Mild volume acute normovolemic hemodilution is associated with lower intraoperative transfusion and postoperative pulmonary infection in patients undergoing cardiac surgery -- a retrospective, propensity matching study

In China, blood shortage is now becoming an important public health concern, and the lack of adequate blood donation is considered to be the main cause [1]. Perioperative allogenic transfusion is required in about 50% of patients undergoing cardiac surgery [2], but it is associated with higher risk of mortality and morbidity (infection, lung injury, renal failure, and stroke) [3‐5]. Hence, many blood conservation techniques are recommended of which acute normovolemic hemodilution (ANH) may be considered as an adjuvant in appropriate patients [2].

Thus far, no consensus has been achieved in the results of published studies on ANH. Many trials have confirmed the positive effects of ANH in reducing perioperative allogeneic transfusions [6, 7]; however, other studies have reported negative effects [8, 9]. Another important debated point is the degree of ANH performed. Some authors consider that only a large volume of ANH is useful or effective in minimizing the need for allogeneic transfusions [7, 10]; however, Kahraman et al. observed no differences between the effect of mild and high volume of ANH on postoperative bleeding and perioperative blood transfusions [11]. Furthermore, there may be a risk of performing moderate or severe ANH in patients with a lower preoperative hematocrit level in cardiac surgery with cardiopulmonary bypass (CPB) which would lead to hemodilution [12].

There is also an increasing concern about the improved outcomes associated with ANH [7, 13, 14]; the safety of ANH still remains uncertain [15]. We performed this study to assess the relationship between mild volume ANH, perioperative transfusions, and outcomes in Chinese patients undergoing cardiac surgery.

Descriptive analyses of variables were used to summarize data. The normal distributed variables were expressed as mean ± standard deviation (SD) and compared with student t-test. Abnormal continuous variables were expressed as median (interquartile range (IQR)) and evaluated with Mann-Whitney U-test.respectively. Chi-square or Fisher’s exact test was used to compare proportions between the two groups. Missing continuous variables of baseline parameters were less than 10% and were replaced by median in Table 1. All reported p values were two sided, and values of p < 0.05 were considered to be statistically significant. Statistical analysis was performed with SPSS version 18.

To minimize the effect of selection bias on outcomes, we used propensity score matching for clinical characteristics to reduce distortion by confounding factors. Using propensity score analysis by the method of nearest-neighbor matching, we generated a set of matched cases (ANH) and controls (non-ANH). According to the propensity score matching, 354 pairs of patients were identified for postoperative analysis. A propensity score was generated for each patient from a multivariable logistic regression model on the basis of the covariates using clinical characteristics data (Table 1) from the institutional registry as independent variables, with treatment type (ANH vs. Non-ANH) as a binary dependent variable. We matched patients using a greedy-matching algorithm with a caliper width of 0.1 of the estimated propensity score. A matching ratio of 1:1 was used. We evaluated post match covariate balance by comparing the balance of baseline covariates between patients with ANH and non-ANH before and after matching using absolute standardized differences [20].

In our retrospective analysis of patients undergoing cardiac surgery with CPB, we found that mild volume ANH was associated with decreased intraoperative RBC transfusions rate and number of RBC units after data adjustment for preoperative risk factors. However, there was no significant difference regarding postoperative and total perioperative allogeneic transfusions. Our results further supported previous findings that the use of ANH could reduce intraoperative RBC transfusions in patients undergoing cardiac surgery [6, 7, 21], even though blood loss was similar between the ANH and non-ANH groups in our study. Some meta-analysis also supported that ANH is effective in minimizing blood transfusion in patients undergoing cardiac surgery [15, 22].

However, the utility of mild volume ANH in reducing allogeneic blood transfusions in cardiac surgery is still controversial. Several studies have proved that mild volume ANH was not effective in reducing the number of allogeneic erythrocytes units [8, 23], but others have proven otherwise [6]. Our results support the positive finding that mild volume ANH could reduce intraoperative blood transfusions. The variations in blood saving strategy and surgery type may be the major reasons for our finding being different from other studies. Although Valter Casati et al.’s study did not find positive efficacy of low-volume ANH [8], we noticed that there was a decreasing trend of intraoperative RBC transfusions in the ANH group compared to non-ANH group (4.9% vs. 7%). Another potential reason was that their case mix was easier (over 50% were single valve surgeries), which leads to less blood loss and transfusions. However, more than 38.7% of the surgeries in our cohort were complex cardiac and aortic surgeries, resulting in that more patients required intraoperative RBC transfusions in both the ANH and non-ANH groups (8.5 and 14.4%). Another point to be noted is that the cell saver technique was routinely applied in our study as a previous study reported that combination of cell saver with ANH produced better blood saving effect than ANH alone [24]. Another previous study of Alireza Mahoori et al. on exclusively elective coronary artery bypass graft (CABG) surgery patients [6] found that mild volume ANH could decrease requirements of total perioperative RBC transfusions. We failed to observe the similar positive effect of mild volume ANH on total perioperative RBC transfusions, this variation may mainly due to the different volumes of blood removed (342 vs. 490 mL) and transfusion triggered criteria between our study and Alireza Mahoori^’s study (hemoglobin concentration <6–7 g/dL vs. <10 g/dL). The less strict transfusion triggered criteria in Alireza Mahoori^’s study may lead to more transfusions rate compared to our cohort (57% vs. 27%).

Although ANH has been proved to reduce postoperative allogenic blood transfusions during cardiac surgery [7], our study failed to show these positive findings. A comprehensive blood saving strategy including antifibrinolytic agent [25] and TEG [26] has been applied and was demonstrated to reduce transfusion requirements. Thus the evidence of ANH may be less effective. The mild volume of ANH may also contribute to the less beneficial blood conservation effect, as Joshua Goldberg found that the reduction in allogeneic transfusions is more significant with greater volume ANH (≥800 mL) in cardiac surgery [7].

There is not much evidence regarding clinical outcome benefits of mild ANH in patients undergoing cardiac surgery. A recent article found that ANH was related to improved outcomes including renal failure, 30-day mortality, and length of hospital stay [7], and moderate ANH provided further cardioprotective effects during cardiac surgery [13, 14]. However, some other authors mentioned that greater hemodilution might be associated with adverse complications, especially in patients with preexisting coronary disease [27]. In another study of patients undergoing pancreaticoduodenectomy, ANH did not seem to decrease blood transfusions, but lead to more pancreatic anastomotic complications for greater intraoperative fluid administration [28]. Some authors criticize ANH for the possibly of causing perioperative adverse outcomes including damaged pulmonary function for increased lung fluid volume [8]. Furthermore, a recent study even found that after moderate ANH, patients undergoing total hip arthroplasty showed a hypocoagulable state [29].

Although we did not observe the positive effect of ANH regarding mortality, stroke, AF, AKI, and resternotomy for postoperative bleeding, our findings suggest that mild volume ANH might be associated with lower incidence of pulmonary infection. Some possible mechanisms may contribute to this protective effect. First, the indirect effect of reducing the rate of RBC transfusions may improve outcomes. RBC transfusions could increase postoperative pneumonia in patients undergoing CABG surgery [17]. Second, ANH blood was associated with a smaller concentration of inflammatory mediators such as interleukin-10 and neutrophil elastase than predonated autologous blood [30]. Third, due to the hemodilution-induced blood viscosity, such protection might be associated with an improved oxygen supply-consumption balance [14]. More evidence is needed to confirm the positive effect of mild volume ANH on cardiac surgery outcomes, including pulmonary complication.

In conclusion, in our large retrospective study, mild volume ANH was associated with lower intraoperative RBC transfusions and postoperative pulmonary infection in Chinese patients undergoing cardiac surgery. However, there was no significant difference regarding postoperative and total perioperative allogeneic transfusions. Further prospective and randomized studies are needed to confirm the effects of mild volume ANH on perioperative outcomes during cardiac surgery.