- Email: [email protected]
Outcomes of adult patients with septic shock receiving extracorporeal membrane oxygenation therapy
Journal Pre-proof Outcomes of adult patients with septic shock receiving extracorporeal membrane oxygenation therapy Laura C. Myers, MD MPH, Charlotte Lee, MD, B. Taylor Thompson, MD, Gaston Cudemus, MD, Yuval Raz, MD MSc, Nathalie Roy, MD PII:
S0003-4975(20)30203-4
DOI:
https://doi.org/10.1016/j.athoracsur.2019.12.075
Reference:
ATS 33477
To appear in:
The Annals of Thoracic Surgery
Received Date: 8 August 2019 Revised Date:
27 November 2019
Accepted Date: 27 December 2019
Please cite this article as: Myers LC, Lee C, Thompson BT, Cudemus G, Raz Y, Roy N, Outcomes of adult patients with septic shock receiving extracorporeal membrane oxygenation therapy, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.12.075. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by The Society of Thoracic Surgeons
Outcomes of adult patients with septic shock receiving extracorporeal membrane oxygenation therapy Running head: ECMO in septic shock
Laura C. Myers MD MPH,1,2 Charlotte Lee MD,1,3 B. Taylor Thompson MD,1,2 Gaston Cudemus MD,1,4 Yuval Raz MD MSc,1,2 Nathalie Roy MD1,5
This work was entirely performed at The Massachusetts General Hospital, and (1) Harvard Medical School, Boston, MA. (2) Division of Pulmonary/Critical Care, Department of Medicine (3) Department of Medicine (4) Department of Anesthesia (5) Department of Cardiac Surgery, now at Boston Children’s Hospital, Boston MA
Classifications: Adult, extracorporeal membrane oxygenation, septic shock, critical care Corresponding Author: Nathalie Roy MD, Instructor in Surgery, Harvard Medical School. Assistant in Cardiac Surgery, Boston Children’s Hospital, 300 Longwood Avenue, Bader-292, Boston, MA 02115. Email: [email protected] Word Count: 4612
Abstract Background: Extracorporeal membrane oxygenation (ECMO) has been shown to provide benefits in children with septic shock, but not adults. We describe the clinical outcomes of adults who received ECMO in septic shock. Methods: We retrospectively studied adults supported on veno-arterial or veno-venous modes of ECMO with septic shock at the time of cannulation from 1/1/2009-12/31/2016 at a quaternary medical center in the United States. The primary outcome was rate of survival to hospital discharge and time to survival using Kaplan-Meier survival estimates. We analyzed survival by mode, previous cardiac arrest and timing of cannulation (<96 and ≥96 hours after admission to the intensive care unit). Secondary outcomes were complications and days of ECMO support, length of stay in the intensive care unit, and hospitalization days. Results: Of 243 patients supported on ECMO during this 7-year period, 32 met the criteria for septic shock and the majority had a pulmonary source of infection (72%). The most common mode of support was VV ECMO (65%) and median ejection fraction was 51%. Median time on ECMO was 5.8 days (IQR 2.6, 11.3). Survival to hospital discharge was 13 of 32 (41%) while median survival was 14.5 days (5.2, 23.7). There was no statistically significant difference in survival by subgroup, including ECMO mode. Healthcare associated infections were frequent (25%). Conclusions: Our cohort of patients receiving ECMO had equivalent median survival compared to literature-based estimates of other cohorts of patients with septic shock.
2
Survival from septic shock in adults is approximately 40%.1 Historically, patients with septic shock have not received extracorporeal membrane oxygenation (ECMO) because it does not improve low systemic vascular resistance, a major aspect of the physiologic state of sepsis. In addition, oxygen delivery remains compromised by the presence of microvascular alterations. Furthermore, endothelial dysfunction leads to fluid extravasation and may compromise the ability to deliver adequate flow on ECMO.2,3 In neonates and children, the American College of Critical Care Medicine recommends the use of ECMO in refractory septic shock (Level II).4 The literature reports better survival in children with septic shock undergoing central cannulation for veno-arterial (VA) ECMO support.5,6 However, the evidence in adults is sparse, and the 2016 Surviving Sepsis Guidelines do not recommend ECMO in septic adults.7 Small retrospective studies have reported the use of ECMO in adults with septic shock8-14 but the most recent publication from an institution in the United States dates 21 years back.15 We sought to evaluate survival outcomes in patients with septic shock unresponsive to maximal medical therapy who received ECMO in the context of respiratory failure or cardiovascular failure and examine if differences existed between patients receiving veno-venous (VV) vs. veno-arterial (VA) ECMO.
Patients and Methods A. Study Design We performed a retrospective, single center case series. The study was approved by the Institutional Review Board (2011P002375) at the Massachusetts General Hospital.
B. Patient Selection and Data Collection
3
A hospital database was queried to identify adults aged ≥18 years who received VV or VA ECMO at the Massachusetts General Hospital between 1/1/2009-12/31/2016. We included all patients with septic shock at the time of ECMO cannulation using the 2016 consensus definition from the Society of Critical Care Medicine and European Society of Intensive Care Medicine: “Patients with life-threatening organ dysfunction caused by a dysregulated host response to infection and persistent hypotension requiring vasopressors to maintain mean arterial pressure to 65mm Hg and a serum lactate >2mmol/L despite adequate volume resuscitation”.1 The source of septic shock was identified and microbiology data was collected. Patients were classified by ECMO mode according to initial cannulation strategy. Additional details are in the supplement.
C. Risk Scores Details regarding the Sequential Organ Failure Assessment (SOFA) score,16 the vasopressor score,17 the Respiratory ECMO Survival Prediction (RESP) score,18 and the Survival After Venoarterial ECMO (SAVE) score,19 are provided in the supplement.
D. Institutional Practice for Treatment of Septic Shock and ECMO Septic shock was treated according to the Surviving Sepsis guidelines.5 Our institutional protocol for delivering ECMO was developed in alignment with the Extracorporeal Life Support Organization (ELSO) guidelines.20 Both are described in the supplement.
E. Outcomes and Survival Analysis
4
The primary outcome was survival to hospital discharge, reported as a percentage. Survival analysis was performed to estimate median survival with confidence limits. Kaplan-Meier plots are presented with time starting at cannulation and censoring at hospital discharge. Intermediate outcomes include survival at decannulation and transfer from the intensive care unit (ICU). The following subgroups were examined: mode (VV versus VA),9 cardiac arrest at/or before cannulation,10 and early vs late cannulation (defined as <96 and ≥96 hours after admission to ICU). Log-Rank tests were calculated to determine differences in survival by subgroup.11 Days of ECMO and complications as defined by ELSO21 are reported. For infection as a complication, we reported acquired culture-positive infection while on ECMO support.
F. Statistical Analysis Binary/categorical variables were presented as numbers and percentages, and comparisons were made via the Fisher Exact Test. Normally distributed continuous variables were reported as means with 95% confidence intervals and compared using T tests, or paired T tests for paired data. Variables with non-normal distributions were reported as medians with interquartile range (IQR) and compared using Wilcoxon rank-sum tests or Wilcoxon signed-rank tests for paired data. All statistics were two-tailed. The threshold for significance was <0.05. SAS software version 9.4 (SAS Institute, Cary, NC) was used.
Results There were 243 patients receiving ECMO at our center over a 7-year period, and 32 met criteria for septic shock at the time of ECMO initiation. Baseline characteristics of patients by survivor status at the time of hospital discharge are presented in Table 1. There were no statistically
5
significant differences in characteristics between survivors (n=13) and non-survivors (n=19), except for a trend test that showed increasing survival between 2010-2016. The majority received VV ECMO (65%) rather than VA (35%). Other than inotropes and vasopressors, the most common method of pre-ECMO management was neuromuscular blockade (78%). Thirty eight percent had a previous cardiac arrest. The median time between admission and cannulation was 23 hours (IQR 6, 65). The median left ventricular ejection fraction was 51% (IQR 30, 67). Patient characteristics by ECMO mode are outlined in Table 2. Only 44% of patients had a source identified by culture or molecular testing. The most common presumed source of septic shock was the lung (72%), of which 26% had influenza and 30% had aspiration. Patients supported on VV ECMO showed differences from those supported on VA ECMO: lower SOFA score (8.9 versus 11.4, p=0.01), vasopressor score (59 versus 171, p=0.04) and PaO2 (57 versus 102, p=0.002). The median RESP score was 3 (IQR 1, 5) for those receiving VV ECMO, which predicts a 70% survival rate but our observed survival was 38%. The median SAVE score was -11 (IQR -13, -6) for those receiving VA ECMO, which predicts a 20% survival rate and the observed survival was 45%. Supplemental Table 1 shows the 2x2 table of expected and observed survival to discharge rates by mode (p=0.06). Characteristics at the time of cannulation and at 48 hours are presented in supplemental Table 2. All patients were either on ECMO (N=27) or dead (N=5); no one was successfully decannulated in the first 48 hours. There was statistically significant improvement in mean arterial pressure, median vasopressor score, ventilatory settings and arterial blood gas at 48 hours. Pump flow was higher at 48 hours (mean 4.4 to 4.6 L/min, p=0.02). Characteristics over time by ECMO mode are further defined in supplemental Tables 3 and 4. Characteristics at 48 hours of ECMO support by survivor status are shown in Table 3. Patients who ultimately survived septic shock with ECMO support experienced early hemodynamic
6
improvement compared to non-survivors. At 48 hours, they had higher mean arterial pressure (79 versus 69, p=0.03) and pH (7.39 vs 7.33, p=0.02), lower lactate (2.4 versus 7.5, p=0.007) and lower rate of vasopressin use (15% versus 42%, p=0.003). They were less likely to be anuric compared to patients who died (23% versus 37%, p=0.02). Clinical outcomes and complications are shown in Table 4. There were no differences by ECMO mode. The median time of ECMO support was 5.8 days (IQR 2.8, 10.2). Among survivors, median ICU length of stay was 17.7 days (IQR 5.9, 42.2) and median hospital length of stay was 40.1 days (IQR 13.1, 44.2). The most common complication was cardiac arrhythmia, which occurred in 41%. Healthcare acquired infections occurred in 25% of patients; the most common organisms were Candida species and Staphylococcus aureus. The most common sites of infection were lung and bloodstream. Bleeding occurred in 38%, and circuit-related complications occurred in 22% of patients. Thirty one percent required dialysis. Complications by survivor status are shown in supplemental Table 5. By univariate analysis, no specific complications were associated with survival status, although all patients with disseminated intravascular coagulation died, and arrhythmias and dialysis tended to be more common in patients who died. Survival to decannulation, ICU transfer and hospital discharge were 44%, 41% and 41%, respectively (Table 4). Figure 1 shows a median survival of 14.5 days (5.2, 23.7). Supplemental Figures 1, 2 and 3 are the Kaplan-Meier plots of patients by mode, previous cardiac arrest and timing of cannulation, respectively, which showed no difference by subgroup. The majority of patients (>50%) were discharged to a rehabilitation center or acute care facility.
Comment We examined 32 adult patients with septic shock who received VV or VA ECMO at a quaternary center in the United States and found that 41% survived to hospital discharge. Most patients
7
died in the first 2 weeks. All but two patients who survived to decannulation survived to discharge, and only one died after transferring out of the ICU. There was no difference in survival by mode, previous cardiac arrest or timing of cannulation. The patients studied were critically ill on maximal medical therapy and survived at a rate equivalent to survival for septic shock in large, epidemiologic studies.1,5 The number of septic patients receiving ECMO and the survival rate increased over the 7-year period. This is likely related to our experience with ECMO, and the willingness to attempt supporting patients while in septic shock. The trend for increasing use of ECMO for any indication is consistent with national trends in the United States.22 Consistent with the literature,23 only 44% of patients in the cohort had an infectious organism identified as a cause of their septic shock. The majority of our cohort was supported on VV ECMO (65%) and some baseline characteristics of patients on VV versus VA ECMO were different. We interpret this to mean that the clinical presentations led ECMO physicians to choose the specific mode of support. Patients receiving VV ECMO typically were patients with acute respiratory failure and associated sepsis. Patients receiving VA ECMO had a component of cardiogenic shock and had higher vasopressor scores than patients supported on VV ECMO. Although the ejection fraction was not statistically different by mode, fewer patients received VA ECMO. Patients in our cohort survived differently by mode than their RESP or SAVE scores would have predicted.18,19 Patients on VV ECMO fared worse. However, the presence of hemodynamic instability is not well captured by the RESP score. Conversely, patients on VA ECMO had higher survival than predicted by their median SAVE score. This could be because their ejection fraction was higher (median 0.37) than patients in cardiogenic shock from other etiologies. Further extrapolation is limited because these risk prediction scores are not validated
8
in this patient population. Additional work is needed to elucidate threshold characteristics for choosing one mode over another in septic patients with preserved ejection fraction. After 48 hours of ECMO, there were clinical markers that differed in patients who lived or died. Patients who survived had nearly normalized lactate levels, greater mean arterial pressures, lower need for vasopressors and less anuria. Our cohort was too small to derive a multivariable model, but registry level data would be amenable to this type of analysis. Complications were frequent. The rate of healthcare associated infections (25%) was higher than previously reported estimates of 10-12% in ECMO studies.24 This may be that downregulated immune pathways in sepsis make patients more prone to subsequent infections.25 Although we examined complications by mode and survivor status, the sample size for comparison was too small to draw meaningful conclusions.
Relationship with Previous Studies Our survival to discharge of 41% was higher than previous reports of patients with septic shock receiving ECMO in Asia.8-11 In these studies, severity of illness at cannulation was higher with SOFA scores ranging from 13-168,10,11 versus 10 in our cohort, despite a similar rate of cardiac arrest (~40%).8-11 Importantly, there were higher rates of VA ECMO, ranging from 67-100%,8,9,11 versus 35%, reflecting our hesitation to support patients on VA ECMO in the setting of predominant respiratory failure with normal cardiac function. Two European studies by von Bahr et al12 and Vogel et al13 reported survival to discharge of 75% and 65%, respectively, in their cohorts of septic patients. However, von Bahr et al included patients with either respiratory failure or sepsis. For the subgroup of patients with severe inflammatory response, similar to our patients, survival to discharge was only 39%.12 Vogel et al studied patients on VA ECMO with respiratory failure and septic cardiomyopathy.13 The
9
median left ventricular ejection fraction of their twelve patients at cannulation was 16%. Patients with sepsis manifesting with septic cardiomyopathy and decreased ejection fraction are more likely to benefit from VA ECMO support than patients manifesting with high cardiac output, preserved function and oxygen extraction deficit at the tissue and mitochondrial level. In the latter case, increasing the cardiac output may not help microvascular alterations and mitochondrial dysfunction. The maladaptive cardiac response to sepsis with severe global ventricular dysfunction appears to be similar to septic children, who have better survival rates on ECMO.26 Central placement of cannulae for VA ECMO can also improve outcomes in children with septic shock.5,6 We could not study this aspect, as only one patient was centrally cannulated. We performed subgroup analyses for cardiac arrest10 and timing of ECMO,11 which are associated with differential survival in the literature. However, our patients with cardiac arrest did not have lower survival. Beside low power as an explanation, this could reflect the American Heart Association’s advocacy of early response to cardiac arrest.27 We interpret this to mean that cardiac arrest is not a contraindication for ECMO support in septic shock.
Limitations This was a retrospective, single center case series with increasing use of ECMO in patients with septic shock over the time period. The major limitation is sample size and insufficient power to perform predictive modeling or models with time-varying covariates. Nonetheless, these results are hypothesis-generating. Additionally, there could be selection bias over time by only offering ECMO to patients with higher likelihood of survival. This is unlikely, however, as our center increased both volume and indications for ECMO during this period.
10
Conclusions ECMO support in septic shock carries a 41% overall survival to discharge at our center regardless of the ECMO mode chosen and appears to be an acceptable strategy to support this population of critically ill patients when they reach maximal medical therapy. Larger studies are needed as well as cost effectiveness evaluation before it is routinely implemented.
11
References: 1.
Singer M, Deutschman CS, Seymour CW, et al. The third international consensus
definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315: 801-810. 2.
Ince C, Mayeux PR, Nguyen T, et al. The endothelium in sepsis. Shock 2016; 45: 259-
270. 2016/02/13. 3.
Volk T and Kox WJ. Endothelium function in sepsis. Inflamm Res 2000; 49: 185-198.
2000/07/13. 4.
Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic
support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37: 666-688. 5.
Maclaren G, Butt W, Best D, et al. Extracorporeal membrane oxygenation for refractory
septic shock in children: one institution's experience. Pediatr Crit Care Med 2007; 8: 447-451. 2007/08/19. 6.
MacLaren G, Butt W, Best D, et al. Central extracorporeal membrane oxygenation for
refractory pediatric septic shock. Pediatr Crit Care Med 2011; 12: 133-136. 2010/05/11. 7.
Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international
guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43: 304-377. 8.
Huang CT, Tsai YJ, Tsai PR, et al. Extracorporeal membrane oxygenation resuscitation
in adult patients with refractory septic shock. J Thorac Cardiovasc Surg 2013; 146: 1041-1046. 2012/09/11.
12
9.
Cheng A, Sun HY, Lee CW, et al. Survival of septic adults compared with nonseptic
adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: a propensity-matched analysis. J Crit Care 2013; 28: 532 e531-510. 10.
Park TK, Yang JH, Jeon K, et al. Extracorporeal membrane oxygenation for refractory
septic shock in adults. Eur J Cardiothorac Surg 2015; 47: e68-74. 11.
Cheng A, Sun HY, Tsai MS, et al. Predictors of survival in adults undergoing
extracorporeal membrane oxygenation with severe infections. J Thorac Cardiovasc Surg 2016; 152: 1526-1536 e1521. 2016/10/04. 12.
von Bahr V, Hultman J, Eksborg S, et al. Long-term survival in adults treated with
extracorporeal membrane oxygenation for respiratory failure and sepsis. Crit Care Med 2017; 45: 164-170. 13.
Vogel DJ, Murray J, Czapran AZ, et al. Veno-arterio-venous ECMO for septic
cardiomyopathy: a single-centre experience. Perfusion 2018; 33: 57-64. 14.
MacLaren G, Pellegrino V, Butt W, et al. Successful use of ECMO in adults with life-
threatening infections. Anaesth Intensive Care 2004; 32: 707-710. 15.
Rich PB, Younger JG, Soldes OS, et al. Use of extracorporeal life support for adult
patients with respiratory failure and sepsis. ASAIO J 1998; 44: 263-266. 16.
Vincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the
incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med 1998; 26: 1793-1800. 17.
Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in
abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 2009; 301: 2445-2452.
13
18.
Schmidt M, Bailey M, Sheldrake J, et al. Predicting survival after extracorporeal
membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med 2014; 189: 1374-1382. 19.
Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory
cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J 2015; 36: 2246-2256. 20.
Extracorporeal Life Support Organization. Guidelines For Extracorporeal Membrane
Oxygenation Centers v1.8, https://www.elso.org/Portals/0/IGD/Archive/FileManager/faf3f6a3c7cusersshyerdocumentselsog uidelinesecmocentersv1.8.pdf (2014, accessed August 25, 2018). 21.
Extracorporeal Life Support Organization. Extracorporeal Life Support Registry Form,
https://www.elso.org/Portals/0/Files/ELSOECLSRegistryForm.pdf (2011, accessed August 20, 2018). 22.
McCarthy FH, McDermott KM, Kini V, et al. Trends in U.S. extracorporeal membrane
oxygenation use and outcomes: 2002-2012. Semin Thorac Cardiovasc Surg 2015; 27: 81-88. 2015/12/22. 23.
Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States
from 1979 through 2000. NEJM 2003; 348:1546-1554. 24.
Biffi S, Di Bella S, Scaravilli V, et al. Infections during extracorporeal membrane
oxygenation: epidemiology, risk factors, pathogenesis and prevention. Int J Antimicrob Agents 2017; 50: 9-16.
14
25.
Hotchkiss RS, Monneret G and Payen D. Immunosuppression in sepsis: a novel
understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13: 260268. 26.
Maclaren G and Butt W. Extracorporeal membrane oxygenation and sepsis. Crit Care
Resusc 2007; 9: 76-80. 27.
Chan PS, Krein SL, Tang F, et al. Resuscitation practices associated with survival after
in-hospital cardiac arrest: a nationwide survey. JAMA Cardiol 2016; 1: 189-197.
15
Table 1: Baseline characteristics of patients with septic shock receiving extracorporeal membrane oxygenation by survivor status
All patients
Survivors (n=13)
Non-survivors
46 (30, 58)
34 (28, 58)
46 (32, 57)
0.35
Gender (% male)
21 (65%)
8 (62%)
13 (68%)
0.72
Race (% Caucasian)
25 (86%)
12 (92%)
14 (74%)
0.55
83 (71, 96)
92 (74, 106)
82 (69, 93)
0.27
Never
12 (38%)
7 (54%)
5 (26%)
0.11
Former
7 (22%)
1 (8%)
6 (32%)
0.11
Current
9 (28%)
5 (38%)
4 (21%)
0.28
Hypertension
10 (31%)
5 (38%)
5 (26%)
0.69
Asthma or chronic obstructive lung disease
7 (22%)
3 (23%)
4 (21%)
0.28
Diabetes
7 (22%)
4 (31%)
3 (16%)
0.40
Psychiatric diagnosis
5 (16%)
3 (23%)
2 (11%)
0.37
Alcohol use
5 (15%)
1 (8%)
4 (21%)
0.62
Obesity
3 (9%)
3 (23%)
0
0.06
Intravenous drug use
2 (6%)
1 (8%)
1 (5%)
>0.99
2010
1 (3%)
0
1 (5%)
2011
3 (9%)
0
3 (16%)
2012
1 (3%)
0
1 (5%)
2013
2 (6%)
0
2 (11%)
2014
5 (16%)
1 (8%)
4 (21%)
2015
13 (41%)
9 (69%)
4 (21%)
2016
7 (22%)
3 (23%)
4 (21%)
Mean age (95% CI)
Median actual body weight, kg (IQR)
p-value
(n=19)
Smoking history
Most common co-morbidities
Year
0.02 a
16
Pre-ECMO support Neuromuscular blockade
25 (78%)
12 (92%)
13 (68%)
0.20
Bicarbonate drip
16 (50%)
8 (61%)
8 (42%)
0.47
Inhaled nitric oxide
16 (50%)
6 (46%)
10 (53%)
>0.99
Renal replacement therapy
9 (28%)
3 (23%)
6 (32%)
0.70
Steroids
5 (16%)
1 (8%)
4 (21%)
0.62
Hypothermia
3 (9%)
0
3 (16%)
0.25
Balloon pump
2 (6%)
1 (8%)
1 (5%)
>0.99
51 (30, 67)
47 (37, 64)
55 (18, 75)
0.89
5.2 (4.6, 6.0)
4.9 (4.3, 5.5)
5.3 (4.5, 5.8)
0.75
Cardiac arrest prior to cannulation
12 (38%)
5 (38%)
7 (37%)
>0.99
Median hours from admission to ECMO (IQR)
23 (6, 65)
16 (4, 64)
24 (10, 65)
0.48
Mode (% veno-venous)
21 (65%)
8 (62%)
13 (68%)
0.72
Pulmonary sepsis
23 (72%)
9 (69%)
14 (73%)
0.78
1 (3%)
0
1 (5%)
>0.99
Median cardiac ejection fraction, % Median cardiac output, L/min
Central cannulation
a
Mantel-Haenszel test for trend.
ECMO: Extracorporeal Membrane Oxygenation. Patients were followed until hospital discharge. Cardiac arrest could be prior to or contemporaneous with cannulation.
17
Table 2: Characteristics at the time of cannulation of patients with septic shock receiving extracorporeal membrane oxygenation by mode Veno-venous
Veno-arterial
(n=21)
(n=11)
8.9 (7.7, 10.1)
11.4 (9.7, 13.0)
0.01
Mean arterial pressure (95% CI)
64.8 (55.4, 74.1)
49.2 (35.8, 62.5)
0.07
Median vasopressor score (IQR)
59 (12, 121)
171 (56, 949)
0.04
11 (52%)
8 (72%)
0.45
Mean lactate, mmol/L (95% CI)
7.1 (4.7, 9.0)
7.1 (2.4, 6.0)
0.99
Mean troponin T, ng/mL (95% CI)
0.74 (0, 2.15)
0.53 (0.06, 0.99)
0.81
65 (50, 81)
90 (52, 128)
0.13
100 (100, 100)
99 (97, 100)
0.17
Mean respiratory rate
30 (27, 32)
29 (23, 35)
0.83
Mean peak inspiratory pressure
35 (31, 39)
32 (27, 37)
0.39
Mean positive end expiratory pressure
14 (10, 19)
12 (8, 16)
0.50
Mean airway pressure
17 (13, 22)
22 (8, 37)
0.31
7.1 (7.1, 7.2)
7.1 (7.0, 7.2)
0.38
Mean PaO2
57 (51, 64)
102 (63, 141)
0.002
Mean PCO2
62 (53, 71)
57 (37, 76)
0.56
4.2 (3.9, 4.6)
4.6 (4.0, 5.3)
0.19
6 (29%)
6 (50%)
0.25
55 (40, 66)
37 (17, 67)
0.32
Median RESP score
3 (1, 5)
Not validated
-
Median SAVE score
Not validated
-11 (-13, -6)
-
17 (81%)
6 (55%)
0.11
Mean SOFA score (95% CI)
Vasopressin infused
P/f ratio (95% CI)
p-value
Ventilator settings (95% CI) Mean FIO2
Blood gas Mean pH
Mean pump flow, L/min (95% CI) Anuric Median cardiac ejection fraction, %
Presumed source of infection Lung
18
Urosepsis
0
1 (9%)
0.58
Abdominal
1(5%)
0
0.72
3 (14%)
4 (36%)
0.15
10 (48%)
4 (36%)
0.54
Unknown Source identified (culture or molecular testing)
SOFA: Sequential Organ Failure. P/f ratio: Pao2 in arterial blood divided by the fraction of oxygen delivered through the ventilator. FIO2: Fraction of oxygen delivered through the ventilator. RESP: Respiratory ECMO Survival Prediction.21 SAVE: Survival After Veno-arterial ECMO.32
19
Table 3: Characteristics at 48 hours by survival status at hospital discharge
Patients living at 48 hours who survive to hospital discharge
Patients living at 48 hours who die before hospital discharge
(n=13)
(n=19)
7.6 (5.9, 9.3)
9.8 (7.1, 12.4)
0.15
Glasgow not assessed due to sedation
13 (100%)
14 (73%)
0.16
Mean arterial pressure (95% CI)
79 (71, 87)
69 (64, 74)
0.03
Median vasopressor score, unitless (IQR)
2 (0, 14)
14 (5, 36)
0.11
Vasopressin infused
2 (15%)
8 (42%)
0.003
Mean lactate, mmol/L (95% CI)
2.4 (0.8, 3.9)
7.5 (4.2, 10.7)
0.007
Mean troponin T, ng/mL (95% CI)
0.31 (0, 0.79)
0.83 (0.16, 1.51)
0.14
Mean p/f ratio (95% CI)
202 (149, 255)
205 (116, 293)
0.95
Mean FIO2
60 (45, 76)
73 (59, 86)
0.20
Mean respiratory rate
13 (12,15)
13 (10, 16)
0.92
Mean peak inspiratory pressure
26 (23, 29)
27 (23,30)
0.77
Mean positive end expiratory pressure
11 (10, 13)
11 (8, 13)
0.71
Mean airway pressure
15 (13, 17)
15 (11, 18)
0.91
7.39 (7.36, 7.43)
7.33 (7.29, 7.37)
0.02
Mean PaO2
129 (86, 172)
136 (86, 187)
0.82
Mean PCO2
41 (38, 45)
42 (37, 47)
0.76
4.9 (4.4, 5.4)
4.3 (3.8, 4.8)
0.10
3 (23%)
7 (37%)
0.02
Mean platelet, th/cumm (95% CI)
111 (80, 141)
75 (41,109)
0.11
Mean total bilirubin, mg/dL (95% CI)
2.3 (1.1, 3.5)
3.6 (2.0, 5.2)
0.18
Mean SOFA score (95% CI)
p-value
Ventilator settings (95% CI)
Blood gas Mean pH
Mean pump flow, L/min (95% CI) Anuric
20
SOFA: Sequential Organ Failure. P/f ratio: Pao2 in arterial blood divided by the fraction of oxygen delivered through the ventilator. FIO2: fraction of oxygen delivered through the ventilator.
21
Table 4: Clinical outcomes and complications of patients with septic shock receiving extracorporeal membrane oxygenation
All patients n=32
Patients on venovenous
Patients on veno-arterial
p-value
n=11
n=21 Median days on ECMO (IQR)
5.8 (2.6, 11.3)
4.2 (2, 9.5)
7.1 (3.2, 14.5)
0.46
Cardiac arrhythmia
13 (41%)
8 (38%)
5 (45%)
0.72
Surgical/cannulation site bleeding
12 (38%)
9 (43%)
3 (27%)
0.46
Dialysis
10 (31%)
5 (24%)
5 (45%)
0.25
Healthcare-associated infection
8 (25%)
5 (24%)
3 (27%)
0.83
Air or clot in membrane
7 (22%)
4 (19%)
3 (27%)
0.67
Pneumothorax
3 (9%)
1 (5%)
2 (18%)
0.27
Disseminated intravascular coagulation
3 (9%)
2 (10%)
1 (9%)
>0.99
Brain death
3 (9%)
2 (10%)
1 (9%)
>0.99
Pulmonary hemorrhage
3 (9%)
2 (10%)
1 (9%)
>0.99
Survival until decannulation
14 (44%)
9 (43%)
5 (45%)
0.86
Survival until ICU transfer
13 (41%)
8 (38%)
5 (45%)
0.72
Survival until hospital discharge
13 (41%)
8 (38%)
5 (45%)
0.72
Complications
22
Figure Legend Figure 1. Kaplan-Meier plot of patients with septic shock receiving extracorporeal membrane oxygenation. The x-axis is days from cannulation. The shaded area represents the 95% confidence limits. The plus sign represents patients who are censored, ie. alive at discharge. The patients at risk over time are shown along the bottom row.
23
S0003-4975(20)30203-4
DOI:
https://doi.org/10.1016/j.athoracsur.2019.12.075
Reference:
ATS 33477
To appear in:
The Annals of Thoracic Surgery
Received Date: 8 August 2019 Revised Date:
27 November 2019
Accepted Date: 27 December 2019
Please cite this article as: Myers LC, Lee C, Thompson BT, Cudemus G, Raz Y, Roy N, Outcomes of adult patients with septic shock receiving extracorporeal membrane oxygenation therapy, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.12.075. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by The Society of Thoracic Surgeons
Outcomes of adult patients with septic shock receiving extracorporeal membrane oxygenation therapy Running head: ECMO in septic shock
Laura C. Myers MD MPH,1,2 Charlotte Lee MD,1,3 B. Taylor Thompson MD,1,2 Gaston Cudemus MD,1,4 Yuval Raz MD MSc,1,2 Nathalie Roy MD1,5
This work was entirely performed at The Massachusetts General Hospital, and (1) Harvard Medical School, Boston, MA. (2) Division of Pulmonary/Critical Care, Department of Medicine (3) Department of Medicine (4) Department of Anesthesia (5) Department of Cardiac Surgery, now at Boston Children’s Hospital, Boston MA
Classifications: Adult, extracorporeal membrane oxygenation, septic shock, critical care Corresponding Author: Nathalie Roy MD, Instructor in Surgery, Harvard Medical School. Assistant in Cardiac Surgery, Boston Children’s Hospital, 300 Longwood Avenue, Bader-292, Boston, MA 02115. Email: [email protected] Word Count: 4612
Abstract Background: Extracorporeal membrane oxygenation (ECMO) has been shown to provide benefits in children with septic shock, but not adults. We describe the clinical outcomes of adults who received ECMO in septic shock. Methods: We retrospectively studied adults supported on veno-arterial or veno-venous modes of ECMO with septic shock at the time of cannulation from 1/1/2009-12/31/2016 at a quaternary medical center in the United States. The primary outcome was rate of survival to hospital discharge and time to survival using Kaplan-Meier survival estimates. We analyzed survival by mode, previous cardiac arrest and timing of cannulation (<96 and ≥96 hours after admission to the intensive care unit). Secondary outcomes were complications and days of ECMO support, length of stay in the intensive care unit, and hospitalization days. Results: Of 243 patients supported on ECMO during this 7-year period, 32 met the criteria for septic shock and the majority had a pulmonary source of infection (72%). The most common mode of support was VV ECMO (65%) and median ejection fraction was 51%. Median time on ECMO was 5.8 days (IQR 2.6, 11.3). Survival to hospital discharge was 13 of 32 (41%) while median survival was 14.5 days (5.2, 23.7). There was no statistically significant difference in survival by subgroup, including ECMO mode. Healthcare associated infections were frequent (25%). Conclusions: Our cohort of patients receiving ECMO had equivalent median survival compared to literature-based estimates of other cohorts of patients with septic shock.
2
Survival from septic shock in adults is approximately 40%.1 Historically, patients with septic shock have not received extracorporeal membrane oxygenation (ECMO) because it does not improve low systemic vascular resistance, a major aspect of the physiologic state of sepsis. In addition, oxygen delivery remains compromised by the presence of microvascular alterations. Furthermore, endothelial dysfunction leads to fluid extravasation and may compromise the ability to deliver adequate flow on ECMO.2,3 In neonates and children, the American College of Critical Care Medicine recommends the use of ECMO in refractory septic shock (Level II).4 The literature reports better survival in children with septic shock undergoing central cannulation for veno-arterial (VA) ECMO support.5,6 However, the evidence in adults is sparse, and the 2016 Surviving Sepsis Guidelines do not recommend ECMO in septic adults.7 Small retrospective studies have reported the use of ECMO in adults with septic shock8-14 but the most recent publication from an institution in the United States dates 21 years back.15 We sought to evaluate survival outcomes in patients with septic shock unresponsive to maximal medical therapy who received ECMO in the context of respiratory failure or cardiovascular failure and examine if differences existed between patients receiving veno-venous (VV) vs. veno-arterial (VA) ECMO.
Patients and Methods A. Study Design We performed a retrospective, single center case series. The study was approved by the Institutional Review Board (2011P002375) at the Massachusetts General Hospital.
B. Patient Selection and Data Collection
3
A hospital database was queried to identify adults aged ≥18 years who received VV or VA ECMO at the Massachusetts General Hospital between 1/1/2009-12/31/2016. We included all patients with septic shock at the time of ECMO cannulation using the 2016 consensus definition from the Society of Critical Care Medicine and European Society of Intensive Care Medicine: “Patients with life-threatening organ dysfunction caused by a dysregulated host response to infection and persistent hypotension requiring vasopressors to maintain mean arterial pressure to 65mm Hg and a serum lactate >2mmol/L despite adequate volume resuscitation”.1 The source of septic shock was identified and microbiology data was collected. Patients were classified by ECMO mode according to initial cannulation strategy. Additional details are in the supplement.
C. Risk Scores Details regarding the Sequential Organ Failure Assessment (SOFA) score,16 the vasopressor score,17 the Respiratory ECMO Survival Prediction (RESP) score,18 and the Survival After Venoarterial ECMO (SAVE) score,19 are provided in the supplement.
D. Institutional Practice for Treatment of Septic Shock and ECMO Septic shock was treated according to the Surviving Sepsis guidelines.5 Our institutional protocol for delivering ECMO was developed in alignment with the Extracorporeal Life Support Organization (ELSO) guidelines.20 Both are described in the supplement.
E. Outcomes and Survival Analysis
4
The primary outcome was survival to hospital discharge, reported as a percentage. Survival analysis was performed to estimate median survival with confidence limits. Kaplan-Meier plots are presented with time starting at cannulation and censoring at hospital discharge. Intermediate outcomes include survival at decannulation and transfer from the intensive care unit (ICU). The following subgroups were examined: mode (VV versus VA),9 cardiac arrest at/or before cannulation,10 and early vs late cannulation (defined as <96 and ≥96 hours after admission to ICU). Log-Rank tests were calculated to determine differences in survival by subgroup.11 Days of ECMO and complications as defined by ELSO21 are reported. For infection as a complication, we reported acquired culture-positive infection while on ECMO support.
F. Statistical Analysis Binary/categorical variables were presented as numbers and percentages, and comparisons were made via the Fisher Exact Test. Normally distributed continuous variables were reported as means with 95% confidence intervals and compared using T tests, or paired T tests for paired data. Variables with non-normal distributions were reported as medians with interquartile range (IQR) and compared using Wilcoxon rank-sum tests or Wilcoxon signed-rank tests for paired data. All statistics were two-tailed. The threshold for significance was <0.05. SAS software version 9.4 (SAS Institute, Cary, NC) was used.
Results There were 243 patients receiving ECMO at our center over a 7-year period, and 32 met criteria for septic shock at the time of ECMO initiation. Baseline characteristics of patients by survivor status at the time of hospital discharge are presented in Table 1. There were no statistically
5
significant differences in characteristics between survivors (n=13) and non-survivors (n=19), except for a trend test that showed increasing survival between 2010-2016. The majority received VV ECMO (65%) rather than VA (35%). Other than inotropes and vasopressors, the most common method of pre-ECMO management was neuromuscular blockade (78%). Thirty eight percent had a previous cardiac arrest. The median time between admission and cannulation was 23 hours (IQR 6, 65). The median left ventricular ejection fraction was 51% (IQR 30, 67). Patient characteristics by ECMO mode are outlined in Table 2. Only 44% of patients had a source identified by culture or molecular testing. The most common presumed source of septic shock was the lung (72%), of which 26% had influenza and 30% had aspiration. Patients supported on VV ECMO showed differences from those supported on VA ECMO: lower SOFA score (8.9 versus 11.4, p=0.01), vasopressor score (59 versus 171, p=0.04) and PaO2 (57 versus 102, p=0.002). The median RESP score was 3 (IQR 1, 5) for those receiving VV ECMO, which predicts a 70% survival rate but our observed survival was 38%. The median SAVE score was -11 (IQR -13, -6) for those receiving VA ECMO, which predicts a 20% survival rate and the observed survival was 45%. Supplemental Table 1 shows the 2x2 table of expected and observed survival to discharge rates by mode (p=0.06). Characteristics at the time of cannulation and at 48 hours are presented in supplemental Table 2. All patients were either on ECMO (N=27) or dead (N=5); no one was successfully decannulated in the first 48 hours. There was statistically significant improvement in mean arterial pressure, median vasopressor score, ventilatory settings and arterial blood gas at 48 hours. Pump flow was higher at 48 hours (mean 4.4 to 4.6 L/min, p=0.02). Characteristics over time by ECMO mode are further defined in supplemental Tables 3 and 4. Characteristics at 48 hours of ECMO support by survivor status are shown in Table 3. Patients who ultimately survived septic shock with ECMO support experienced early hemodynamic
6
improvement compared to non-survivors. At 48 hours, they had higher mean arterial pressure (79 versus 69, p=0.03) and pH (7.39 vs 7.33, p=0.02), lower lactate (2.4 versus 7.5, p=0.007) and lower rate of vasopressin use (15% versus 42%, p=0.003). They were less likely to be anuric compared to patients who died (23% versus 37%, p=0.02). Clinical outcomes and complications are shown in Table 4. There were no differences by ECMO mode. The median time of ECMO support was 5.8 days (IQR 2.8, 10.2). Among survivors, median ICU length of stay was 17.7 days (IQR 5.9, 42.2) and median hospital length of stay was 40.1 days (IQR 13.1, 44.2). The most common complication was cardiac arrhythmia, which occurred in 41%. Healthcare acquired infections occurred in 25% of patients; the most common organisms were Candida species and Staphylococcus aureus. The most common sites of infection were lung and bloodstream. Bleeding occurred in 38%, and circuit-related complications occurred in 22% of patients. Thirty one percent required dialysis. Complications by survivor status are shown in supplemental Table 5. By univariate analysis, no specific complications were associated with survival status, although all patients with disseminated intravascular coagulation died, and arrhythmias and dialysis tended to be more common in patients who died. Survival to decannulation, ICU transfer and hospital discharge were 44%, 41% and 41%, respectively (Table 4). Figure 1 shows a median survival of 14.5 days (5.2, 23.7). Supplemental Figures 1, 2 and 3 are the Kaplan-Meier plots of patients by mode, previous cardiac arrest and timing of cannulation, respectively, which showed no difference by subgroup. The majority of patients (>50%) were discharged to a rehabilitation center or acute care facility.
Comment We examined 32 adult patients with septic shock who received VV or VA ECMO at a quaternary center in the United States and found that 41% survived to hospital discharge. Most patients
7
died in the first 2 weeks. All but two patients who survived to decannulation survived to discharge, and only one died after transferring out of the ICU. There was no difference in survival by mode, previous cardiac arrest or timing of cannulation. The patients studied were critically ill on maximal medical therapy and survived at a rate equivalent to survival for septic shock in large, epidemiologic studies.1,5 The number of septic patients receiving ECMO and the survival rate increased over the 7-year period. This is likely related to our experience with ECMO, and the willingness to attempt supporting patients while in septic shock. The trend for increasing use of ECMO for any indication is consistent with national trends in the United States.22 Consistent with the literature,23 only 44% of patients in the cohort had an infectious organism identified as a cause of their septic shock. The majority of our cohort was supported on VV ECMO (65%) and some baseline characteristics of patients on VV versus VA ECMO were different. We interpret this to mean that the clinical presentations led ECMO physicians to choose the specific mode of support. Patients receiving VV ECMO typically were patients with acute respiratory failure and associated sepsis. Patients receiving VA ECMO had a component of cardiogenic shock and had higher vasopressor scores than patients supported on VV ECMO. Although the ejection fraction was not statistically different by mode, fewer patients received VA ECMO. Patients in our cohort survived differently by mode than their RESP or SAVE scores would have predicted.18,19 Patients on VV ECMO fared worse. However, the presence of hemodynamic instability is not well captured by the RESP score. Conversely, patients on VA ECMO had higher survival than predicted by their median SAVE score. This could be because their ejection fraction was higher (median 0.37) than patients in cardiogenic shock from other etiologies. Further extrapolation is limited because these risk prediction scores are not validated
8
in this patient population. Additional work is needed to elucidate threshold characteristics for choosing one mode over another in septic patients with preserved ejection fraction. After 48 hours of ECMO, there were clinical markers that differed in patients who lived or died. Patients who survived had nearly normalized lactate levels, greater mean arterial pressures, lower need for vasopressors and less anuria. Our cohort was too small to derive a multivariable model, but registry level data would be amenable to this type of analysis. Complications were frequent. The rate of healthcare associated infections (25%) was higher than previously reported estimates of 10-12% in ECMO studies.24 This may be that downregulated immune pathways in sepsis make patients more prone to subsequent infections.25 Although we examined complications by mode and survivor status, the sample size for comparison was too small to draw meaningful conclusions.
Relationship with Previous Studies Our survival to discharge of 41% was higher than previous reports of patients with septic shock receiving ECMO in Asia.8-11 In these studies, severity of illness at cannulation was higher with SOFA scores ranging from 13-168,10,11 versus 10 in our cohort, despite a similar rate of cardiac arrest (~40%).8-11 Importantly, there were higher rates of VA ECMO, ranging from 67-100%,8,9,11 versus 35%, reflecting our hesitation to support patients on VA ECMO in the setting of predominant respiratory failure with normal cardiac function. Two European studies by von Bahr et al12 and Vogel et al13 reported survival to discharge of 75% and 65%, respectively, in their cohorts of septic patients. However, von Bahr et al included patients with either respiratory failure or sepsis. For the subgroup of patients with severe inflammatory response, similar to our patients, survival to discharge was only 39%.12 Vogel et al studied patients on VA ECMO with respiratory failure and septic cardiomyopathy.13 The
9
median left ventricular ejection fraction of their twelve patients at cannulation was 16%. Patients with sepsis manifesting with septic cardiomyopathy and decreased ejection fraction are more likely to benefit from VA ECMO support than patients manifesting with high cardiac output, preserved function and oxygen extraction deficit at the tissue and mitochondrial level. In the latter case, increasing the cardiac output may not help microvascular alterations and mitochondrial dysfunction. The maladaptive cardiac response to sepsis with severe global ventricular dysfunction appears to be similar to septic children, who have better survival rates on ECMO.26 Central placement of cannulae for VA ECMO can also improve outcomes in children with septic shock.5,6 We could not study this aspect, as only one patient was centrally cannulated. We performed subgroup analyses for cardiac arrest10 and timing of ECMO,11 which are associated with differential survival in the literature. However, our patients with cardiac arrest did not have lower survival. Beside low power as an explanation, this could reflect the American Heart Association’s advocacy of early response to cardiac arrest.27 We interpret this to mean that cardiac arrest is not a contraindication for ECMO support in septic shock.
Limitations This was a retrospective, single center case series with increasing use of ECMO in patients with septic shock over the time period. The major limitation is sample size and insufficient power to perform predictive modeling or models with time-varying covariates. Nonetheless, these results are hypothesis-generating. Additionally, there could be selection bias over time by only offering ECMO to patients with higher likelihood of survival. This is unlikely, however, as our center increased both volume and indications for ECMO during this period.
10
Conclusions ECMO support in septic shock carries a 41% overall survival to discharge at our center regardless of the ECMO mode chosen and appears to be an acceptable strategy to support this population of critically ill patients when they reach maximal medical therapy. Larger studies are needed as well as cost effectiveness evaluation before it is routinely implemented.
11
References: 1.
Singer M, Deutschman CS, Seymour CW, et al. The third international consensus
definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315: 801-810. 2.
Ince C, Mayeux PR, Nguyen T, et al. The endothelium in sepsis. Shock 2016; 45: 259-
270. 2016/02/13. 3.
Volk T and Kox WJ. Endothelium function in sepsis. Inflamm Res 2000; 49: 185-198.
2000/07/13. 4.
Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic
support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37: 666-688. 5.
Maclaren G, Butt W, Best D, et al. Extracorporeal membrane oxygenation for refractory
septic shock in children: one institution's experience. Pediatr Crit Care Med 2007; 8: 447-451. 2007/08/19. 6.
MacLaren G, Butt W, Best D, et al. Central extracorporeal membrane oxygenation for
refractory pediatric septic shock. Pediatr Crit Care Med 2011; 12: 133-136. 2010/05/11. 7.
Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international
guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43: 304-377. 8.
Huang CT, Tsai YJ, Tsai PR, et al. Extracorporeal membrane oxygenation resuscitation
in adult patients with refractory septic shock. J Thorac Cardiovasc Surg 2013; 146: 1041-1046. 2012/09/11.
12
9.
Cheng A, Sun HY, Lee CW, et al. Survival of septic adults compared with nonseptic
adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: a propensity-matched analysis. J Crit Care 2013; 28: 532 e531-510. 10.
Park TK, Yang JH, Jeon K, et al. Extracorporeal membrane oxygenation for refractory
septic shock in adults. Eur J Cardiothorac Surg 2015; 47: e68-74. 11.
Cheng A, Sun HY, Tsai MS, et al. Predictors of survival in adults undergoing
extracorporeal membrane oxygenation with severe infections. J Thorac Cardiovasc Surg 2016; 152: 1526-1536 e1521. 2016/10/04. 12.
von Bahr V, Hultman J, Eksborg S, et al. Long-term survival in adults treated with
extracorporeal membrane oxygenation for respiratory failure and sepsis. Crit Care Med 2017; 45: 164-170. 13.
Vogel DJ, Murray J, Czapran AZ, et al. Veno-arterio-venous ECMO for septic
cardiomyopathy: a single-centre experience. Perfusion 2018; 33: 57-64. 14.
MacLaren G, Pellegrino V, Butt W, et al. Successful use of ECMO in adults with life-
threatening infections. Anaesth Intensive Care 2004; 32: 707-710. 15.
Rich PB, Younger JG, Soldes OS, et al. Use of extracorporeal life support for adult
patients with respiratory failure and sepsis. ASAIO J 1998; 44: 263-266. 16.
Vincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the
incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med 1998; 26: 1793-1800. 17.
Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in
abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 2009; 301: 2445-2452.
13
18.
Schmidt M, Bailey M, Sheldrake J, et al. Predicting survival after extracorporeal
membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med 2014; 189: 1374-1382. 19.
Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory
cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J 2015; 36: 2246-2256. 20.
Extracorporeal Life Support Organization. Guidelines For Extracorporeal Membrane
Oxygenation Centers v1.8, https://www.elso.org/Portals/0/IGD/Archive/FileManager/faf3f6a3c7cusersshyerdocumentselsog uidelinesecmocentersv1.8.pdf (2014, accessed August 25, 2018). 21.
Extracorporeal Life Support Organization. Extracorporeal Life Support Registry Form,
https://www.elso.org/Portals/0/Files/ELSOECLSRegistryForm.pdf (2011, accessed August 20, 2018). 22.
McCarthy FH, McDermott KM, Kini V, et al. Trends in U.S. extracorporeal membrane
oxygenation use and outcomes: 2002-2012. Semin Thorac Cardiovasc Surg 2015; 27: 81-88. 2015/12/22. 23.
Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States
from 1979 through 2000. NEJM 2003; 348:1546-1554. 24.
Biffi S, Di Bella S, Scaravilli V, et al. Infections during extracorporeal membrane
oxygenation: epidemiology, risk factors, pathogenesis and prevention. Int J Antimicrob Agents 2017; 50: 9-16.
14
25.
Hotchkiss RS, Monneret G and Payen D. Immunosuppression in sepsis: a novel
understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13: 260268. 26.
Maclaren G and Butt W. Extracorporeal membrane oxygenation and sepsis. Crit Care
Resusc 2007; 9: 76-80. 27.
Chan PS, Krein SL, Tang F, et al. Resuscitation practices associated with survival after
in-hospital cardiac arrest: a nationwide survey. JAMA Cardiol 2016; 1: 189-197.
15
Table 1: Baseline characteristics of patients with septic shock receiving extracorporeal membrane oxygenation by survivor status
All patients
Survivors (n=13)
Non-survivors
46 (30, 58)
34 (28, 58)
46 (32, 57)
0.35
Gender (% male)
21 (65%)
8 (62%)
13 (68%)
0.72
Race (% Caucasian)
25 (86%)
12 (92%)
14 (74%)
0.55
83 (71, 96)
92 (74, 106)
82 (69, 93)
0.27
Never
12 (38%)
7 (54%)
5 (26%)
0.11
Former
7 (22%)
1 (8%)
6 (32%)
0.11
Current
9 (28%)
5 (38%)
4 (21%)
0.28
Hypertension
10 (31%)
5 (38%)
5 (26%)
0.69
Asthma or chronic obstructive lung disease
7 (22%)
3 (23%)
4 (21%)
0.28
Diabetes
7 (22%)
4 (31%)
3 (16%)
0.40
Psychiatric diagnosis
5 (16%)
3 (23%)
2 (11%)
0.37
Alcohol use
5 (15%)
1 (8%)
4 (21%)
0.62
Obesity
3 (9%)
3 (23%)
0
0.06
Intravenous drug use
2 (6%)
1 (8%)
1 (5%)
>0.99
2010
1 (3%)
0
1 (5%)
2011
3 (9%)
0
3 (16%)
2012
1 (3%)
0
1 (5%)
2013
2 (6%)
0
2 (11%)
2014
5 (16%)
1 (8%)
4 (21%)
2015
13 (41%)
9 (69%)
4 (21%)
2016
7 (22%)
3 (23%)
4 (21%)
Mean age (95% CI)
Median actual body weight, kg (IQR)
p-value
(n=19)
Smoking history
Most common co-morbidities
Year
0.02 a
16
Pre-ECMO support Neuromuscular blockade
25 (78%)
12 (92%)
13 (68%)
0.20
Bicarbonate drip
16 (50%)
8 (61%)
8 (42%)
0.47
Inhaled nitric oxide
16 (50%)
6 (46%)
10 (53%)
>0.99
Renal replacement therapy
9 (28%)
3 (23%)
6 (32%)
0.70
Steroids
5 (16%)
1 (8%)
4 (21%)
0.62
Hypothermia
3 (9%)
0
3 (16%)
0.25
Balloon pump
2 (6%)
1 (8%)
1 (5%)
>0.99
51 (30, 67)
47 (37, 64)
55 (18, 75)
0.89
5.2 (4.6, 6.0)
4.9 (4.3, 5.5)
5.3 (4.5, 5.8)
0.75
Cardiac arrest prior to cannulation
12 (38%)
5 (38%)
7 (37%)
>0.99
Median hours from admission to ECMO (IQR)
23 (6, 65)
16 (4, 64)
24 (10, 65)
0.48
Mode (% veno-venous)
21 (65%)
8 (62%)
13 (68%)
0.72
Pulmonary sepsis
23 (72%)
9 (69%)
14 (73%)
0.78
1 (3%)
0
1 (5%)
>0.99
Median cardiac ejection fraction, % Median cardiac output, L/min
Central cannulation
a
Mantel-Haenszel test for trend.
ECMO: Extracorporeal Membrane Oxygenation. Patients were followed until hospital discharge. Cardiac arrest could be prior to or contemporaneous with cannulation.
17
Table 2: Characteristics at the time of cannulation of patients with septic shock receiving extracorporeal membrane oxygenation by mode Veno-venous
Veno-arterial
(n=21)
(n=11)
8.9 (7.7, 10.1)
11.4 (9.7, 13.0)
0.01
Mean arterial pressure (95% CI)
64.8 (55.4, 74.1)
49.2 (35.8, 62.5)
0.07
Median vasopressor score (IQR)
59 (12, 121)
171 (56, 949)
0.04
11 (52%)
8 (72%)
0.45
Mean lactate, mmol/L (95% CI)
7.1 (4.7, 9.0)
7.1 (2.4, 6.0)
0.99
Mean troponin T, ng/mL (95% CI)
0.74 (0, 2.15)
0.53 (0.06, 0.99)
0.81
65 (50, 81)
90 (52, 128)
0.13
100 (100, 100)
99 (97, 100)
0.17
Mean respiratory rate
30 (27, 32)
29 (23, 35)
0.83
Mean peak inspiratory pressure
35 (31, 39)
32 (27, 37)
0.39
Mean positive end expiratory pressure
14 (10, 19)
12 (8, 16)
0.50
Mean airway pressure
17 (13, 22)
22 (8, 37)
0.31
7.1 (7.1, 7.2)
7.1 (7.0, 7.2)
0.38
Mean PaO2
57 (51, 64)
102 (63, 141)
0.002
Mean PCO2
62 (53, 71)
57 (37, 76)
0.56
4.2 (3.9, 4.6)
4.6 (4.0, 5.3)
0.19
6 (29%)
6 (50%)
0.25
55 (40, 66)
37 (17, 67)
0.32
Median RESP score
3 (1, 5)
Not validated
-
Median SAVE score
Not validated
-11 (-13, -6)
-
17 (81%)
6 (55%)
0.11
Mean SOFA score (95% CI)
Vasopressin infused
P/f ratio (95% CI)
p-value
Ventilator settings (95% CI) Mean FIO2
Blood gas Mean pH
Mean pump flow, L/min (95% CI) Anuric Median cardiac ejection fraction, %
Presumed source of infection Lung
18
Urosepsis
0
1 (9%)
0.58
Abdominal
1(5%)
0
0.72
3 (14%)
4 (36%)
0.15
10 (48%)
4 (36%)
0.54
Unknown Source identified (culture or molecular testing)
SOFA: Sequential Organ Failure. P/f ratio: Pao2 in arterial blood divided by the fraction of oxygen delivered through the ventilator. FIO2: Fraction of oxygen delivered through the ventilator. RESP: Respiratory ECMO Survival Prediction.21 SAVE: Survival After Veno-arterial ECMO.32
19
Table 3: Characteristics at 48 hours by survival status at hospital discharge
Patients living at 48 hours who survive to hospital discharge
Patients living at 48 hours who die before hospital discharge
(n=13)
(n=19)
7.6 (5.9, 9.3)
9.8 (7.1, 12.4)
0.15
Glasgow not assessed due to sedation
13 (100%)
14 (73%)
0.16
Mean arterial pressure (95% CI)
79 (71, 87)
69 (64, 74)
0.03
Median vasopressor score, unitless (IQR)
2 (0, 14)
14 (5, 36)
0.11
Vasopressin infused
2 (15%)
8 (42%)
0.003
Mean lactate, mmol/L (95% CI)
2.4 (0.8, 3.9)
7.5 (4.2, 10.7)
0.007
Mean troponin T, ng/mL (95% CI)
0.31 (0, 0.79)
0.83 (0.16, 1.51)
0.14
Mean p/f ratio (95% CI)
202 (149, 255)
205 (116, 293)
0.95
Mean FIO2
60 (45, 76)
73 (59, 86)
0.20
Mean respiratory rate
13 (12,15)
13 (10, 16)
0.92
Mean peak inspiratory pressure
26 (23, 29)
27 (23,30)
0.77
Mean positive end expiratory pressure
11 (10, 13)
11 (8, 13)
0.71
Mean airway pressure
15 (13, 17)
15 (11, 18)
0.91
7.39 (7.36, 7.43)
7.33 (7.29, 7.37)
0.02
Mean PaO2
129 (86, 172)
136 (86, 187)
0.82
Mean PCO2
41 (38, 45)
42 (37, 47)
0.76
4.9 (4.4, 5.4)
4.3 (3.8, 4.8)
0.10
3 (23%)
7 (37%)
0.02
Mean platelet, th/cumm (95% CI)
111 (80, 141)
75 (41,109)
0.11
Mean total bilirubin, mg/dL (95% CI)
2.3 (1.1, 3.5)
3.6 (2.0, 5.2)
0.18
Mean SOFA score (95% CI)
p-value
Ventilator settings (95% CI)
Blood gas Mean pH
Mean pump flow, L/min (95% CI) Anuric
20
SOFA: Sequential Organ Failure. P/f ratio: Pao2 in arterial blood divided by the fraction of oxygen delivered through the ventilator. FIO2: fraction of oxygen delivered through the ventilator.
21
Table 4: Clinical outcomes and complications of patients with septic shock receiving extracorporeal membrane oxygenation
All patients n=32
Patients on venovenous
Patients on veno-arterial
p-value
n=11
n=21 Median days on ECMO (IQR)
5.8 (2.6, 11.3)
4.2 (2, 9.5)
7.1 (3.2, 14.5)
0.46
Cardiac arrhythmia
13 (41%)
8 (38%)
5 (45%)
0.72
Surgical/cannulation site bleeding
12 (38%)
9 (43%)
3 (27%)
0.46
Dialysis
10 (31%)
5 (24%)
5 (45%)
0.25
Healthcare-associated infection
8 (25%)
5 (24%)
3 (27%)
0.83
Air or clot in membrane
7 (22%)
4 (19%)
3 (27%)
0.67
Pneumothorax
3 (9%)
1 (5%)
2 (18%)
0.27
Disseminated intravascular coagulation
3 (9%)
2 (10%)
1 (9%)
>0.99
Brain death
3 (9%)
2 (10%)
1 (9%)
>0.99
Pulmonary hemorrhage
3 (9%)
2 (10%)
1 (9%)
>0.99
Survival until decannulation
14 (44%)
9 (43%)
5 (45%)
0.86
Survival until ICU transfer
13 (41%)
8 (38%)
5 (45%)
0.72
Survival until hospital discharge
13 (41%)
8 (38%)
5 (45%)
0.72
Complications
22
Figure Legend Figure 1. Kaplan-Meier plot of patients with septic shock receiving extracorporeal membrane oxygenation. The x-axis is days from cannulation. The shaded area represents the 95% confidence limits. The plus sign represents patients who are censored, ie. alive at discharge. The patients at risk over time are shown along the bottom row.
23