To our knowledge, this is the first study reporting the incidence of postoperative vasoplegia associated with the implantation of different cfLVADs with their various effects on hemocompatibility and generating different flow profiles. Although there seems a tendency in a diminished incidence of vasoplegia in the centrifugal flow with artificial pulse group compared to axial flow, we showed that flow profiles are not an independent predictor of vasoplegia. In contrast to flow profiles, previous cardiothoracic surgery, the use of angiotensin II receptor blockers, preoperative bilirubin and creatinine, and the use of fresh frozen plasma were found to be independent predictors for postoperative vasoplegia.

There is increasing evidence that differences in hemocompatibility, shear stress on the endothelial wall, and the release of pro- and anti-inflammatory cytokines may contribute to the development of postoperative vasoplegia [13, 21,22,23,24]. Axial flow (HMII) is thought to be less hemocompatible compared to centrifugal flow with a hybrid magnetic/hydrodynamic impeller (HVAD) and compared to centrifugal flow with an intrinsic artificial pulse with rapid changes in rotor speed (HM3), because of more degradation of von Willebrand factor high-molecular-weight multimers, low-grade hemolysis, and cytokine release. An increase in shear stress on the endothelial wall, caused by the continuous flow generated by the cfLVAD, causes a release of nitric oxide (NO) by endothelial signaling mechanisms with an effect on actin–myosin filaments contributing to vasodilation and thus contributing to the development of vasoplegia [13, 22]. This raised the question whether the unique flow profiles are related to the occurrence of postoperative vasoplegia. Although the artificial pulse rate provided by the HM3 is slower (maximum 30–40 per min) than and asynchronous with the innate heart rhythm, and with a different flow profile than that generated by cardiac ejection itself, systolic and diastolic blood pressures and pulse pressures can be measured or calculated [10, 11].

In our retrospective cohort, flow profiles were not an independent predictor, although there might be a tendency of a lower incidence of vasoplegia in patients with a continuous flow with artificial pulse device. However, several patient and procedural characteristics may carry more significance in the occurrence of postoperative vasoplegia than flow profiles, such as male gender, lower preoperative systolic and diastolic blood pressures, lower preoperative hemoglobin levels, higher bilirubin and creatine levels with a lower GFR, and the medical treatment of end-stage heart failure.

Firstly, in this retrospective cohort, axial flow cfLVADs (HMII) were implanted from 2006 to 2016 (Figure 1b), the implantation of centrifugal flow cfLVADs (HVAD) started in 2010 in our hospital, and the first centrifugal flow with artificial pulse cfLVAD (HM3) implantation was in 2015, and both latter devices were implanted until the end of the inclusions. The size of the axial flow pump requires opening of the peritoneum for its implantation. The newer LVADs are smaller, and the extent of the implantation procedure is less. Together with an improved surgical experience and improved surgical techniques and perioperative care, this must have an impact on the extent and duration of the operation, perioperative bleeding, use of blood products, and the possibility of reoperation for tamponade and/or bleeding probably having a role in better early and long-term outcomes after cfLVAD implantation.

Secondly, the medical treatment of end-stage chronic heart failure has undergone changes in the past with the more frequent use of newer drugs, such as angiotensin II receptor blockers —sometimes in combination with sacubitril — instead of ACE inhibitors, and the more frequent use of aldosterone antagonists in more recently implanted patients. ACE inhibitors and angiotensin II receptor blockers may possibly contribute to postoperative vasoplegia causing a lower systolic vascular resistance [25]. As shown in Table 1, patients implanted with an axial flow pump used significantly more often ACE inhibitors compared to the other patients (p=0.002). On the contrary, patients who received a centrifugal flow cfLVAD with(out) artificial pulse used more often angiotensin II receptor blockers (p=0.013) and aldosterone antagonists (p=0.034).

Thirdly, significantly more patients implanted with a centrifugal flow cfLVAD with or without artificial pulse were classified as INTERMACS IV to VI compared to patients who received an axial flow pump as these were more often classified as INTERMACS I and II. So, patients receiving a centrifugal flow cfLVAD were operated on earlier in their disease process, preventing a stage with sliding on inotropes or even worse. Moreover, it was reported that preoperative IL-6 and CRP levels were higher in INTERMACS I patients scheduled for cfLVAD implantation, suggesting that patients with end-stage heart failure classified in a lower class of INTERMACS score (e.g., INTERMACS I or II) probably have a more pronounced disbalance in inflammatory biomarkers preoperatively with a probable worse outcome, such as vasoplegia and related early post-cfLVAD implantation complications, such as right ventricular failure and kidney failure [26].

Fourthly, patients who received an axial flow pump had a statistically significant lower preoperative hemoglobin level probably necessitating significantly more perioperative blood transfusion compared to patients who received a centrifugal flow cfLVAD with(out) artificial pulse. This higher demand of blood transfusion is thought to cause a release of cytokines such as TNF-α, IL-1, and TNF-γ. The longer red blood cell units are stored, the higher is the level of inflammatory cytokines in these units [27]. These cytokines might contribute to a release of NO which is a factor in the development of vasoplegia [23, 28].

Finally, there are still several unknown factors that might have an effect on the incidence of cardiac vasoplegia syndrome in these patients, such as the use or not use of corticosteroids, the use of pulsatile flow profiles during extracorporeal circulation, and the use of cell saving techniques. These factors may have an impact on changes in inflammatory biomarkers and postoperative vasoplegia.

In summary, postoperative cardiac vasoplegia is a complex process provoked by many factors: preoperative factors, intraoperative factors, and postoperative factors. In end-stage heart failure, important preoperative factors, such as the severity of end-stage heart failure (INTERMACS class) with concomitant liver and kidney failure, the use of vasodilatory drugs, previous cardiothoracic surgery, intraoperative factors, such as used medications, the duration of extracorporeal circulation and the administration of blood products, and postoperative factors, such as LVAD flow profiles and postoperative bleeding, all play a crucial role in this complex nature of cardiac vasoplegia syndrome. All these factors more or less come together sometimes resulting in early (eventually intraoperatively) cardiac vasoplegia syndrome or late cardiac vasoplegia syndrome in the ICU. This may have a concomitant effect on further organ failure with most often worse outcomes.

Patients with postoperative vasoplegia suffered from more postoperative complications compared to patients without postoperative vasoplegia. Affected patients were significantly longer mechanically ventilated, developed more often renal failure and right ventricular failure, and more often major bleedings and cardiac tamponade (supplemental table 5a). Moreover, patients with a bad RV function preoperatively had a higher chance of RV failure postoperatively in the vasoplegia group. Patients with vasoplegia have a lower blood pressure despite higher vasopressor dosages, with probably a higher chance on lower right coronary artery blood flow and thus a higher chance to develop postoperative RV failure.

Regarding longer term outcomes, patients with postoperative vasoplegia had a longer ICU and hospital length of stay and a higher ICU and in-hospital mortality (supplemental table 5a). Moreover, ICU length of stay, hospital length of stay, and 1-year mortality improved from axial flow to centrifugal flow to centrifugal flow with intrinsic artificial pulse, while there was no difference observed in ICU, in-hospital, and 30-day mortality (supplemental table 5b). It is uncertain if the flow profile itself counts for this improved outcome or that it is caused by the abovementioned pre- and intraoperative factors.

We evaluated the impact of the various flow profile cfLVADs on vasoplegia and related early postoperative outcomes. However, several limitations exist. First, some of the variables used for analysis were incomplete. The maximum missingness percentage was less than 3% per variable (supplemental table 1), and therefore, the bias is minimal. We used multiple imputations to deal with the missing data, so no patients were excluded for analysis. Due to the retrospective nature of the study, it was necessary to adjust for other important variables. An extensive set of clinical variables were included for analysis. Therefore, LASSO logistic regression was used to reduce the number of variables. However, possibly other unmeasured or unknown factors may have affected the risk of vasoplegia and thus outcomes.

Since both axial flow and the centrifugal flow cfLVADs are no longer available on the market, a prospective study in a larger multicenter study to evaluate the effect of axial and centrifugal flow profiles on vasoplegia itself and many confounders is no longer indicated. A deeper knowledge of the effect of flow profiles on vasoplegia may contribute to the development of newer cfLVADs, such as the Cleveland clinic continuous-flow total artificial heart (CFTAH) generating pulsatile flows by speed modulation in continuous-flow pumps [29, 30], the CorWave [31] (CorWave SA, Clichy, France), the Aeson TAH [32] (Carmat SA, Velizy-Villacoublay, France), Icoms flowmaker [33] (FineHeart, Sorigny, France), and EVAHEART®2 left ventricular assist device (EVA2) [34] (Evaheart Inc, Bellaire, TX, USA). It was suggested that pulsatility imitates the normal physiologic circulation with mechanical energy transmission to the vascular endothelium influencing cyclic endothelial shear stress and release of vasoactive molecules with improved end-organ microcirculation. Identifying perioperative specific biomarkers and cytokines in patients scheduled for cfLVAD implantation with different cfLVAD flow profiles may be of interest to assess the added value of pulsatility on the microcirculation.