby a lung Murray injury score of 3 or higher; circulatory failure was defined by the requirement for continuous CPR, inability to maintain mean arterialpressure above 60 mm Hg, or progressive lactic acidosis and end-organ dysfunction despite 2 or more continuous infusions of high-dose inotropes.

532.e4 A. Cheng et al.

Page 5: Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

Table 2 Clinical outcomes of propensity score–matched 108 septic and 108 nonseptic adults undergoing ECMO

Variables Septic (n = 108) Nonseptic (n = 108) P

ECMO mode a, % (n)VA 79.6 (86) 79.6 (86) 1.000VV 20.4 (22) 20.4 (22)Cardiac events, % (n)CPR before ECMO 28.7 (31) 35.2 (38) .307CPR during ECMO 25.9 (28) 37.0 (40) .079IABP during ECMO 19.0 (20) 25.3 (25) .285Complications b on ECMO, % (n)ECMO circuit clot 34.3 (37) 33.3 (36) .886Major bleeding 15.7 (17) 18.5 (20) .588Post-ECMO neurologic deficit 1.9 (2) 4.6 (5) .445Survived with neurologic disability 19.4 (21) 20.4 (22) .865Pneumothorax 7.4 (8) 4.6 (5) .391Post-ECMO dialysis dependence 57.4 (62) 42.6 (46) .029Post-ECMO infection 12.0 (13) 10.2 (11) .665Hypoglycemia 4.6 (5) 5.6 (6) .757Peripheral limb ischemia 44.4 (48) 46.3 (50) .785Transfusion within first 72 h (units), mean (SD)Whole blood 0.31 (1.41) 0.68 (1.91) .111Packed red blood cells 5.75 (6.17) 6.44 (7.01) .438Fresh-frozen plasma 2.23 (4.74) 2.43 (5.22) .770Platelet 8.66 (12.66) 8.48 (14.24) .924Survival outcomes, % (n)Overall mortality 71.3 (77) 63.0 (68) .192Death b3 d of ECMO use 35.1 (27/77) 39.7 (27/68) .564Death b7 d of ECMO use 58.4 (45/77) 52.9 (36/68) .506Removal ECMO and ICU death 12.0 (13) 18.5 (20) .424Removal ECMO and ward death 0.9 (1) 0.9 (1)Bridge to definitive treatment 3.7 (4) 4.6 (5)Survived beyond ECMO 44.4 (48) 56.5 (61)Survived beyond discharge 28.7 (31) 37.0 (40) .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 orradiographic evidence of brain infarction or hemorrhage; Survived with neurologic disability, as indicated by Glasgow-Pittsburgh cerebral performancecategories scores of 3 to 4 after discharge from hospital [35]; pneumothorax, radiologic or chest-tube evidence of any volume of pneumothorax; post-ECMOdialysis dependence, need for intermittent hemodialysis or continuous VV hemofiltration after ECMO removal; post-ECMO infection, infections occurring inthe 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 forcompartment syndrome.

532.e5Extracorporeal life support in septic adults

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

3.3. Multivariate analysis for in-hospital mortalityof a matched cohort of 216 patients

In-hospital mortality did not differ between those withand 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 beselected for multivariate analysis model. After analysis asdescribed in Methods, septic adults on VA-ECMOwere at anincreased 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 dominantcovariates (Table 4). Patients with sepsis on VV-ECMOhad outcomes equivalent to those without sepsis on VV-ECMO. The generalized additive model detected the non-linear effect of age on mortality with a plateau of risk after 55years. Hence, those older than 55 years were more likely todie in hospital compared with those 55 years and younger(HR, 1.56; P = .017).

Page 6: Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

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

Variables Survived to discharge(n = 71)

Died in hospital(n = 145)

P

Age (y), mean (SD) 44.8 (16.3) 53.5 (16.2) b .001Charlson comorbidity index, mean (SD) 2.4 (2.5) 3.0 (2.66) .023Congestive heart failure NYHA II-IV, % (n) 29.6 (21) 42.8 (62) .074Ischemic stroke history, % (n) 0.0 (0) 6.9 (10) .033Preexisting sepsis, % (n) 43.7 (31) 53.1 (77) .247VA mode, % (n) 71.8 (51) 84.1 (122) .052Preexisting sepsis undergoing VA mode, % (n) 29.6 (21) 44.8 (65) .045Admission to ECMO (d), mean (SD) 11.0 (36.4) 16.7 (24.3) .001Initial disease severityAPACHE II score, mean (SD) 18.2 (8.4) 23.6 (9.2) b .001Inotropic equivalent score, mean (SD) 59.2 (184.4) 77.0 (154.3) .024Serum lactate a pre-ECMO, mean (SD) 6.0 (4.5) 7.6 (5.5) .085Serum lactate a 24 h post-ECMO, mean (SD) 6.3 (5.2) 8.2 (6.0) .046CPR before ECMO, % (n) 29.6 (21) 33.1 (48) .714CPR during ECMO, % (n) 22.5 (16) 35.9 (52) .068ECMO complications, % (n)ECMO circuit clot 43.7 (31) 29.0 (42) .046Major bleeding 18.3 (13) 16.6 (24) .897Post-ECMO neurologic deficit 5.6 (4) 26.2 (38) b .001Post-ECMO dialysis dependence 29.6 (21) 60.0 (87) b .001Post-ECMO infection 39.4 (28) 24.1 (55) .948Hypoglycemia 1.4 (1) 6.9 (10) .106Peripheral limb ischemia 36.7 (26) 49.7 (72) .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 hadthe worst cumulative survival compared with septic patients on VA-ECMO and patients with and without sepsis on VV-ECMO. P valuewas .006 among the 4 groups, .063 for sepsis and VA model vs nonsepsis and VA model, and .659 for sepsis and VV model vsnonsepsis and VV model.

532.e6 A. Cheng et al.

Page 7: Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: A propensity-matched analysis

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

Covariate HR Lower95% CI

Upper95% CI

P

Logit of estimatedpropensity score a

1.06 0.87 1.29 .580

Age N55 y vs ≤55 y 1.56 1.08 2.24 .017History of ischemicstroke × survival time c

1.12 1.04 1.20 .002

Acute myocarditis 0.23 0.11 0.48 b .001CPR during ECMO 2.18 1.48 3.21 b .001Post-ECMO dialysisdependence × survivaltime c

1.03 1.01 1.05 .010

Post-ECMO neurologicdeficit

2.13 1.43 3.18 b .001

Sepsis and VA ECMO d 2.54 1.75 3.70 b .001

The goodness-of-fit measure, adjusted generalized R2 = 0.322, indicateda good fit because the value of that measure is usually low.

a The 108 pairs of subjects were matched by the logit (estimatedpropensity score), and thus, the logit (estimated propensity score)was purposefully kept in the above regression model to reduceselection bias.

b Although we performed multivariate analysis, mechanical circuitclot appeared to be protective with an HR less than 1, but its effect wasneither time dependent nor constant so that the final model wasstratified by the presence or absence of thrombotic complications.

c History of ischemic stroke and post-ECMO dialysis dependencewere nonproportional hazards risk factors for hospital mortality so thatthey were multiplied by survival time to indicate that their hazard risksincreased as time passed.

d The significant negative effect of the interaction between sepsisand VA mode was motivated by biological plausibility and endorsedby the differences in the crude Kaplan-Meir estimates of survivalcurves among the 4 subgroups classified by the sepsis and VA vsVV mode.

532.e7Extracorporeal life support in septic adults

In summary, age greater than 55 years, history of stroke,CPR during ECMO, post-ECMO neurologic deficits, anddialysis dependence were independent predictors of hospitalmortality. Myocarditis was a protective factor (HR, 0.23; P b.001). In the subgroup analysis excluding all myocarditispatients, the same set of covariates remained significant, andseptic 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 mortalityof matched 172 patients on VA-ECMO only

In a further subgroup analysis excluding 68 patients onVV-ECMO from the original cohort of 514 patients, weapplied the same methodology to match septic vs nonsepticpatients on VA-ECMO. Of 446 adults on VA-ECMO, a totalof 86 pairs of patients were analyzed; 67 of the 172individuals were not included in the previous survivalanalysis, whereas 105 were among the matched cohort of

more than 216 patients. Multivariate analysis confirmed therobustness of the above findings (Supplement Table 4);preexisting sepsis became an independent predictor ofhospital 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 adultpopulation with life-threatening infections undergoing VA-or VV-ECMO. We demonstrated that outcomes in the settingof sepsis were conditional on the ECMO mode. Whenpatients had conditions necessitating VA-ECMO, those withsepsis had worse outcomes than did their counterparts withnon–sepsis-related shock on VA-ECMO (Fig. 2 andTable 4). In contrast, when sepsis resulted in refractoryrespiratory failure, no excess mortality was observed forpatients undergoing VV-ECMO.

Consistent with these findings, noninferior outcomes foradults receiving VV-ECMO for respiratory failure caused bysepsis based on one center's retrospective review of 100patients (14 of whom were septic), later accumulated to 255patients (22 of whom were septic), were reported [22,23],whereas higher risks of death have been associated with VA-ECMO under conditions of sepsis in a single-centerretrospective cohort of 607 adults and in 40 recipientsundergoing heart transplant [24,25].

Hence, the view that primary sepsis does not contribute toincreased mortality in adults receiving ECMO is supportedby 2 series for adults with respiratory failure [22,23]. Thisview is reasonable because VV-ECMO comparators includepatients with similar likelihoods and time courses forrecovery, for example, aspiration or chemical pneumonitis,pulmonary vasculitides, pancreatitis, trauma, or obstetrics-related acute respiratory distress syndrome [11]. There are nodata suggesting that the same applies to adults withcirculatory collapse. In fact, we showed that septic adultson VA-ECMO relative to their counterparts with surgicallycorrectable diseases may not be weaned off VA-ECMOquickly enough (Supplement Table 2).

Hence, the questions raised were as follows: first, whyshould sepsis result in greater mortality among adults on VA-ECMO but not on VV-ECMO? Second, why are VA modeoutcomes equivalent for children irrespective of sepsis butnot adults? Third, how do we fit these findings in the contextof conflicting case reports of exemplary success? Someplausible explanations ensue (summarized in SupplementTable 5).

Better outcomes are associated in general with VV-ECMOfor reasons attributed both to the less moribund patientsrequiring only respiratory support and the more physiologicalcircuit [26]. In other words, VA-ECMO was reserved forcases of septic shock that failed or was likely to fail VVmode.Our results do not refute the view that patients who were

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532.e8 A. Cheng et al.

“more ill” required VA-ECMO and were more likely to diebecause we are not comparing the outcomes of patients onVA mode vs VV mode. Nevertheless, after adjusting forunderlying disease severity by multivariate analysis, thelower benefit of VA-ECMO for septic patients compared withVA-ECMO for nonseptic patients was highlighted.

Prolonged ECMO in septic adults on VA-ECMOincreased the potential for morbidity and mortality relatedto subsequent complications and was indicative of delayed ordiminished likelihoods of recovery. Our results showed ahigher frequency of post-ECMO dialysis dependence amongseptic patients (Table 2). Septic patients experience not onlyshock-related ischemic insults but also the superimposednephrotoxic effects of antimicrobial agents and endotoxins.Hence, sepsis by predisposing to irreversible kidney injuryplausibly contributes excess mortality [27].

Venoarterial ECMO by femoral vascular access prefer-entially predisposes septic adults, with relative rather thanabsolute myocardial dysfunction to upper body hypoxemia(Supplement Fig 2). The best outcomes for children withseptic shock have been reported using central (atrioaortic)rather than conventional VA-ECMO [28]. Selective upperbody hypoxemia was observed clinically, but we areinsufficiently experienced to know whether alternativeapproaches to return oxygenated blood to the proximalaorta can circumvent the flaw of the less physiologicalfemoral access and improve outcomes for septic adults onVA-ECMO.

Furthermore, VA-ECMO does not ameliorate adult septicshock that is predominantly vasoplegic rather than cardio-genic. In other words, the contribution of VA-ECMO inproviding macrocirculatory hemodynamic support or addingflow to low-flow states is not the solution to the impairedmicrocirculation in developed sepsis and septic shock. Thecontinuous flow provided by VA-ECMO may also affect thehomeostatic adjustments of the microvasculature, giving riseto the lower benefit of VA-ECMO seen in septic patients.Indeed peripheral vascular failure is a major determinant ofmortality in septic shock because patients with high cardiacoutput and low systemic vascular resistance experiencedhigher mortality [29].

In instances when VA-ECMO has been successfully usedin adults with septic shock, the contribution of myocardialfailure has been an important feature. This is interestingbecause myocardial dysfunction with sepsis is well described[30]. However, use of VA-ECMO for this indication in theadults is rare. Five such cases reports comprise a patient withprosthesis-related osteomyelitis, 2 with necrotizing fasciitis,1 with novel H1N1 influenza, and one with sternal woundinfection, all of them had left ventricular ejection fractionless than 35% [9,12,16,31]. The hemodynamic responses ofthese patients were similar to those seen in septic youngchildren (Supplement Table 5). This may explain theirfavorable outcomes after VA-ECMO.

Altogether, our results concur with the view that VA-ECMO should rarely be indicated for septic shock in adults.

Perhaps, owing to the differences in the hemodynamicmanifestations of sepsis, the VA circuitry (proximal aorta orinternal carotid artery cannulation rather than femoral arterycannulation in children), timing of rescue (adults presentlater than children), and intrinsic capabilities to heal (whichdecline with age), VA-ECMO appears to rescue more septicchildren than septic adults.

Overall survival to discharge of adults with preexistingsepsis is 29% in this study. This is comparable with thepooled survival rate of adults supported with extracorporealcirculation for cardiac failure in general (34%) and forextracorporeal CPR (ECPR; 27%) [7]. Importantly, thissurvival is not marred by significant disability, which maynot be true for survivors of ECPR (namely, 94% of ourpatients were neurologically preserved in contrast to only30% of patients on ECPR) [17]. However, it remains to beproven whether survival can be improved by fine-tuningpatient selection.

4.1. Limitations

This study was observational and retrospective. Despitean attempt to control for prognostic factors, our study is apoor substitute to efficacy trials. However, given thelogistical and ethical concerns with conducting such trials,our findings offer relevant information for intensivists whocannot keep septic adults alive by conventional managementand are considering ECMO. There may be occult con-founders that were not matched. The chances of missing asignificant confounder were not high based on the adjustedR2 of our final model (0.3224). We were unable to explicitlydefine maximal conventional therapy because of importantsecular changes over the last decade. However, because thesechanges applied to both septic and nonseptic patients, theyshould not subtract from our ability to compare the survivalof these 2 groups of patients.

We restricted enrollment to ensure standardized care to asingle center. The suboptimal survival seen at this centerreflects the suboptimal selection of candidates for ECMO.Owing to local customs and culture, intensivists are oftenunder pressure from patients' families to initiate ECMO,despite informed low likelihoods of survival [32]. Ourmostly male (71% vs 17%-58%) [33,34], leaner (body massindex, 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 directlycomparable with other published institutional experiences.Our center has a low trigger point to start ECMO asevidenced 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 24hours post-ECMO). Other centers, probably, would not useECMO in such high-risk patients. Whether ECMO isappropriate therapy for septic adults is beyond the scopehere. Subgroup analysis to define factors that may predictpoorer outcomes for septic adults deserves urgent study tolimit potential harm and futility.

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532.e9Extracorporeal life support in septic adults

5. Conclusions

We documented that ECMO rescued approximately 30%of septic adult patients with life-threatening cardiopulmonaryfailure. Although overall survival is low, ECMO represents apossible form of rescue therapy in adults when all othertreatments have failed. We concur that VV-ECMO need notbe withheld from patients with active sepsis. However, giventhe inferior outcomes for septic adult patients on VA mode,we would advocate careful risk-benefit assessment on anindividual basis before VA-ECMO is initiated for adultrefractory septic shock.

Acknowledgments

Y.C. Chen received a grant (DOH100-TD-B-111-001)from the Department of Health, Taiwan. The funder had norole in study design, data collection and analysis, decisionto publish, or preparation of the manuscript. The authorshave declared that no competing interests exist. Theauthors are indebted to Dr Victor L. Yu (University ofPittsburgh) and Dr Chi-Ming Lee (NTUH) for criticalreview of the manuscript.

Appendix A. Supplementary Data

Supplementary data to this article can be found online athttp://dx.doi.org/10.1016/j.jcrc.2012.11.021.

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