Original Contribution

Sex-Specific Outcomes of Patients Treated With Extracorporeal Cardiopulmonary Resuscitation

Bernhard Wernly, MD, PhD1,2; Sandra Büter, MD3; Maryna Masyuk, MD3; Diyar Saeed, MD4,5; Alexander Albert, MD4,6; Georg Fuernau, MD7; Hug Aubin, MD4; Malte Kelm, MD3; Ralf Westenfeld, MD3; Christian Jung, MD, PhD3,6

Bernhard Wernly, MD, PhD1,2; Sandra Büter, MD3; Maryna Masyuk, MD3; Diyar Saeed, MD4,5; Alexander Albert, MD4,6; Georg Fuernau, MD7; Hug Aubin, MD4; Malte Kelm, MD3; Ralf Westenfeld, MD3; Christian Jung, MD, PhD3,6

Abstract: Introduction. Patients after cardiac arrest (CA) treated with extracorporeal cardiopulmonary resuscitation (eCPR) evidence high mortality. Recently, women were reported to evidence even worse outcomes after CA. However, sex-specific data on CA patients treated with eCPR are lacking. We therefore aimed to evaluate potential sex differences in risk distribution, management, and outcomes in patients treated with eCPR. Methods. Sixty-four patients — 16 females (25%) and 48 males (75%) — were included in this retrospective analysis. Two propensity scores were calculated on sex using multivariable logistic regression. Propensity score 1 included baseline characteristics only, and propensity score 2 included the previous variables plus pH as well as lactate concentration. Univariable and multivariable logistic regression models were used to assess associations with the endpoints. Results. The distribution of risk factors and baseline characteristics showed no sex-specific differences. Sex was neither associated with mortality nor with bad neurological outcomes, and remained so after adjustment for both propensity scores. Baseline lactate (adjust odds ratio [aOR], 1.18; 95% confidence interval [CI], 1.02-1.38; P=.03), lactate after 6 hours (aOR, 1.23; 95% CI, 1.04-1.45; P=.01), and lactate clearance at 6 hours (aOR, 0.979; 95% CI, 0.959-0.999; P=.04) were independently associated with 30-day mortality. Higher lactate clearance after 6 hours was associated with lower rates of bad Glasgow Outcomes Scale both in univariable (OR, 0.967; 95% CI, 0.941-0.991; P=.02) and multivariable logistic regression models (aOR, 0.967; 95% CI, 0.941-0.994; P=.02). Conclusion. There were no sex-specific outcome differences in patients treated with eCPR. Both lactate concentration and lactate clearance could help with the selection of patients for inclusion in eCPR trials. 

J INVASIVE CARDIOL 2020 July 10 (Epub Ahead of Print).

Key words: CPR, gender-specific outcomes, sex-specific data


Patients after cardiac arrest (CA) evidence high mortality and high morbidity in survivors.1 Efforts to improve outcomes of patients undergoing cardiopulmonary resuscitation (CPR) by promoting early defibrillation, immediate bystander CPR, and optimization of the rescue chain were undertaken.2 However, the mortality rates of CA patients after CPR declined only minimally.3 

Therefore, hope was put into mechanical circulatory support (MCS) in the setting of ongoing CPR and refractory CA, and extracorporeal CPR (eCPR) has been shown to be associated with decreased mortality rates at least for in-hospital CA (IHCA).4 Parameters of the microcirculation, but also end-organ perfusion and microcirculation, are improved in patients treated with eCPR.5,6 Therefore, guidelines recommend the consideration of eCPR application in the setting of refractory CA.7 However, large randomized trials are lacking and in a review of the available evidence, the mortality rate of patients treated with eCPR was at a sobering 78%.8 Recently, a large registry-based study failed to show improved outcomes in CA patients with vs without eCPR application.9

Several factors, such as early diagnosis of CA, bystander CPR, and treatment of critical coronary vessel stenosis or occlusion, were described to be associated with favorable outcomes after CA.10 We and others could consistently show that lactate concentration is likely predictive for mortality and neurological outcomes.11,12 In a recent analysis, Blom et al found lower rates of bystander CPR, initial shockable rhythm, and hence, survival in women suffering from CA compared with men.13 Sex disparities might, therefore, influence outcomes in CA patients. For other MCS devices used in the setting of cardiogenic shock (CS), such as Impella, sex-specific analyses were conducted but showed inconsistent results.14-18 However, to our knowledge, a sex-specific analysis in patients treated with eCPR is lacking. Therefore, we aimed to compare sex-specific distributions of risk factors, management, and outcomes both in an unadjusted and adjusted retrospective analysis of a European registry of patients treated with eCPR for refractory CA. 

Methods

Study population. Sixty-four total patients — 16 females (25%) and 48 males (75%) — with complete data on in-hospital/out-of hospital cardiac arrest (IHCA and OHCA), 30-day-mortality, and lactate concentration at baseline receiving eCPR after CA were retrospectively included in this analysis, which was partially published elsewhere in another context.12 The local institutional ethics boards approved the study (Jena, #2081; Duesseldorf, #5194) and no patient consent was needed in this retrospective study. Patients were treated with eCPR and included in this registry based on the treating physician’s discretion. Based on guidelines, patients were deemed eligible for eCPR after CPR for >20 minutes without return of spontaneous circulation. Clinically evident irreversible neurological damage, malignant comorbidities, and an initial pH below 7.0 were clinical contraindications for eCPR application based on local policy. Three different eCPR systems have been implemented: Biocal 370 (Medtronic), Lifebridge (Zoll Lifebridge), and Sorin Lifebox (Sorin Group). Each system comprises a centrifugal pump, membrane oxygenator, heat exchanger, and bypass cannulas.

Statistical analysis. Continuous variables were expressed as mean ± standard deviation, and compared using analysis of variance (ANOVA). Categorical data were compared using Chi-square testing. The primary endpoint was 30-day mortality; the secondary endpoints included bad neurological outcomes and major bleeding complications. The neurological outcome, as assessed by Glasgow Outcome Scale (GOS), was pooled in two groups: 1, 2, and 3 (bad GOS), and 4 and 5 (good GOS). Two propensity scores were calculated on sex using multivariable logistic regression. The propensity score 1 included OHCA vs IHCA, bystander CPR, ventricular fibrillation at presentation, acute myocardial infarction, age, and body mass index (BMI). Propensity score 2 included the previous variables plus pH and lactate concentration. Univariable and multivariable logistic regression models were used to assess associations with the endpoints.  

Results

Baseline characteristics. Male and female patients were of similar age and BMI. The rates of bystander CPR were low and similar in both sexes (13% vs 13%; P>.99). The rates of patients with OHCA were not dissimilar between males and females (44% vs 31%, respectively; P=.56). The baseline characteristics are provided in Table 1.

Outcomes and management. The rates of pacemaker implantations (23% vs 31%; P=.52), therapeutic hypothermia (40% vs 25%; P=.38) and initiation of hemofiltration (31% vs 31%; P>.99) were similar between males and females, respectively. In the unadjusted analysis, rates of major bleeding complications (10% vs 13%; P>.99) and limb ischemia (8% vs 13%; P=.64) did not show sex-specific outcome differences.

The mortality was high (80%), but similar between sexes (77% in males vs 88% in females; P=.49) (Figure 1A). Sex remained non-associated with mortality after correction for both propensity score 1 (adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 0.37-10.01; P=.43) and propensity score 2 (aOR, 1.55; 95% CI, 0.28-8.49; P=.62). The rates of good GOS were low in both groups receiving eCPR (15% for males vs 13% for females; P>.99) (Figure 1B). After adjustment for both propensity score 1 (aOR, 1.12; 95% CI, 0.20-6.17; P=.90) and propensity score 2 (aOR, 0.92; 95% CI, 0.16-5.48; P=.93), sex was not associated with higher odds for bad GOS. 

The lactate concentration at baseline (OR, 1.17; 95% CI, 1.02-1.36; P=.03) and after 6 hours (OR, 1.23; 95% CI, 1.04-1.45; P=.02) was associated with higher odds and lactate clearance after 6 hours (reduction in odds per % increase in lactate clearance: OR, 0.980; 95% CI, 0.960-0.999; P=.04) with lower odds of 30-day mortality. These associations remained independent after forcing propensity score 1 and sex in a multivariable logistic regression model for baseline lactate (aOR, 1.18; 95% CI, 1.02-1.38; P=.03), lactate after 6 hours (aOR, 1.23; 95% CI, 1.04-1.45; P=.01), and lactate clearance at 6 hours (aOR, 0.979; 95% CI, 0.959-0.999; P=.04).

In univariable logistic regression, higher baseline lactate (OR, 1.20; 95% CI, 1.01-1.43; P=.04) and higher lactate after 6 hours (OR, 1.33; 95% CI, 1.04-1.70; P=.03) were associated with higher odds for bad GOS. These associations of baseline lactate (aOR, 1.22; 95% CI, 1.01-1.47; P=.04) and 6-hour lactate (aOR, 1.32; 95% CI, 1.04-1.69; P=.02) remained independent after correction for sex and propensity score 1 in multivariable analysis. Higher lactate clearance after 6 hours was associated with lower rates of bad GOS, both in univariable (OR, 0.967; 95% CI, 0.941-0.991; P=.02) and multivariable logistic regression models (aOR, 0.967; 95% CI, 0.941-0.994; P=.02).

Discussion

In this retrospective analysis, the distribution of baseline risk factors was equal between sexes. There were no differences, either in crude mortality or in good neurological outcomes between male and female patients receiving eCPR. Lactate concentration at baseline and after 6 hours, as well as early lactate clearance, were independently associated with 30-day mortality and neurological outcome.

The survival and neurological outcomes in patients with CA leave room for vast improvement, even after significant efforts to improve early management, including public health advances in CA patients.8,9 The situation is thus far comparable with CS, as in both conditions, conservative medical management did not significantly improve the often-catastrophic outcomes.19,20 Therefore, great hope was put into the applications of MCS devices. However, in both CS as well as in CA, MCS failed to consistently produce superior outcomes compared with medical treatment alone.21,22 However, given the high rates of patients with irreversible end-organ damage, most often of neurological origin, prior to MCS application, the patient selection issue came into the spotlight. Therefore, subgroups with distinct outcomes need to be identified to tailor future randomized trials in the setting of CS and eCPR.

Lactate concentrations, as well as dynamics in lactate concentration, are well-established predictors of mortality in distinct shock etiologies.23 We and others have previously shown that lactate concentrations predicted outcomes in patients on eCPR.12,24 This study confirms these previous findings, as both lactate and lactate dynamics were independently associated with both mortality and neurological outcomes. Of note, for this sex-specific analysis, we forced sex in the multivariable analysis and found lactate concentrations predictive for outcomes independent of sex.

A deeper understanding could help to improve outcomes in cardiovascular patients.25 In patients with CS, few studies reported sex-specific outcomes in the setting of MCS. Shah et al reported higher rates of 30-day readmission in male compared with female CS patients.17 In CS patients receiving Impella, several studies indicate sex-specific outcomes. Abaunza et al found female sex, along with CS, to be associated with higher vascular complication rates in patients receiving Impella for high-risk interventional cardiac interventions.14 Recently, Doshi et al reported higher rates of secondary outcomes, but similar mortality rates in male and female patients receiving MCS for high-risk PCI.26 In a recent sex-specific analysis of the cVAD registry, Alraies et al found women undergoing high-risk percutaneous intervention to be older and have more concomitant diseases, but to have similar outcomes compared with men.15 In another study on CS patients receiving Impella and undergoing percutaneous intervention, no differences between sexes could be found.16 Generally, in CS patients, early MCS is proposed to be associated with favorable outcomes, although randomized data are lacking.27 Interestingly, Joseph et al reported that early Impella application might yield an even more significant benefit in women suffering from CS.18 

A recent analysis by Blom et al, who showed higher rates of bystander CPR and survival, but also initial shockable rhythm in men compared with women in a large registry reporting data of OHCA patients, served as a wake-up call for more sex-specific investigations.13 In our analysis of patients treated with eCPR, no sex differences in management or outcomes could be observed. Most likely, other more potent factors, such as irreversible neurological damage, full-blown post-CA systemic inflammation response syndrome, and already established end-organ damage, might dilute potential sex-specific outcomes in the selected patient collective of patients treated with eCPR. Of note, in this study, no differences in rates of bystander CPR or other CA management could be observed. However, in comparison with the recent study by Blom et al, our study might be prone to sex-specific bias, as we have no information on “screened” patients vs included patients.13 In our study, no sex differences in management and outcomes after eCPR application were observed. However, future studies reporting data on an all-comer CA patient population evaluated for eCPR would be of utmost interest to further evaluate potential sex differences in both OHCA and IHCA patients. Although no sex differences could be found in this study, we agree that further sex-specific research in cardiovascular medicine is warranted.25

Study limitations. This retrospective post hoc analysis of a two-center German registry has several limitations that need to be acknowledged. First, only patients with complete datasets on relevant baseline demographics were included in this analysis to enable propensity-score adjustment and sex-specific outcomes. These exclusions might make our analysis prone to selection bias. Second, the total patient number is low and might be underpowered to detect subtle outcome differences between sexes. Third, as already discussed above, the initial inclusion process in this study could specifically be prone to sex bias. As only patients fulfilling the inclusion criteria were included in this registry, we cannot exclude that an all-comer population of CA patients evidenced sex-specific outcome differences. We underscore that such an investigation would be of utmost interest and importance to rule out sex bias in MCS applications. However, for a recent registry reporting data on CA patients, no such signal was described.9 

Conclusion 

There were no sex-specific outcome differences in patients treated with eCPR. However, both lactate concentration and lactate clearance could help with the selection of patients for inclusion in eCPR trials. 


From the 1Department of Cardiology, Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Salzburg, Austria; 2Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 3Division of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 4Division of Cardiovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Medical Faculty, Division of Cardiovascular Surgery; 5Department of Cardiovascular Surgery, Heart Center Leipzig at University of Leipzig, Leipzig, Germany; 6Department of Cardiovascular Surgery, Klinikum Dortmund, Dortmund, Germany; 7University Heart Center Lübeck, Clinic for Internal Medicine/Cardiology/Angiology/Intensive Care Medicine, Lübeck, Germany; and 8the Department of Internal Medicine and Department of Cardiology, Friedrich-Schiller-University Jena, Jena, Germany.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kernly reports grant support from Philips, Abbott Vascular, Medtronik, Boston Scientific, Mars, Boehringer Ingelheim, Amgen, and B. Braun; personal fees from Daiichi-Sankyo, Amgen, and Ancora Heart. Dr Jung reports grant support from Bayer Healthcare, Vifor Pharma, and Medicure Pharma; personal fees from Bayer Healthcare, Vifor Pharma, Bristol Meyer Squibb, Boston Scientific, Boehringer Ingelheim, Novartis, and Orion Pharma. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 22, 2020, provisional acceptance given January 29, 2020, final version accepted February 4, 2020.

Address for correspondence: Christian Jung, MD, PhD, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Email: christian.jung@med.uni-duesseldorf.de

References
  1. Jung C, Janssen K, Kaluza M, et al. Outcome predictors in cardiopulmonary resuscitation facilitated by extracorporeal membrane oxygenation. Clin Res Cardiol. 2016;105:196-205.
  2. Girotra S, Nallamothu BK, Spertus JA, et al; the American Heart Association. Get with the guidelines-resuscitation I. Trends in survival after in-hospital cardiac arrest. N Engl J Med. 2012;367:1912-1920.
  3. Leick J, Liebetrau C, Szardien S, et al. Door-to-implantation time of extracorporeal life support systems predicts mortality in patients with out-of-hospital cardiac arrest. Clin Res Cardiol. 2013;102:661-669.
  4. Avalli L, Maggioni E, Formica F, et al. Favourable survival of in-hospital compared to out-of-hospital refractory cardiac arrest patients treated with extracorporeal membrane oxygenation: an Italian tertiary care centre experience. Resuscitation. 2012;83:579-583.
  5. Jung C, Ferrari M, Gradinger R, et al. Evaluation of the microcirculation during extracorporeal membrane-oxygenation. Clin Hemorheol Microcirc. 2008;40:311-314.
  6. Jung C. Assessment of microcirculation in cardiogenic shock. Curr Opin Crit Care. 2019;25:410-416.
  7. Neumar RW, Shuster M, Callaway CW, et al. Part 1: executive summary: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132:S315-S367.
  8. Ortega-Deballon I, Hornby L, Shemie SD, Bhanji F, Guadagno E. Extracorporeal resuscitation for refractory out-of-hospital cardiac arrest in adults: a systematic review of international practices and outcomes. Resuscitation. 2016;101:12-20.
  9. Bougouin W, Dumas F, Lamhaut L, et al; Sudden Death Expertise Center Investigators. Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study. Eur Heart J. 2020;41:1961-1971. 
  10. Ha TS, Yang JH, Cho YH, et al. Clinical outcomes after rescue extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest. Emerg Med J. 2017;34:107-111.
  11. Dennis M, McCanny P, D’Souza M, et al. Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest: a multicentre experience. Int J Cardiol. 2017;231:131-136.
  12. Jung C, Bueter S, Wernly B, et al. Lactate clearance predicts good neurological outcomes in cardiac arrest patients treated with extracorporeal cardiopulmonary resuscitation. J Clin Med. 2019;8:374.
  13. Blom MT, Oving I, Berdowski J, van Valkengoed IGM, Bardai A, Tan HL. Women have lower chances than men to be resuscitated and survive out-of-hospital cardiac arrest. Eur Heart J. 2019;40:3824-3834.
  14. Abaunza M, Kabbani LS, Nypaver T, et al. Incidence and prognosis of vascular complications after percutaneous placement of left ventricular assist device. J Vasc Surg. 2015;62:417-423.
  15. Alraies MC, Kaki A, Kajy M, et al. Sex-related difference in the use of percutaneous left ventricular assist device in patients undergoing complex high-risk percutaneous coronary intervention: insight from the cVAD registry. Catheter Cardiovasc Interv. 2019 Oct 19 (Epub ahead of print).
  16. Doshi R, Patel K, Decter D, Jauhar R, Meraj P. Gender disparities with the use of percutaneous left ventricular assist device in patients undergoing percutaneous coronary intervention complicated by cardiogenic shock: from pVAD Working Group. Indian Heart J. 2018;70(Suppl 1):S90-S95.
  17. Shah M, Patel B, Tripathi B, et al. Hospital mortality and thirty day readmission among patients with non-acute myocardial infarction related cardiogenic shock. Int J Cardiol. 2018;270:60-67.
  18. Joseph SM, Brisco MA, Colvin M, et al. Women with cardiogenic shock derive greater benefit from early mechanical circulatory support: an update from the cVAD registry. J Interv Cardiol. 2016;29:248-256.
  19. Mebazaa A, Combes A, van Diepen S, et al. Management of cardiogenic shock complicating myocardial infarction. Intensive Care Med. 2018;44:760-773. Epub 2018 May 16.
  20. Feistritzer HJ, Desch S, de Waha S, Jobs A, Zeymer U, Thiele H. German contribution to development and innovations in the management of acute myocardial infarction and cardiogenic shock. Clin Res Cardiol. 2018;107:74-80.
  21. Wernly B, Seelmaier C, Leistner D, et al. Mechanical circulatory support with Impella versus intra-aortic balloon pump or medical treatment in cardiogenic shock-a critical appraisal of current data. Clin Res Cardiol. 2019;108:1249-1257.
  22. Ouweneel DM, Schotborgh JV, Limpens J, et al. Extracorporeal life support during cardiac arrest and cardiogenic shock: a systematic review and meta-analysis. Intensive Care Med. 2016;42:1922-1934.
  23. Masyuk M, Wernly B, Lichtenauer M, et al. Prognostic relevance of serum lactate kinetics in critically ill patients. Intensive Care Med. 2019;45:55-61.
  24. Lee WC, Fang CY, Chen HC, et al. Associations with 30-day survival following extracorporeal membrane oxygenation in patients with acute ST segment elevation myocardial infarction and profound cardiogenic shock. Heart Lung. 2016;45:532-537.
  25. Luscher TF. Cardiovascular issues in women: expanding diversity in medicine. Eur Heart J. 2019;40:3807-3811.
  26. Doshi R, Singh A, Jauhar R, Meraj PM. Gender difference with the use of percutaneous left ventricular assist device in patients undergoing complex high-risk percutaneous coronary intervention: from pVAD Working Group. Eur Heart J Acute Cardiovasc Care. 2019;8:369-378.
  27. Flaherty MP, Khan AR, O’Neill WW. Early Initiation of Impella in acute myocardial infarction complicated by cardiogenic shock improves survival: a meta-analysis. JACC Cardiovasc Interv. 2017;10:1805-1806.
/sites/invasivecardiology.com/files/articles/images/Wernly%20JIC%202020%20Jul%2010%20AOP%20wm.pdf