ORIGINAL ARTICLE
Venovenous extracorporeal life support improves survival in adult trauma patients with acute hypoxemic respiratory failure: A multicenter retrospective cohort study Derek M. Guirand, MD, Obi T. Okoye, MD, Benjamin S. Schmidt, MD, Nicky J. Mansfield, BS, James K. Aden, PhD, R. Shayn Martin, MD, Ramon F. Cestero, MD, Michael H. Hines, MD, Thomas Pranikoff, MD, Kenji Inaba, MD, and Jeremy W. Cannon, MD, San Antonio, Texas
Venovenous extracorporeal life support (VV ECLS) has been reported in adult trauma patients with severe respiratory failure; however, ECLS is not available in many trauma centers, few trauma surgeons have experience initiating ECLS and managing ECLS patients, and there is currently little evidence supporting its use in severely injured patients. This study seeks to determine if VV ECLS improves survival in such patients. METHODS: Data from two American College of SurgeonsYverified Level 1 trauma centers, which maintain detailed records of patients with acute hypoxemic respiratory failure (AHRF), were evaluated retrospectively. The study population included trauma patients between 16 years and 55 years of age treated for AHRF between January 2001 and December 2009. These patients were divided into two cohorts as follows: patients who received VV ECLS after an incomplete or no response to other rescue therapies (ECLS) versus patients who were managed with mechanical ventilation (CONV). The primary outcome was survival to discharge, and secondary outcomes were intensive care unit and hospital length of stay (LOS), total ventilator days, and rate of complications requiring intervention. RESULTS: Twenty-six ECLS patients and 76 CONV patients were compared. Adjusted survival was greater in the ECLS group (adjusted odds ratio, 0.193; 95% confidence interval, 0.042Y0.884; p = 0.034). Ventilator days, intensive care unit LOS, and hospital LOS did not differ between the groups. ECLS patients received more blood transfusions and had more bleeding complications, while the CONV patients had more pulmonary complications. A cohort of 17 ECLS and 17 CONV patients matched for age and lung injury severity also demonstrated a significantly greater survival in the ECLS group (adjusted odds ratio, 0.038; 95% confidence interval, 0.004Y0.407; p = 0.007). CONCLUSION: VV ECLS is independently associated with survival in adult trauma patients with AHRF. ECLS should be considered in trauma patients with AHRF when conventional therapies prove ineffective; if ECLS is not readily available, transfer to an ECLS center should be pursued. (J Trauma Acute Care Surg. 2014;76: 1275Y1281. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Therapeutic study, level III. KEY WORDS: Adult respiratory distress syndrome (ARDS); extracorporeal life support (ECLS); lung injury; respiratory failure; trauma. BACKGROUND:
A
dult trauma patients with severe injuries are at risk for developing adult respiratory distress syndrome (ARDS),1 which carries an increased risk of morbidity and mortality.2Y4 Lungprotective ventilation using low-tidal volumes, limited plateau pressure, and moderate levels of positive end-expiratory pressure
Submitted: August 18, 2013, Revised: January 17, 2014, Accepted: February 10, 2014. From the Wake Forest School of Medicine (D.M.G., B.S.S., R.S.M., T.P.), Winston-Salem, North Carolina; Los Angeles County + University of Southern California Medical Center (O.T.O., N.J.M., K.I.), Los Angeles, California; US Army Institute of Surgical Research (J.K.A.); University of Texas Health Science Center at San Antonio, (R.C.F.); and San Antonio Military Medical Center (J.W.C.), San Antonio; University of Texas Health Science Center at Houston (M.H.H.), Houston, Texas; Norman M. Rich Department of Surgery (J.W.C.), Uniformed Services University of the Health Sciences, Bethesda, Maryland. D.M.G. and O.T.O. contributed equally to this study. This study was presented in part at the American College of Chest Physicians, CHEST 2011, October 22Y26, 2011, in Honolulu, Hawaii. The opinions expressed in this article are solely those of the authors and do not represent an endorsement by or the views of the US Air Force, the US Army, the US Navy, the Department of Defense, or the US Government. Address for reprints: Jeremy W. Cannon, MD, Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, JBSA Fort Sam Houston, TX 78234; email: [email protected]. DOI: 10.1097/TA.0000000000000213
(PEEP) has a proven survival benefit in ARDS patients.5 Rescue oxygenation strategies are also commonly used in these patients including recruitment maneuvers, high PEEP, airway pressure release ventilation, high-frequency oscillatory ventilation, neuromuscular blockade, prone positioning, and inhaled vasoactive agents including nitric oxide (iNO) and prostacyclins. These strategies improve ventilator synchrony, correct ventilation-perfusion mismatch, reduce oxygen consumption, increase alveolar recruitment, and decrease the shunt fraction resulting in improved oxygenation.6 Recent evidence also suggests that a brief period of neuromuscular blockade7 and prone positioning8 improve survival in moderate-to-severe ARDS patients. Some patients with ARDS remain hypoxemic despite the use of these measures in which case extracorporeal life support (ECLS) should be considered according to the Extracorporeal Life Support Organization patient management guidelines9 and current expert opinion.10 Y12 ECLS has advanced significantly since the first successful use in an adult patient with severe respiratory failure after blunt trauma was reported in 1972.13 Venovenous (VV) ECLS supports oxygen delivery by shunting deoxygenated blood from the systemic venous circulation through a gas exchange membrane. Oxygenated blood from the membrane is then
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returned to the venous system for circulation to peripheral tissue beds. Following initiation of ECLS, ventilator settings can be reduced, thereby mitigating the various mediators of ventilatorinduced lung injury including high transpulmonary pressures (barotrauma), alveolar overdistention (volutrauma), repetitive opening and closing of alveolar units (atelectrauma), and the amplified systemic inflammatory response mediated by these mechanical insults (biotrauma).14 Although several centers have reported the use of ECLS in trauma patients,15Y19 ECLS has not been widely incorporated into trauma critical care management for numerous reasons including lack of access to ECLS, limited familiarity with ECLS within the trauma community, and no proven survival benefit in the trauma population. In this study, we compare the use of ECLS with conventional mechanical ventilation for the management of acute hypoxemic respiratory failure (AHRF) in acutely traumatized adult patients to determine if such a benefit exists.
PATIENTS AND METHODS Study Design A review of the ECLS registry at the Wake Forest School of Medicine and the Trauma and Surgical Intensive Care Unit database at the Los Angeles County + University of Southern California (LAC + USC) Medical Center from January 2001 through December 2009 was performed after institutional review board approval with waiver of consent was obtained at both centers. Trauma patients between 16 years and 55 years with severe life-threatening AHRF were identified. AHRF was defined as a PaO2/FiO2 of 80 or less with an FIO2 greater than 0.9 with no evidence of cardiogenic pulmonary edema and with a Murray Lung Injury Score (LIS) score of 3.0 or greater. This degree of respiratory failure has historically resulted in death in up to 80% of patients and is used as a threshold for initiating ECLS by the Extracorporeal Life Support Organization.9 All of these patients had ‘‘severe’’ ARDS using the new Berlin definition.1 Excluded from the analysis were nontrauma patients, those with ECLS primarily for cardiogenic shock, patients with acute intracranial hemorrhage, and patients who expired within 24 hours of admission. Patients were divided into those managed with VV ECLS and those managed with mechanical ventilation (CONV). Patient demographics included age, sex, mechanism of injury, chest Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), base excess, fluid balance, days to ECLS, PaO2/FIO2, and LIS at the time of AHRF diagnosis. The primary outcome measure of the study was survival to hospital discharge. Secondary outcome measures included intensive care unit (ICU) length of stay (LOS), hospital LOS, and number of mechanical ventilation days. Hemorrhagic, pulmonary, and renal complications were recorded. Hemorrhagic complications included gastrointestinal bleeding, ECLS cannulation site bleeding, other surgical site bleeding, hemolysis, and disseminated intravascular coagulation (DIC). The number of transfused packed red blood cell (PRBC) units during the hospital stay was also recorded. Pulmonary complications included pneumothorax, pulmonary hemorrhage, and new-onset pneumonia. Pneumonia was defined as new or persistent radiographic infiltrate or consolidation without another obvious cause after meeting ECLS initiation 1276
criteria along with any two of the following clinical features: a temperature exceeding 38-C (CONV group only), leukocytosis/ leukopenia (leukocyte count 9 11.0 103/mL or G3.5 103/mL), purulent endotracheal secretions, or potentially pathogenic bacteria isolated from the endotracheal aspirate. Renal complications were defined as the development of Acute Kidney Injury Network (AKIN) acute kidney injury by serum creatinine criteria or the need for supplemental renal replacement therapy (RRT).20 In the CONV group, RRT was performed as hemofiltration or hemodialysis at the bedside using either Fresenius (Waltham, MA) or Baxter (Deerfield, IL) hemodialysis system, while the ECLS group was managed with either Prismaflex System (Gambro Americas, Lakewood, CO) or NxStage (Lawrence, MA) hemodialysis device in line with the ECLS circuit. At both centers, RRTwas initiated at the discretion of the physician team in consultation with nephrology to manage volume overload, electrolyte derangements, or azotemia.
Ventilator Management and ECLS Patients in the CONV group were managed with a range of ventilator modes including volume control modes, pressure control modes, and high-frequency ventilation (HFV). ARDSNet protocol goals were used as a general guideline for O2, CO2, and airway pressure management before implementing HFV.5 On HFV, adjustments were made based on the experience of the LAC + USC intensivists. All patients treated with ECLS for AHRF were cannulated percutaneously with either a femoral venous drainage cannula paired with an internal jugular return cannula or with a dual lumen Elite Bi-caval Cannula (Maquet Cardiovascular, Wayne, NJ). The principal components of the ECLS circuit included a Sorin SIII roller pump (SORIN GROUP USA, Inc, Arvada, CO), a Medtronic gas exchange membrane (sizes 0800-4500; Medtronic, Minneapolis, MN) or the Quadrox D polymethylpentene membrane (Maquet Cardiovascular), and a Cincinnati Sub Zero heater/ cooler (Cincinnati Sub-Zero Products, Inc., Cincinnati, OH). Following ECLS initiation, the goal was to maintain blood and gas flow through the circuit to keep SaO2 at 85% or greater with adequate end-organ oxygen delivery. Circuit blood gasses were continuously analyzed using the CDI 500 blood gas monitor (Terumo Cardiovascular Systems, Ann Arbor, MI). Full anticoagulation was achieved by titrating a continuous infusion of unfractionated heparin to maintain an activated clotting time of 180 seconds to 220 seconds. During ECLS support, ventilator settings were reduced to rest settings of pressure control ventilation FIO2 of 0.4, rate of 8 to 12, peak inspiratory pressure of 24 cm H2O, and PEEP of 12 cm H2O using the lung rest protocol at the ECLS center in this study. As lung function improved, a trial off ECLS was performed by discontinuing the circuit gas flow with the ventilator set initially at peak inspiratory pressure of 28 cm H2O, PEEP of 8 cm H2O, and FIO2 of 1. The FIO2 was then decreased hourly to a target an FIO2 of 0.4. If adequate gas exchange was maintained for 12 hours at these settings, the patient was decannulated.
Statistical Analysis Univariate analysis was performed to compare the two cohorts. The two-sample t test was used to compare the means for continuous variables, and the two-sided Fisher’s exact test was * 2014 Lippincott Williams & Wilkins
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used to compare proportion. Significant risk factors from the univariate analysis were entered into a multivariate logistic regression to determine the odds ratio for survival. We also used propensity scoring to develop two cohorts of patients matched for age and PaO2/FIO2. Univariate and multivariate analyses were then performed on the matched cohorts to determine if additional covariates were needed to establish matched cohorts. Sixty-day Kaplan-Meier survival curves were developed for these matched cohorts. A p G 0.05 was considered significant. All statistical analyses were performed using SPSS, version 17 (IBM, Chicago, IL) and SAS version 9.2 (Cary, NC).
RESULTS From January 2001 through December 2009, the Wake Forest School of Medicine treated 453 patients with ECLS. Of these, 26 patients met inclusion criteria (ECLS group). During the same period, LAC + USC Medical Center treated a total of 561 surgical patients with ARDS. Of these, 76 met study inclusion criteria as trauma patients with AHRF and no contraindications for ECLS (CONV group) (Fig. 1). All patients in the ECLS arm were from Wake Forest, and all patients in the CONV arm were from LAC + USC because ECLS was not provided at this institution during the study period. The patients in both groups were predominantly young males with a similar mean age (Table 1). Blunt trauma was the primary injury mechanism with a very high injury severity and a significant thoracic component in both groups. At the time of AHRF diagnosis, patients in the ECLS cohort had a higher positive fluid balance (9.9 [9.6] L vs. 3.0 [3.2] L, p G 0.001), had a significantly lower PaO2/ FIO2 (49.6 [10.7] vs. 59.0 [12.3], p = 0.001), and had a higher LIS (3.8 [0.3] vs. 3.5 [0.3], p G 0.001) (Table 1). In the CONV group, 8 patients (11%) were treated with volume control ventilation, 10 patients (13%) were treated with pressure control ventilation, and 58 patients (76%) were treated with HFV. Of the 26 patients in the ECLS group, 15 survived to discharge, whereas in the CONV group, 42 survived for a crude survival of 58% versus 55%, respectively. After adjusting for
Figure 1. Study population demonstrating the application of exclusion criteria resulting in the final study cohorts and the matched cohorts.
differences in fluid balance, PaO2/ FIO2 and LIS, open abdomen, RRT, hemorrhagic complications, and pulmonary complications, ECLS was independently associated with improved survival (Table 2) as was increased chest AIS score. Independent predictors of mortality included ISS, increased pre-ECLS fluid balance, and LIS. Propensity score matching for age and PaO2/ FIO2 resulted in subgroups of 17 ECLS and 17 CONV patients. Univariate analysis on the covariates in Table 1 demonstrated only a difference in days to ECLS criteria met between the matched cohorts. This difference did not persist on multivariate logistic regression, so no further matching was performed. Survival to discharge was significantly greater in the ECLS group by log rank (Fig. 2) and by multivariate logistic regression (Table 2). ISS independently predicted mortality in these patients. Secondary outcomes including ICU LOS, hospital LOS, and days of mechanical ventilation did not significantly differ between the groups in the full study (Table 3). However, patients receiving ECLS were transfused more PRBCs (8.4 [3.4] U vs. 0.6 [0.3] U, p G 0.001). There was a significantly increased hospital LOS in the matched ECLS group. This difference did not persist among survivors in the matched ECLS versus CONV cohorts. The overall rate of complications did not differ between the ECLS and CONV groups; however, hemorrhagic complications occurred more frequently in the ECLS cohort (15% vs. 1%, p = 0.014), while there were more pulmonary complications in the CONV cohort (0% vs. 28%, p = 0.001), and no difference in renal complications between the groups (Table 4). There were no differences in complications between the matched cohorts. On multivariate logistic regression, none of these complications increased mortality (Table 2).
DISCUSSION AHRF in adult trauma patients remains a significant cause of morbidity and mortality. In this study, we demonstrate that the use of VV ECLS is independently associated with survival in adult trauma patients with AHRF when compared with conventional ventilatory management. Although the ECLS cohort was transfused with more blood and had more bleeding complications, the reported hemorrhagic complications in the ECLS cohort had no effect on in-hospital survival. Although this retrospective study was not designed to determine a mechanism for increased survival in patients treated with VV ECLS, others have attributed this observation to improved gas exchange without ongoing lung injury in a mixed population of ECLS patients.21 Furthermore, although VV ECLS does not provide direct cardiac support, improved myocardial oxygenation often permits weaning of inotropes and vasopressors in these critically ill patients. Outcomes in adult patients with AHRF treated with ECLS have improved significantly since the first randomized study of adult patients was reported in 1979.22,23 In addition to AHRF, ECLS has been used in trauma patients as a resuscitation adjunct,18,24 to facilitate repair of major airway injuries,25 to enable the drainage of a large lung abscess,26 and for active rewarming.27 To date, the largest series of ECLS used for respiratory failure in trauma patients is by Michaels et al.16 at the University of Michigan. In this single-center, retrospective study of 30 patients treated with
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TABLE 1. Characteristics of the Study Cohorts Full Study Cohorts
Demographics Age, y Male sex Trauma description Blunt trauma Chest AIS score ISS Base excess G j6 Pre-ECLS criteria fluid balance, L Days from injury to ECLS criteria met Lung injury severity PaO2/FIO2 LIS Hospital course Open abdomen** Tracheostomy RRT Diuretics
Matched Cohorts
ECLS (n = 26)
CONV (n = 76)
p
ECLS (n = 17)
CONV (n = 17)
p
33.0 (11.5) 20 (77)
33.2 (10.9) 61 (80)
0.944 0.781
30.9 (11.4) 12 (71)
34.1 (10.7) 15 (88)
0.413* 0.398
21 (81) 2.7 (1.6) 29.0 (12.4) 19 (76) 9.9 (9.6) 4.6 (5.8)
56 (74) 2.1 (1.9) 28.6 (13.4) 41 (54) 3.0 (3.2) 6.4 (8.5)
0.601 0.116 0.922 0.062 G0.001 0.337
15 (88) 2.9 (1.5) 30.6 (14.4) 10 (59) 8.9 (9.9) 2.9 (2.7)
11 (65) 1.8 (2.0) 29.4 (13.1) 9 (53) 4.4 (3.6) 8.4 (9.6)
0.225 0.079 0.796 1.0 0.084 0.037
49.6 (10.7) 3.8 (0.3)
59.0 (12.3) 3.5 (0.3)
0.001 G0.001
52.2 (10.8) 3.9 (0.2)
51.1 (9.3) 3.8 (0.2)
0.761* 0.134
13 (19) 30 (39) 8 (11) 40 (53)
0.001 1 0.003 0.498
8 (47) 7 (41) 6 (35) 12 (71)
14 10 10 16
(54) (38) (38) (62)
4 (24) 3 (18) 4 (24) 9 (53)
0.282 0.259 0.708 0.481
*Indicates the covariates used in the propensity score to develop the matched cohorts. **Data available on 68 patients in the CONV cohort. Data are shown as mean (SD) or n (%).
ECLS from 1989 to 1997, survival to discharge was 50%. The patient population was similar in age, sex, and injury mechanism to what we report; however, injury severity was lower (mean ISS, 19.75), and the PaO2/FIO2 was higher (mean, 56.9) compared with our ECLS cohort. Bleeding complications were frequent, with 18 patients (59%) requiring additional transfusion or operative intervention for hemorrhage relative to 4 patients (15%) in our study. Because anticoagulation protocols between our studies were similar; this difference may be explained by recent advances
in ECLS technology, particularly the new polymethylpentene membrane, which was used in many of the patients in our ECLS cohort. Michaels et al. concluded that ECLS was safe in this group of severely injured patients with severe respiratory failure. A contemporary series of 26 trauma patients treated with VV ECLS was recently reported by the group from Regensburg, Germany, together with 26 trauma patients managed with pumpless extracorporeal lung assist for a total of 52 patients over 10 years.28 This series included both civilian trauma patients and
TABLE 2. Mortality Analysis Full cohorts ECLS Chest AIS ISS Pre-ECLS fluid balance LIS Matched cohorts ECLS ISS
AOR (95% CI)
p
0.193 (0.042Y0.884) 0.693 (0.496Y0.967) 1.112 (1.056Y1.171) 1.156 (1.022Y1.309) 10.939 (1.805Y66.305)
0.034 0.031 G0.001 0.022 0.009
0.038 (0.004Y0.407) 1.123 (1.029Y1.226)
0.007 0.009
Multivariate logistic regression with backwards elimination was used to determine factors independently associated with survival and mortality. A value less than 1 indicates an independent survival advantage, whereas a value more than 1 indicates an independent predictor of mortality. Variables included in the original model included ECLS, age, and any demographic, therapeutic, or complication variable with a p e 0.02 on univariate analysis comparing treatments (ECLS vs. CONV) or survival: ECLS, age, chest AIS score, ISS, base excess G j6, Pre-ECLS fluid balance, days from injury to ECLS criteria met, PaO2/FIO2, LIS, open abdomen, any RRT, any hemorrhagic complication, and any pulmonary complication. AOR, adjusted odds ratio; CI, confidence interval.
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Figure 2. Kaplan-Meier survival curve for the cohorts of ECLS versus CONV patients matched for age and PaO2/FIO2 carried out to 60 days. Patients were censored at death or hospital discharge. Survival in the ECLS versus CONV matched cohorts was 64.7% versus 23.5% (p = 0.01). * 2014 Lippincott Williams & Wilkins
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TABLE 3. Secondary Outcome Measures in the Study Cohorts Full Study Cohorts
ICU LOS, d Hospital LOS, d Positive pressure ventilation, d PRBC, h ECLS hours
Matched Cohorts
ECLS (n = 26)
CONV (n = 76)
p
ECLS (n = 17)
CONV (n = 17)
p
36.7 (7.1) 39.8 (7.3) 24.9 (4.4) 8.4 (3.4) 224 (227)
25.4 (3.6) 35.4 (4.9) 20.7 (3.2) 0.6 (8.2) V
0.108 0.713 0.485 1.6 (4.1) V
38.5 (36.9) 45.9 (41.6) 28.5 (23.1) 0.070 256 (214)
18.2 (22.9) 21.1 (23.6) 15.4 (22.7)
0.064 0.040 0.105
V
V
Data are shown as mean (SD) or n (%).
combat casualties with a very high mean ISS of 58.9. The VV ECLS group had an excellent survival rate of 80.8% despite a mean PaO2/FIO2 of 54, a pH of 7.21, and a lactate of 38 mg/dL (4.2 mmol/L). Although multiple surgical procedures were performed during ECLS support, bleeding complications were minimal, with only one patient death attributable to hemorrhage and a median of three PRBC units transfused per patient. Remarkably, 18 of 26 VV ECLS patients were started on support in another facility and then transported to University Medical Center Regensburg. This practice model is gaining wider acceptance with miniaturized ECLS transport systems being used by both civilian and military teams to safely transport critically ill patients with AHRF to ECLS centers.29Y33 In our ECLS cohort, all bleeding complications were able to be managed with local interventions or component replacement and did not contribute to overall mortality. Our data do show that the ECLS group received more blood;
however, the number of transfused PRBC units was relatively low given the severity of injuries in this group and was also far less than has been reported in historic adult ECLS studies.23,34 It should also be noted that in many instances, transfusions were given to compensate for the drop in hemoglobin concentration that occurs after an initiation of ECLS using a crystalloid or albumin prime in a relatively long circuit (386 inches) and to maintain a hemoglobin greater than 10 g/dL and platelets greater than 75,000/KL. As ECLS technology and management techniques evolve, however, circuits are becoming significantly shorter with smaller priming volumes, and the practice of transfusing to an arbitrary target level is being questioned in favor of using a blood conservation strategy.10 Finally, for those patients with overt contraindications to anticoagulation (e.g., brain injury with intracranial hemorrhage), a recent small series indicates that heparinfree ECLS management may be performed for up to 5 days without circuit thrombosis.35
TABLE 4. Comparison of Complications in the Study Cohorts Full Study Cohorts
Any complication Hemorrhagic Gastrointestinal Cannulation site Surgical site Hemolysis* DIC** Pulmonary Pneumothorax Pulmonary hemorrhage Pneumonia Renal AKIN 1 AKIN 2 AKIN 3
Matched Cohorts
ECLS (n = 26)
CONV (n = 76)
p
ECLS (n = 17)
CONV (n = 17)
p
23 (88) 4 (15) 1 (4) 0 3 (12) 0 1 (4) 0 0 0 0 23 (88) 6 (23) 4 (15) 13 (50)
73 (96) 1 (1) 0 V 0 0 1 (1) 21 (28) 0 0 21 (28) 71 (93) 24 (32) 21 (28) 26 (34)
0.334 0.014
16 (94) 3 (18) 1 (6) 0 2 (12) 0 1 (6) 0 0 0 0 16 (94) 4 (24) 3 (18) 9 (53)
16 (94) 0 0 V 0 0 0 3 (18) 0 0 3 (18) 16 (94) 4 (24) 4 (24) 8 (47)
1 0.227
0.004
0.676
0.227
1
*Indicated by a plasma-free hemoglobin greater than 50 mg/dL. **Defined as the presence of two or more systemic inflammatory response syndrome criteria, a reduction in platelet count (G80,000/KL, a Q50% decrease in 24 hours, or a value from 80,000/KL to 120,000/KL with 930% decrease in 24 hours), a prolonged prothrombin time of greater than or equal to 1.2 times the patient’s baseline, and a decrease in fibrinogen levels to less than 350 mg/dL with an associated increase in detection of fibrin degradation products of 10 mg/dL or greater. In the absence of laboratory criteria, diffuse clinical bleeding was also accepted as evidence of DIC. Data are shown as n (%). Any complication represents the total number of patients with a reported complication. Organ system specific complications are the number of patients with a complication in that category.
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In this study, the CONV group had a much higher rate of pneumonia diagnosed after ECLS criteria were met. In the ECLS group, no new pulmonary complications were reported after the initiation of VV ECLS. ECLS theoretically permits early transition to minimal or no ventilator support, while advances in ECLS cannula technology permit early mobilization of these patients even while on ECLS. Thus, ECLS may help avoid not only pulmonary complications but also the neuromuscular deconditioning, which is now widely recognized as the principal cause of long-term disability in patients with severe respiratory failure,36 although these theoretical benefits need to be evaluated in a large, prospective study. There is growing evidence that any AKIN stage is an important marker for poor outcomes in trauma patients.37,38 In the present study, both groups had a high incidence of acute kidney injury, and although RRTwas used more often in the ECLS group, this was not independently associated with increased survival or mortality on multivariate logistic regression. It is important to note, however, that the ECLS group had a higher positive fluid balance before ECLS initiation compared with the CONV group, which was independently associated with increased mortality. This finding further emphasizes the importance of judicious intravenous fluid administration in severely injured trauma patients.39 Limitations of this study include its retrospective design and the comparison of patients managed by geographically remote medical teams. The relatively small numbers in the two cohorts also make any conclusions about the use of hospital resources and complications preliminary until larger studies can be completed. We also had no data on the use of iNO, chemical paralysis, and proning in either group. Finally, there were no long-term outcome data available on the patients in the CONV arm of this study. Despite these limitations, this study does follow the recommended approach for evaluating advanced therapies in the early phases of technology dissemination before wide acceptance.40 In summary, VV ECLS is independently associated with improved survival in adult trauma patients with AHRF. Furthermore, there seems to be no significant increase in ICU or hospital LOS. Finally, the increased rate of hemorrhagic complications in the ECLS cohort had no significant effect on survival and was clinically manageable. Consequently, trauma surgeons should gain familiarity with ECLS initiation and management and should use ECLS in select trauma patients with severe acute respiratory failure. If ECLS is not readily available, early transfer to an ECLS center should be considered. Future efforts should focus on establishing ECLS programs in large medical centers across the United States to enable robust prospective studies of this promising capability in adult patients. AUTHORSHIP D.M.G., O.T.O, K.I., and J.W.C. designed the study. D.M.G., O.T.O., B.S.S., N.J.M., R.S.M., M.H.H., T.P., R.F.C, and K.I. contributed to the data acquisition. D.M.G., O.T.O., J.K.A., and J.W.C. performed the data analysis. D.M.G., O.T.O., J.K.A., and J.W.C. interpreted the data. D.M.G. and J.W.C. prepared the manuscript, which all authors critically revised.
ACKNOWLEDGMENT We thank Scott Copus, BS, RRT, for the assistance with the data collection; Linda Chan, PhD, for the biostatistical support; Mitchell J. Cohen, MD, for his
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insightful comments on the manuscript; and Kevin K. Chung, MD, for his assistance with AKIN staging.
DISCLOSURE D.M.G. was funded by the Rose Family Educational Research Fund for Extracorporeal Life Support and Critical Care and the Departments of Cardiothoracic Surgery and General Surgery, Wake Forest School of Medicine. J.W.C. was funded by a grant from the Defense Medical Research and Development Program.
REFERENCES 1. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526Y2533. 2. Salim A, Martin M, Constantinou C, Sangthong B, Brown C, Kasotakis G, Demetriades D, Belzberg H. Acute respiratory distress syndrome in the trauma intensive care unit: morbid but not mortal. Arch Surg. 2006;141: 655Y658. 3. Shah CV, Localio AR, Lanken PN, Kahn JM, Bellamy S, Gallop R, Finkel B, Gracias VH, Fuchs BD, Christie JD. The impact of development of acute lung injury on hospital mortality in critically ill trauma patients. Crit Care Med. 2008;36:2309Y2315. 4. Treggiari MM, Hudson LD, Martin DP, Weiss NS, Caldwell E, Rubenfeld G. Effect of acute lung injury and acute respiratory distress syndrome on outcome in critically ill trauma patients. Crit Care Med. 2004;32:327Y331. 5. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342: 1301Y1308. 6. Esan A, Hess DR, Raoof S, George L, Sessler CN. Severe hypoxemic respiratory failure: part 1Vventilatory strategies. Chest. 2010;137:1203Y1216. 7. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107Y1116. 8. Gue´rin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159Y2168. 9. Extracorporeal Life Support Organization (ELSO) patient specific supplements to the ELSO general guidelines [Internet]. 1Y24. Available at: http://elsonet.org/ index.php/resources/guidelines.html. Accessed August 1, 2013. 10. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med. 2011;365:1905Y1914. 11. Diaz JV, Brower R, Calfee CS, Matthay MA. Therapeutic strategies for severe acute lung injury. Crit Care Med. 2010;38:1644Y1650. 12. Raoof S, Goulet K, Esan A, Hess DR, Sessler CN. Severe hypoxemic respiratory failure: part 2Vnonventilatory strategies. Chest. 2010;137:1437Y1448. 13. Hill JD, O’Brien TG, Murray JJ, Dontigny L, Bramson ML, Osborn JJ, Gerbode F. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med. 1972;286:629Y634. 14. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369:2126Y2136. 15. Arlt M, Philipp A, Voelkel S, Rupprecht L, Mueller T, Hilker M, Graf BM, Schmid C. Extracorporeal membrane oxygenation in severe trauma patients with bleeding shock. Resuscitation. 2010;81:804Y809. 16. Michaels AJ, Schriener RJ, Kolla S, Awad SS, Rich PB, Reickert C, Younger J, Hirschl RB, Bartlett RH. Extracorporeal life support in pulmonary failure after trauma. J Trauma. 1999;46:638Y645. 17. Voelckel W, Wenzel V, Rieger M, Antretter H, Padosch S, Schobersberger W. Temporary extracorporeal membrane oxygenation in the treatment of acute traumatic lung injury. Can J Anaesth. 1998;45:1097Y1102. 18. Bonacchi M, Spina R, Torracchi L, Harmelin G, Sani G, Peris A. Extracorporeal life support in patients with severe trauma: an advanced treatment strategy for refractory clinical settings. J Thorac Cardiovasc Surg. 2013;145:1617Y1626. 19. Biderman P, Einav S, Fainblut M, Stein M, Singer P, Medalion B. Extracorporeal life support in patients with multiple injuries and severe respiratory
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failure: a single-center experience? J. Trauma Acute Care Surg. 2013;75: 907Y912. Costantini TW, Fraga G, Fortlage D, Wynn S, Fraga A, Lee J, Doucet J, Bansal V, Coimbra R. Redefining renal dysfunction in trauma: implementation of the Acute Kidney Injury Network staging system. J Trauma. 2009;67:283Y287; discussion 287Y288. Hemmila MR, Rowe SA, Boules TN, Miskulin J, McGillicuddy JW, Schuerer DJ, Haft JW, Swaniker F, Arbabi S, Hirschl RB, et al. Extracorporeal life support for severe acute respiratory distress syndrome in adults. Ann Surg. 2004;240:595Y597. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, Hibbert CL, Truesdale A, Clemens F, Cooper N, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351Y1363. Zapol WM, Snider MT, Hill JD, Fallat RJ, Bartlett RH, Edmunds LH, Morris AH, Peirce EC 2nd, Thomas AN, Proctor HJ, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979;242:2193Y2196. Mattox KL, Beall AC Jr. Resuscitation of the moribund patient using portable cardiopulmonary bypass. Ann Thorac Surg. 1976;22:436Y442. Korvenoja P, Pitkanen O, Berg E, Berg L. Veno-venous extracorporeal membrane oxygenation in surgery for bronchial repair. Ann Thorac Surg. 2008;86:1348Y1349. Brenner M, O’Connor JV, Scalea TM. Use of ECMO for resection of posttraumatic ruptured lung abscess with empyema. Ann Thorac Surg. 2010; 90:2039Y2041. Kirkpatrick AW, Garraway N, Brown DR, Nash D, Ng A, Lawless B, Cunningham J, Chun R, Simons RK. Use of a centrifugal vortex blood pump and heparin-bonded circuit for extracorporeal rewarming of severe hypothermia in acutely injured and coagulopathic patients. J Trauma. 2003;55:407Y412. Ried M, Bein T, Philipp A, Mu¨ller T, Graf B, Schmid C, Zonies D, Diez C, Hofmann HS. Extracorporeal lung support in trauma patients with severe chest injury and acute lung failure: a 10-year institutional experience. Crit Care. 2013;17. Arlt M, Philipp A, Zimmermann M, Voelkel S, Hilker M, Hobbhahn J, Schmid C. First experiences with a new miniaturised life support system for mobile percutaneous cardiopulmonary bypass. Resuscitation. 2008;77:345Y350. Bein T, Zonies D, Philipp A, Zimmermann M, Osborn EC, Allan PF, Nerlich M, Graf BM, Fang R. Transportable extracorporeal lung support for rescue of severe respiratory failure in combat casualties. J Trauma Acute Care Surg. 2012;73:1450Y1456.
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31. Cannon JW, Zonies DH, Benfield RJ, Elster EA, Wanek SM. Advanced en-route critical care during combat operations. Bull Am Coll Surg. 2011;96:21Y29. 32. Javidfar J, Brodie D, Takayama H, Mongero L, Zwischenberger J, Sonett J, Bacchetta M. Safe transport of critically ill adult patients on extracorporeal membrane oxygenation support to a regional extracorporeal membrane oxygenation center. ASAIO J. 2011;57:421Y425. 33. Neff LP, Cannon JW, Stewart IJ, Batchinsky AI, Zonies DH, Pamplin JC, Chung KK. Extracorporeal organ support following trauma: the dawn of a new era in combat casualty critical care. J Trauma Acute Care Surg. 2013;75: S120Y129. 34. Morris AH, Wallace CJ, Menlove RL, Clemmer TP, Orme Jr. JF, Weaver LK, Dean NC, Thomas F, East TD, Pace NL, et al. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;149: 295Y305. 35. Muellenbach RM, Kredel M, Kunze E, Kranke P, Kuestermann J, Brack A, Gorski A, Wunder C, Roewer N, Wurmb T. Prolonged heparin-free extracorporeal membrane oxygenation in multiple injured acute respiratory distress syndrome patients with traumatic brain injury. J Trauma Acute Care Surg. 2012;72:1444Y1447. 36. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364:1293Y1304. 37. Bihorac A, Delano MJ, Schold JD, Lopez MC, Nathens AB, Maier RV, Layon AJ, Baker HV, Moldawer LL. Incidence, clinical predictors, genomics, and outcome of acute kidney injury among trauma patients. Ann Surg. 2010;252:158Y165. 38. Brandt MM, Falvo AJ, Rubinfeld IS, Blyden D, Durrani NK, Horst HM. Renal dysfunction in trauma: even a little costs a lot. J Trauma. 2007;62: 1362Y1364. 39. Kasotakis G, Sideris A, Yang Y, de Moya M, Alam H, King DR, Tompkins R, Velmahos G. Aggressive early crystalloid resuscitation adversely affects outcomes in adult blunt trauma patients: an analysis of the Glue Grant database. J. Trauma Acute Care Surg. 2013;74:1215Y1221; discussion 1221Y1222. 40. McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, Nicholl J, Aronson JK, Barkun JS, Blazeby JM, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374: 1105Y1112.
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Venovenous extracorporeal life support improves survival in adult trauma patients with acute hypoxemic respiratory failure: A multicenter retrospective cohort study Derek M. Guirand, MD, Obi T. Okoye, MD, Benjamin S. Schmidt, MD, Nicky J. Mansfield, BS, James K. Aden, PhD, R. Shayn Martin, MD, Ramon F. Cestero, MD, Michael H. Hines, MD, Thomas Pranikoff, MD, Kenji Inaba, MD, and Jeremy W. Cannon, MD, San Antonio, Texas
Venovenous extracorporeal life support (VV ECLS) has been reported in adult trauma patients with severe respiratory failure; however, ECLS is not available in many trauma centers, few trauma surgeons have experience initiating ECLS and managing ECLS patients, and there is currently little evidence supporting its use in severely injured patients. This study seeks to determine if VV ECLS improves survival in such patients. METHODS: Data from two American College of SurgeonsYverified Level 1 trauma centers, which maintain detailed records of patients with acute hypoxemic respiratory failure (AHRF), were evaluated retrospectively. The study population included trauma patients between 16 years and 55 years of age treated for AHRF between January 2001 and December 2009. These patients were divided into two cohorts as follows: patients who received VV ECLS after an incomplete or no response to other rescue therapies (ECLS) versus patients who were managed with mechanical ventilation (CONV). The primary outcome was survival to discharge, and secondary outcomes were intensive care unit and hospital length of stay (LOS), total ventilator days, and rate of complications requiring intervention. RESULTS: Twenty-six ECLS patients and 76 CONV patients were compared. Adjusted survival was greater in the ECLS group (adjusted odds ratio, 0.193; 95% confidence interval, 0.042Y0.884; p = 0.034). Ventilator days, intensive care unit LOS, and hospital LOS did not differ between the groups. ECLS patients received more blood transfusions and had more bleeding complications, while the CONV patients had more pulmonary complications. A cohort of 17 ECLS and 17 CONV patients matched for age and lung injury severity also demonstrated a significantly greater survival in the ECLS group (adjusted odds ratio, 0.038; 95% confidence interval, 0.004Y0.407; p = 0.007). CONCLUSION: VV ECLS is independently associated with survival in adult trauma patients with AHRF. ECLS should be considered in trauma patients with AHRF when conventional therapies prove ineffective; if ECLS is not readily available, transfer to an ECLS center should be pursued. (J Trauma Acute Care Surg. 2014;76: 1275Y1281. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Therapeutic study, level III. KEY WORDS: Adult respiratory distress syndrome (ARDS); extracorporeal life support (ECLS); lung injury; respiratory failure; trauma. BACKGROUND:
A
dult trauma patients with severe injuries are at risk for developing adult respiratory distress syndrome (ARDS),1 which carries an increased risk of morbidity and mortality.2Y4 Lungprotective ventilation using low-tidal volumes, limited plateau pressure, and moderate levels of positive end-expiratory pressure
Submitted: August 18, 2013, Revised: January 17, 2014, Accepted: February 10, 2014. From the Wake Forest School of Medicine (D.M.G., B.S.S., R.S.M., T.P.), Winston-Salem, North Carolina; Los Angeles County + University of Southern California Medical Center (O.T.O., N.J.M., K.I.), Los Angeles, California; US Army Institute of Surgical Research (J.K.A.); University of Texas Health Science Center at San Antonio, (R.C.F.); and San Antonio Military Medical Center (J.W.C.), San Antonio; University of Texas Health Science Center at Houston (M.H.H.), Houston, Texas; Norman M. Rich Department of Surgery (J.W.C.), Uniformed Services University of the Health Sciences, Bethesda, Maryland. D.M.G. and O.T.O. contributed equally to this study. This study was presented in part at the American College of Chest Physicians, CHEST 2011, October 22Y26, 2011, in Honolulu, Hawaii. The opinions expressed in this article are solely those of the authors and do not represent an endorsement by or the views of the US Air Force, the US Army, the US Navy, the Department of Defense, or the US Government. Address for reprints: Jeremy W. Cannon, MD, Department of Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Dr, JBSA Fort Sam Houston, TX 78234; email: [email protected]. DOI: 10.1097/TA.0000000000000213
(PEEP) has a proven survival benefit in ARDS patients.5 Rescue oxygenation strategies are also commonly used in these patients including recruitment maneuvers, high PEEP, airway pressure release ventilation, high-frequency oscillatory ventilation, neuromuscular blockade, prone positioning, and inhaled vasoactive agents including nitric oxide (iNO) and prostacyclins. These strategies improve ventilator synchrony, correct ventilation-perfusion mismatch, reduce oxygen consumption, increase alveolar recruitment, and decrease the shunt fraction resulting in improved oxygenation.6 Recent evidence also suggests that a brief period of neuromuscular blockade7 and prone positioning8 improve survival in moderate-to-severe ARDS patients. Some patients with ARDS remain hypoxemic despite the use of these measures in which case extracorporeal life support (ECLS) should be considered according to the Extracorporeal Life Support Organization patient management guidelines9 and current expert opinion.10 Y12 ECLS has advanced significantly since the first successful use in an adult patient with severe respiratory failure after blunt trauma was reported in 1972.13 Venovenous (VV) ECLS supports oxygen delivery by shunting deoxygenated blood from the systemic venous circulation through a gas exchange membrane. Oxygenated blood from the membrane is then
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returned to the venous system for circulation to peripheral tissue beds. Following initiation of ECLS, ventilator settings can be reduced, thereby mitigating the various mediators of ventilatorinduced lung injury including high transpulmonary pressures (barotrauma), alveolar overdistention (volutrauma), repetitive opening and closing of alveolar units (atelectrauma), and the amplified systemic inflammatory response mediated by these mechanical insults (biotrauma).14 Although several centers have reported the use of ECLS in trauma patients,15Y19 ECLS has not been widely incorporated into trauma critical care management for numerous reasons including lack of access to ECLS, limited familiarity with ECLS within the trauma community, and no proven survival benefit in the trauma population. In this study, we compare the use of ECLS with conventional mechanical ventilation for the management of acute hypoxemic respiratory failure (AHRF) in acutely traumatized adult patients to determine if such a benefit exists.
PATIENTS AND METHODS Study Design A review of the ECLS registry at the Wake Forest School of Medicine and the Trauma and Surgical Intensive Care Unit database at the Los Angeles County + University of Southern California (LAC + USC) Medical Center from January 2001 through December 2009 was performed after institutional review board approval with waiver of consent was obtained at both centers. Trauma patients between 16 years and 55 years with severe life-threatening AHRF were identified. AHRF was defined as a PaO2/FiO2 of 80 or less with an FIO2 greater than 0.9 with no evidence of cardiogenic pulmonary edema and with a Murray Lung Injury Score (LIS) score of 3.0 or greater. This degree of respiratory failure has historically resulted in death in up to 80% of patients and is used as a threshold for initiating ECLS by the Extracorporeal Life Support Organization.9 All of these patients had ‘‘severe’’ ARDS using the new Berlin definition.1 Excluded from the analysis were nontrauma patients, those with ECLS primarily for cardiogenic shock, patients with acute intracranial hemorrhage, and patients who expired within 24 hours of admission. Patients were divided into those managed with VV ECLS and those managed with mechanical ventilation (CONV). Patient demographics included age, sex, mechanism of injury, chest Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), base excess, fluid balance, days to ECLS, PaO2/FIO2, and LIS at the time of AHRF diagnosis. The primary outcome measure of the study was survival to hospital discharge. Secondary outcome measures included intensive care unit (ICU) length of stay (LOS), hospital LOS, and number of mechanical ventilation days. Hemorrhagic, pulmonary, and renal complications were recorded. Hemorrhagic complications included gastrointestinal bleeding, ECLS cannulation site bleeding, other surgical site bleeding, hemolysis, and disseminated intravascular coagulation (DIC). The number of transfused packed red blood cell (PRBC) units during the hospital stay was also recorded. Pulmonary complications included pneumothorax, pulmonary hemorrhage, and new-onset pneumonia. Pneumonia was defined as new or persistent radiographic infiltrate or consolidation without another obvious cause after meeting ECLS initiation 1276
criteria along with any two of the following clinical features: a temperature exceeding 38-C (CONV group only), leukocytosis/ leukopenia (leukocyte count 9 11.0 103/mL or G3.5 103/mL), purulent endotracheal secretions, or potentially pathogenic bacteria isolated from the endotracheal aspirate. Renal complications were defined as the development of Acute Kidney Injury Network (AKIN) acute kidney injury by serum creatinine criteria or the need for supplemental renal replacement therapy (RRT).20 In the CONV group, RRT was performed as hemofiltration or hemodialysis at the bedside using either Fresenius (Waltham, MA) or Baxter (Deerfield, IL) hemodialysis system, while the ECLS group was managed with either Prismaflex System (Gambro Americas, Lakewood, CO) or NxStage (Lawrence, MA) hemodialysis device in line with the ECLS circuit. At both centers, RRTwas initiated at the discretion of the physician team in consultation with nephrology to manage volume overload, electrolyte derangements, or azotemia.
Ventilator Management and ECLS Patients in the CONV group were managed with a range of ventilator modes including volume control modes, pressure control modes, and high-frequency ventilation (HFV). ARDSNet protocol goals were used as a general guideline for O2, CO2, and airway pressure management before implementing HFV.5 On HFV, adjustments were made based on the experience of the LAC + USC intensivists. All patients treated with ECLS for AHRF were cannulated percutaneously with either a femoral venous drainage cannula paired with an internal jugular return cannula or with a dual lumen Elite Bi-caval Cannula (Maquet Cardiovascular, Wayne, NJ). The principal components of the ECLS circuit included a Sorin SIII roller pump (SORIN GROUP USA, Inc, Arvada, CO), a Medtronic gas exchange membrane (sizes 0800-4500; Medtronic, Minneapolis, MN) or the Quadrox D polymethylpentene membrane (Maquet Cardiovascular), and a Cincinnati Sub Zero heater/ cooler (Cincinnati Sub-Zero Products, Inc., Cincinnati, OH). Following ECLS initiation, the goal was to maintain blood and gas flow through the circuit to keep SaO2 at 85% or greater with adequate end-organ oxygen delivery. Circuit blood gasses were continuously analyzed using the CDI 500 blood gas monitor (Terumo Cardiovascular Systems, Ann Arbor, MI). Full anticoagulation was achieved by titrating a continuous infusion of unfractionated heparin to maintain an activated clotting time of 180 seconds to 220 seconds. During ECLS support, ventilator settings were reduced to rest settings of pressure control ventilation FIO2 of 0.4, rate of 8 to 12, peak inspiratory pressure of 24 cm H2O, and PEEP of 12 cm H2O using the lung rest protocol at the ECLS center in this study. As lung function improved, a trial off ECLS was performed by discontinuing the circuit gas flow with the ventilator set initially at peak inspiratory pressure of 28 cm H2O, PEEP of 8 cm H2O, and FIO2 of 1. The FIO2 was then decreased hourly to a target an FIO2 of 0.4. If adequate gas exchange was maintained for 12 hours at these settings, the patient was decannulated.
Statistical Analysis Univariate analysis was performed to compare the two cohorts. The two-sample t test was used to compare the means for continuous variables, and the two-sided Fisher’s exact test was * 2014 Lippincott Williams & Wilkins
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used to compare proportion. Significant risk factors from the univariate analysis were entered into a multivariate logistic regression to determine the odds ratio for survival. We also used propensity scoring to develop two cohorts of patients matched for age and PaO2/FIO2. Univariate and multivariate analyses were then performed on the matched cohorts to determine if additional covariates were needed to establish matched cohorts. Sixty-day Kaplan-Meier survival curves were developed for these matched cohorts. A p G 0.05 was considered significant. All statistical analyses were performed using SPSS, version 17 (IBM, Chicago, IL) and SAS version 9.2 (Cary, NC).
RESULTS From January 2001 through December 2009, the Wake Forest School of Medicine treated 453 patients with ECLS. Of these, 26 patients met inclusion criteria (ECLS group). During the same period, LAC + USC Medical Center treated a total of 561 surgical patients with ARDS. Of these, 76 met study inclusion criteria as trauma patients with AHRF and no contraindications for ECLS (CONV group) (Fig. 1). All patients in the ECLS arm were from Wake Forest, and all patients in the CONV arm were from LAC + USC because ECLS was not provided at this institution during the study period. The patients in both groups were predominantly young males with a similar mean age (Table 1). Blunt trauma was the primary injury mechanism with a very high injury severity and a significant thoracic component in both groups. At the time of AHRF diagnosis, patients in the ECLS cohort had a higher positive fluid balance (9.9 [9.6] L vs. 3.0 [3.2] L, p G 0.001), had a significantly lower PaO2/ FIO2 (49.6 [10.7] vs. 59.0 [12.3], p = 0.001), and had a higher LIS (3.8 [0.3] vs. 3.5 [0.3], p G 0.001) (Table 1). In the CONV group, 8 patients (11%) were treated with volume control ventilation, 10 patients (13%) were treated with pressure control ventilation, and 58 patients (76%) were treated with HFV. Of the 26 patients in the ECLS group, 15 survived to discharge, whereas in the CONV group, 42 survived for a crude survival of 58% versus 55%, respectively. After adjusting for
Figure 1. Study population demonstrating the application of exclusion criteria resulting in the final study cohorts and the matched cohorts.
differences in fluid balance, PaO2/ FIO2 and LIS, open abdomen, RRT, hemorrhagic complications, and pulmonary complications, ECLS was independently associated with improved survival (Table 2) as was increased chest AIS score. Independent predictors of mortality included ISS, increased pre-ECLS fluid balance, and LIS. Propensity score matching for age and PaO2/ FIO2 resulted in subgroups of 17 ECLS and 17 CONV patients. Univariate analysis on the covariates in Table 1 demonstrated only a difference in days to ECLS criteria met between the matched cohorts. This difference did not persist on multivariate logistic regression, so no further matching was performed. Survival to discharge was significantly greater in the ECLS group by log rank (Fig. 2) and by multivariate logistic regression (Table 2). ISS independently predicted mortality in these patients. Secondary outcomes including ICU LOS, hospital LOS, and days of mechanical ventilation did not significantly differ between the groups in the full study (Table 3). However, patients receiving ECLS were transfused more PRBCs (8.4 [3.4] U vs. 0.6 [0.3] U, p G 0.001). There was a significantly increased hospital LOS in the matched ECLS group. This difference did not persist among survivors in the matched ECLS versus CONV cohorts. The overall rate of complications did not differ between the ECLS and CONV groups; however, hemorrhagic complications occurred more frequently in the ECLS cohort (15% vs. 1%, p = 0.014), while there were more pulmonary complications in the CONV cohort (0% vs. 28%, p = 0.001), and no difference in renal complications between the groups (Table 4). There were no differences in complications between the matched cohorts. On multivariate logistic regression, none of these complications increased mortality (Table 2).
DISCUSSION AHRF in adult trauma patients remains a significant cause of morbidity and mortality. In this study, we demonstrate that the use of VV ECLS is independently associated with survival in adult trauma patients with AHRF when compared with conventional ventilatory management. Although the ECLS cohort was transfused with more blood and had more bleeding complications, the reported hemorrhagic complications in the ECLS cohort had no effect on in-hospital survival. Although this retrospective study was not designed to determine a mechanism for increased survival in patients treated with VV ECLS, others have attributed this observation to improved gas exchange without ongoing lung injury in a mixed population of ECLS patients.21 Furthermore, although VV ECLS does not provide direct cardiac support, improved myocardial oxygenation often permits weaning of inotropes and vasopressors in these critically ill patients. Outcomes in adult patients with AHRF treated with ECLS have improved significantly since the first randomized study of adult patients was reported in 1979.22,23 In addition to AHRF, ECLS has been used in trauma patients as a resuscitation adjunct,18,24 to facilitate repair of major airway injuries,25 to enable the drainage of a large lung abscess,26 and for active rewarming.27 To date, the largest series of ECLS used for respiratory failure in trauma patients is by Michaels et al.16 at the University of Michigan. In this single-center, retrospective study of 30 patients treated with
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TABLE 1. Characteristics of the Study Cohorts Full Study Cohorts
Demographics Age, y Male sex Trauma description Blunt trauma Chest AIS score ISS Base excess G j6 Pre-ECLS criteria fluid balance, L Days from injury to ECLS criteria met Lung injury severity PaO2/FIO2 LIS Hospital course Open abdomen** Tracheostomy RRT Diuretics
Matched Cohorts
ECLS (n = 26)
CONV (n = 76)
p
ECLS (n = 17)
CONV (n = 17)
p
33.0 (11.5) 20 (77)
33.2 (10.9) 61 (80)
0.944 0.781
30.9 (11.4) 12 (71)
34.1 (10.7) 15 (88)
0.413* 0.398
21 (81) 2.7 (1.6) 29.0 (12.4) 19 (76) 9.9 (9.6) 4.6 (5.8)
56 (74) 2.1 (1.9) 28.6 (13.4) 41 (54) 3.0 (3.2) 6.4 (8.5)
0.601 0.116 0.922 0.062 G0.001 0.337
15 (88) 2.9 (1.5) 30.6 (14.4) 10 (59) 8.9 (9.9) 2.9 (2.7)
11 (65) 1.8 (2.0) 29.4 (13.1) 9 (53) 4.4 (3.6) 8.4 (9.6)
0.225 0.079 0.796 1.0 0.084 0.037
49.6 (10.7) 3.8 (0.3)
59.0 (12.3) 3.5 (0.3)
0.001 G0.001
52.2 (10.8) 3.9 (0.2)
51.1 (9.3) 3.8 (0.2)
0.761* 0.134
13 (19) 30 (39) 8 (11) 40 (53)
0.001 1 0.003 0.498
8 (47) 7 (41) 6 (35) 12 (71)
14 10 10 16
(54) (38) (38) (62)
4 (24) 3 (18) 4 (24) 9 (53)
0.282 0.259 0.708 0.481
*Indicates the covariates used in the propensity score to develop the matched cohorts. **Data available on 68 patients in the CONV cohort. Data are shown as mean (SD) or n (%).
ECLS from 1989 to 1997, survival to discharge was 50%. The patient population was similar in age, sex, and injury mechanism to what we report; however, injury severity was lower (mean ISS, 19.75), and the PaO2/FIO2 was higher (mean, 56.9) compared with our ECLS cohort. Bleeding complications were frequent, with 18 patients (59%) requiring additional transfusion or operative intervention for hemorrhage relative to 4 patients (15%) in our study. Because anticoagulation protocols between our studies were similar; this difference may be explained by recent advances
in ECLS technology, particularly the new polymethylpentene membrane, which was used in many of the patients in our ECLS cohort. Michaels et al. concluded that ECLS was safe in this group of severely injured patients with severe respiratory failure. A contemporary series of 26 trauma patients treated with VV ECLS was recently reported by the group from Regensburg, Germany, together with 26 trauma patients managed with pumpless extracorporeal lung assist for a total of 52 patients over 10 years.28 This series included both civilian trauma patients and
TABLE 2. Mortality Analysis Full cohorts ECLS Chest AIS ISS Pre-ECLS fluid balance LIS Matched cohorts ECLS ISS
AOR (95% CI)
p
0.193 (0.042Y0.884) 0.693 (0.496Y0.967) 1.112 (1.056Y1.171) 1.156 (1.022Y1.309) 10.939 (1.805Y66.305)
0.034 0.031 G0.001 0.022 0.009
0.038 (0.004Y0.407) 1.123 (1.029Y1.226)
0.007 0.009
Multivariate logistic regression with backwards elimination was used to determine factors independently associated with survival and mortality. A value less than 1 indicates an independent survival advantage, whereas a value more than 1 indicates an independent predictor of mortality. Variables included in the original model included ECLS, age, and any demographic, therapeutic, or complication variable with a p e 0.02 on univariate analysis comparing treatments (ECLS vs. CONV) or survival: ECLS, age, chest AIS score, ISS, base excess G j6, Pre-ECLS fluid balance, days from injury to ECLS criteria met, PaO2/FIO2, LIS, open abdomen, any RRT, any hemorrhagic complication, and any pulmonary complication. AOR, adjusted odds ratio; CI, confidence interval.
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Figure 2. Kaplan-Meier survival curve for the cohorts of ECLS versus CONV patients matched for age and PaO2/FIO2 carried out to 60 days. Patients were censored at death or hospital discharge. Survival in the ECLS versus CONV matched cohorts was 64.7% versus 23.5% (p = 0.01). * 2014 Lippincott Williams & Wilkins
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TABLE 3. Secondary Outcome Measures in the Study Cohorts Full Study Cohorts
ICU LOS, d Hospital LOS, d Positive pressure ventilation, d PRBC, h ECLS hours
Matched Cohorts
ECLS (n = 26)
CONV (n = 76)
p
ECLS (n = 17)
CONV (n = 17)
p
36.7 (7.1) 39.8 (7.3) 24.9 (4.4) 8.4 (3.4) 224 (227)
25.4 (3.6) 35.4 (4.9) 20.7 (3.2) 0.6 (8.2) V
0.108 0.713 0.485 1.6 (4.1) V
38.5 (36.9) 45.9 (41.6) 28.5 (23.1) 0.070 256 (214)
18.2 (22.9) 21.1 (23.6) 15.4 (22.7)
0.064 0.040 0.105
V
V
Data are shown as mean (SD) or n (%).
combat casualties with a very high mean ISS of 58.9. The VV ECLS group had an excellent survival rate of 80.8% despite a mean PaO2/FIO2 of 54, a pH of 7.21, and a lactate of 38 mg/dL (4.2 mmol/L). Although multiple surgical procedures were performed during ECLS support, bleeding complications were minimal, with only one patient death attributable to hemorrhage and a median of three PRBC units transfused per patient. Remarkably, 18 of 26 VV ECLS patients were started on support in another facility and then transported to University Medical Center Regensburg. This practice model is gaining wider acceptance with miniaturized ECLS transport systems being used by both civilian and military teams to safely transport critically ill patients with AHRF to ECLS centers.29Y33 In our ECLS cohort, all bleeding complications were able to be managed with local interventions or component replacement and did not contribute to overall mortality. Our data do show that the ECLS group received more blood;
however, the number of transfused PRBC units was relatively low given the severity of injuries in this group and was also far less than has been reported in historic adult ECLS studies.23,34 It should also be noted that in many instances, transfusions were given to compensate for the drop in hemoglobin concentration that occurs after an initiation of ECLS using a crystalloid or albumin prime in a relatively long circuit (386 inches) and to maintain a hemoglobin greater than 10 g/dL and platelets greater than 75,000/KL. As ECLS technology and management techniques evolve, however, circuits are becoming significantly shorter with smaller priming volumes, and the practice of transfusing to an arbitrary target level is being questioned in favor of using a blood conservation strategy.10 Finally, for those patients with overt contraindications to anticoagulation (e.g., brain injury with intracranial hemorrhage), a recent small series indicates that heparinfree ECLS management may be performed for up to 5 days without circuit thrombosis.35
TABLE 4. Comparison of Complications in the Study Cohorts Full Study Cohorts
Any complication Hemorrhagic Gastrointestinal Cannulation site Surgical site Hemolysis* DIC** Pulmonary Pneumothorax Pulmonary hemorrhage Pneumonia Renal AKIN 1 AKIN 2 AKIN 3
Matched Cohorts
ECLS (n = 26)
CONV (n = 76)
p
ECLS (n = 17)
CONV (n = 17)
p
23 (88) 4 (15) 1 (4) 0 3 (12) 0 1 (4) 0 0 0 0 23 (88) 6 (23) 4 (15) 13 (50)
73 (96) 1 (1) 0 V 0 0 1 (1) 21 (28) 0 0 21 (28) 71 (93) 24 (32) 21 (28) 26 (34)
0.334 0.014
16 (94) 3 (18) 1 (6) 0 2 (12) 0 1 (6) 0 0 0 0 16 (94) 4 (24) 3 (18) 9 (53)
16 (94) 0 0 V 0 0 0 3 (18) 0 0 3 (18) 16 (94) 4 (24) 4 (24) 8 (47)
1 0.227
0.004
0.676
0.227
1
*Indicated by a plasma-free hemoglobin greater than 50 mg/dL. **Defined as the presence of two or more systemic inflammatory response syndrome criteria, a reduction in platelet count (G80,000/KL, a Q50% decrease in 24 hours, or a value from 80,000/KL to 120,000/KL with 930% decrease in 24 hours), a prolonged prothrombin time of greater than or equal to 1.2 times the patient’s baseline, and a decrease in fibrinogen levels to less than 350 mg/dL with an associated increase in detection of fibrin degradation products of 10 mg/dL or greater. In the absence of laboratory criteria, diffuse clinical bleeding was also accepted as evidence of DIC. Data are shown as n (%). Any complication represents the total number of patients with a reported complication. Organ system specific complications are the number of patients with a complication in that category.
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In this study, the CONV group had a much higher rate of pneumonia diagnosed after ECLS criteria were met. In the ECLS group, no new pulmonary complications were reported after the initiation of VV ECLS. ECLS theoretically permits early transition to minimal or no ventilator support, while advances in ECLS cannula technology permit early mobilization of these patients even while on ECLS. Thus, ECLS may help avoid not only pulmonary complications but also the neuromuscular deconditioning, which is now widely recognized as the principal cause of long-term disability in patients with severe respiratory failure,36 although these theoretical benefits need to be evaluated in a large, prospective study. There is growing evidence that any AKIN stage is an important marker for poor outcomes in trauma patients.37,38 In the present study, both groups had a high incidence of acute kidney injury, and although RRTwas used more often in the ECLS group, this was not independently associated with increased survival or mortality on multivariate logistic regression. It is important to note, however, that the ECLS group had a higher positive fluid balance before ECLS initiation compared with the CONV group, which was independently associated with increased mortality. This finding further emphasizes the importance of judicious intravenous fluid administration in severely injured trauma patients.39 Limitations of this study include its retrospective design and the comparison of patients managed by geographically remote medical teams. The relatively small numbers in the two cohorts also make any conclusions about the use of hospital resources and complications preliminary until larger studies can be completed. We also had no data on the use of iNO, chemical paralysis, and proning in either group. Finally, there were no long-term outcome data available on the patients in the CONV arm of this study. Despite these limitations, this study does follow the recommended approach for evaluating advanced therapies in the early phases of technology dissemination before wide acceptance.40 In summary, VV ECLS is independently associated with improved survival in adult trauma patients with AHRF. Furthermore, there seems to be no significant increase in ICU or hospital LOS. Finally, the increased rate of hemorrhagic complications in the ECLS cohort had no significant effect on survival and was clinically manageable. Consequently, trauma surgeons should gain familiarity with ECLS initiation and management and should use ECLS in select trauma patients with severe acute respiratory failure. If ECLS is not readily available, early transfer to an ECLS center should be considered. Future efforts should focus on establishing ECLS programs in large medical centers across the United States to enable robust prospective studies of this promising capability in adult patients. AUTHORSHIP D.M.G., O.T.O, K.I., and J.W.C. designed the study. D.M.G., O.T.O., B.S.S., N.J.M., R.S.M., M.H.H., T.P., R.F.C, and K.I. contributed to the data acquisition. D.M.G., O.T.O., J.K.A., and J.W.C. performed the data analysis. D.M.G., O.T.O., J.K.A., and J.W.C. interpreted the data. D.M.G. and J.W.C. prepared the manuscript, which all authors critically revised.
ACKNOWLEDGMENT We thank Scott Copus, BS, RRT, for the assistance with the data collection; Linda Chan, PhD, for the biostatistical support; Mitchell J. Cohen, MD, for his
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insightful comments on the manuscript; and Kevin K. Chung, MD, for his assistance with AKIN staging.
DISCLOSURE D.M.G. was funded by the Rose Family Educational Research Fund for Extracorporeal Life Support and Critical Care and the Departments of Cardiothoracic Surgery and General Surgery, Wake Forest School of Medicine. J.W.C. was funded by a grant from the Defense Medical Research and Development Program.
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