Sex-Related Differences in Short-Term Outcomes after Mobile VA-ECMO Implantation: Five-Year Experience of an ECMO Retrieval Program

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) represents an increasingly used method for circulatory support. Despite the ongoing research, survival following VA-ECMO therapy remains low. Sex-related differences might impact the outcome of therapeutic measures. We aimed to compare all-cause mortality among female and male patients who underwent VA-ECMO as a bridge to recovery investigating sex-related differences. From January 2015 until August 2020, 87 patients were supported by VA-ECMO as a part of our out-of-center mobile ECMO program. In order to analyze sex-associated differences in early clinical outcomes, patients were divided into two sex categories: men (n = 62) and women (n = 25). All relevant data (in-hospital mortality, ICU and hospital stay, renal failure requiring dialysis, lung failure, bleeding, stroke and septic shock) were analyzed retrospectively after the extraction from our institutional database. Mean age of the study population was 53 ± 14 years. Mean EuroSCORE II predicted mortality was 6.5 ± 3.7. In-hospital mortality rate was not significantly lower in the female group (58.3%) vs. the male group (71.2%), p = 0.190. The mean length of ICU and hospital stay was 9 ± 11 in the male group vs. 10 ± 13 in the female group, p = 0.901, and 10 ± 12 (male group) vs. 11 ± 13 (female group), p = 0.909, respectively. Renal failure requiring hemodialysis (36.2% (males) vs. 28.6% (females), p = 0.187) was comparable between both groups. Respiratory failure was diagnosed in 31 (56.4%) male vs. 8 (34.8%) female patients, p = 0.068, while 16 (28.6%) male vs. 3 (13.0%) female patients (p = 0.118) suffered from septic shock. Based on our data, there were no sex-specific outcome discrepancies in patients treated with mobile VA-ECMO implantation.


Introduction
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) represents an increasingly used method for circulatory support. VA-ECMO in cardiogenic environments facilitates improvement of hemodynamic status and significant increase in tissue perfusion [1]. Despite the ongoing research, survival following VA-ECMO therapy remains low [2]. The impact of gender-related specifics on patients after VA-ECMO support is still controversially discussed [3]. However, gender-related differences might impact the outcome of therapeutic measures [2,3].
Several published studies demonstrated a significantly higher incidence of cardiopulmonary resuscitation and subsequent extracorporeal cardiopulmonary resuscitation in male patients [4,5]. In general, sex-based differences are known to influence the development of cardiac diseases [6]. Most studies on VA-ECMO have focused on outcomes [7][8][9], and several of them reported that approximately 50% of patients supported by VA-ECMO were male [10,11]. Furthermore, male patients undergo VA-ECMO implantation more frequently during catecholamine-refractory cardiogenic shock or low-cardiac-output-syndrome [12]. On the other side, authors have reported higher long-term survival rates in reproductive-aged women than in same-aged men [13].
Therefore, we aimed to compare all-cause mortality among female and male patients who underwent VA-ECMO as a bridge to recovery as part of our mobile ECMO program.

Materials and Methods
The study was designed as a retrospective single center nonrandomized analysis of mobile VA-ECMO cohort. Over a 5-year-and-8-month period, from January 2015 until August 2020, a total of 87 patients underwent mobile VA-ECMO therapy (Cardiohelp, Maquet, Rastatt, Germany). In order to analyze sex-associated differences in early clinical outcomes, patients were divided into two categories divided by sex. This study included 62 men and 25 women.

ECMO-Center Protocol
Our mobile ECMO program is organized as previously described [14,15]. ECMO therapy was initialized corresponding to Extracorporeal Life Support Organization (ELSO) guidelines for VA-ECMO implantation [16]. General clinical examination and transthoracic echocardiography (TTE) were used for an on-site ECMO evaluation. ECMO therapy was implemented at peripheral hospitals and by patients transported to our center.
Our anticoagulant protocol aimed for an activated clotting time (ACT) of 160-180 s and activated partial thromboplastin time (aPTT) of 60-80 s after intravenous infusion of unfractionated heparin to avoid potential thromboembolic events. In order to evaluate hemodynamic stability and possible weaning ability echocardiography, laboratory parameters and chest X-ray were performed. Moreover, heart function was evaluated daily using transesophageal echocardiography (TEE).
ECMO weaning was initialized after haemodynamic stabilization. ECMO flow rate was decreased by 100-200 mL/h. Moreover, lactate and urine output was assessed hourly. ECMO removal was feasible when TEE showed partial or full recovery under 2.0 L/min ECMO support without increasing lactate concentration in the blood and decreasing urine output. All patients assumed suitable for weaning underwent surgical explantation of ECMO cannulas.

Data Collection
All relevant data were analyzed retrospectively after extraction from our institutional database and were collected on standardized forms and entered into a computerized database. The variables evaluated included such parameters as: patient demographic (age, sex, BMI, EuroSCORE II), patients' status before ECMO support, laboratory parameter (creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count) and early outcome data (in-hospital mortality, ICU and hospital stay, renal failure requiring dialysis, lung failure, bleeding, stroke and septic shock).

Outcome Analysis
In this research we highlighted primary and secondary outcomes. The primary outcome in our study was in-hospital mortality after VA-ECMO therapy. Secondary outcome parameters were acute renal failure requiring dialysis, acute respiratory failure, bleeding, limb ischemia, septic shock, stroke, length of intensive care unit (ICU) and in-hospital stay.

Ethics
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of the Medical Faculty of the University of Cologne stated Life 2022, 12, 1746 3 of 10 that we are exempted from applying for ethical approval, as under German law no separate ethics application or statement of ethical approval by the local ethics committee are required for performing purely retrospective clinical studies.

Statistical Methods
Statistics was performed using Student's t-test or Mann-Whitney U test, each depending on whether continuous variables are normally distributed or not, and the chi-squared test was used for categorical variables (confidence internal for the difference of two means). Continuous variables are expressed as mean ± standard deviation (SD). Categorical variables are presented as percentage of the sample. Fisher exact test was performed when the minimum expected count of cells was <5. The optimal cut-off values were defined as the values that provided highest sensitivity and specificity. A p-value < 0.05 was considered to be significant. Statistical analysis was performed using Statistical Package for Social Sciences, version 28.0 (SPSS Inc., Chicago, IL, USA).
bleeding, limb ischemia, septic shock, stroke, length of intensive care unit (ICU) and in-hospital stay.

Ethics
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of the Medical Faculty of the University of Cologne stated that we are exempted from applying for ethical approval, as under German law no separate ethics application or statement of ethical approval by the local ethics committee are required for performing purely retrospective clinical studies.

Statistical Methods
Statistics was performed using Student's t-test or Mann-Whitney U test, each depending on whether continuous variables are normally distributed or not, and the chi-squared test was used for categorical variables (confidence internal for the difference of two means). Continuous variables are expressed as mean ± standard deviation (SD). Categorical variables are presented as percentage of the sample. Fisher exact test was performed when the minimum expected count of cells was <5. The optimal cut-off values were defined as the values that provided highest sensitivity and specificity. A p-value < 0.05 was considered to be significant. Statistical analysis was performed using Statistical Package for Social Sciences, version 28.0 (SPSS Inc., Chicago, IL, USA).

Discussion
In our study, we investigated sex-related differences regarding short-term outcomes after VA-ECMO therapy. According to our findings, sex has no impact on early outcomes after VA-ECMO therapy in patients after mobile ECMO implantation.
There is a lack of studies investigating the effect of sex on short-and long-term outcomes of patients who underwent VA-ECMO implantation [2,3,9,11]. In general several studies stated that female patients suffered from postoperative complications more often compared to men [17]. Likewise, women suffered more frequently from limb

Discussion
In our study, we investigated sex-related differences regarding short-term outcomes after VA-ECMO therapy. According to our findings, sex has no impact on early outcomes after VA-ECMO therapy in patients after mobile ECMO implantation.
There is a lack of studies investigating the effect of sex on short-and long-term outcomes of patients who underwent VA-ECMO implantation [2,3,9,11]. In general, several studies stated that female patients suffered from postoperative complications more often compared to men [17]. Likewise, women suffered more frequently from limb ischemia due to the anatomically smaller diameter of femoral vessels [18,19]. Smaller cannula sizes and an advanced cannulation technique could avoid such serious complications [3]. Moreover, female sex was an independent risk factor for haemorrhagic stroke among patients after VA-ECMO implantation due to cardiogenic shock [20]. Based on our data, no differences were obvious between male and female groups in contrast to the current literature.
Several studies showed an increased rate of end-organ failure in male patients compared to female patients [21]. Acute renal failure is a feared complication and affected up to 80% of patients under VA-ECMO support [22]. Thrombosis, bleeding and coagulopathy were the most common risk factors for acute kidney injury requiring dialysis [22,23]. An increased creatinine level was shown to be an independent predictor of mortality in extracorporeal cardiopulmonary resuscitation (eCPR) patients [2,23]. Neugarten et al. [24] (2018) showed that female gender might be protective in prevention of renal failure in patients on ECMO. Furthermore, Gaisendrees et al. [2] (2021) found that female gender was associated with significantly lower risk for renal failure requiring dialysis after eCPR. In contrast, we found no differences between both groups.
Our study showed no difference in stroke rates between female and male patients after VA-ECMO implantation. Likewise, various studies suggested that sex does not influence neurological outcomes in ECMO patients [25,26].
Moreover, we found no differences (p = 0.326) in acute hepatic failure between both groups. Similarly, Han et al. [25] stated no significant difference in extensive hepatic cell damage between male and female patients after eCPR. In contrast, further studies showed a significantly higher rate of liver damage in male patients compared to female ones [2,4,24,27]. On the contrary, we found a significantly higher rate of liver damage markers (AST (p = 0.004), ALT (p = 0.004)) in the male group. Moreover, we detected a significantly higher bilirubin level (p = 0.033) in the male group compared to the female group. Authors stated that hemolysis might be a responsible factor for elevated bilirubin level by patients on ECMO [28][29][30]. Moreover, Kaetner et al. [28] (2018) hypothesized that an elevated bilirubin level was a risk factor for a higher mortality rate after VA-ECMO implantation. Furthermore, authors highlighted that the increased bilirubin level (≥10mg/dL) and lactate (≥2.25 mmol/L) were associated with higher all-cause mortality [28]. Despite the significantly higher bilirubin rate (p = 0.033) in the male group, all-cause in-hospital mortality did not differ between both groups in our study. However, we could speculate that the similar mortality in male and female groups is related to the similar lactate level in both groups. Likewise, authors stated that all abovementioned risk factors (bilirubin and lactate) affect mortality, but only lactate showed a strong prognostic value [28,30].
Furthermore, female gender presented a significantly higher (p < 0.001) platelet count compared with male gender in our study. However, we found no significantly higher (p = 0.586) bleeding rate between both groups. Hermann et al. [31] (2019) stated that severe thrombocytopenia was associated with significantly higher (p < 0.001) risk for bleeding. Moreover, authors showed that bleeding events were more common than extracorporeal circuit clotting events [31]. Various studies showed that thrombocytopenia could subsequently increase the bleeding risk [32][33][34]. However, multiple further risk factors such as elderly age, central cannulation, delayed sternal closure and excessive anticoagulation were also associated with bleeding events [32,35]. Further studies showed that haemorrhagic complications due to thrombocytopenia and platelet dysfunction could increase the mortality rate to 17% [32,35,36].
Despite advances in perioperative management and use of modern technologies, allcause mortality after VA-ECMO implantation remains high [32,35,[37][38][39]. Based on our study, in-hospital all-cause mortality rate was 67.5% in patients who underwent mobile VA-ECMO implantation. Moreover, no significant differences (p = 0.190) in the mortality rate between both groups were found in our study. Likewise, an all-cause in-hospital mortality rate did not differ between male and female groups after VA-ECMO implantation in further studies [2,3,40].
Analyzing data from our study, differences in procedural techniques, surgeon experience, patient selection and perioperative care should be taken into account. Thus, further prospective randomized studies are needed in the future for more accurate sex-related analysis of end-organ damage and its correlation with short-, mid-and long-term results after VA-ECMO implantation.

Conclusions
Based on our data, sex does not affect short-term outcomes after VA-ECMO implantation. Mortality rates were almost the same in both groups (p = 0.190). Secondary outcome parameters (ICU (p = 0.901) and in-hospital stay (p = 0.909), renal failure requiring dialysis (p = 0.187), respiratory failure (p = 0.068), bleeding (p = 0.586), stroke (p = 0.320) and septic shock (p = 0.118)) did not significantly differ between male and female groups. However, prospective randomized trials are needed to investigate the impact of sex differences on short-, mid-and long-term outcomes after mobile VA-ECMO implantation.