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a Department of Cardiothoracic and Vascular Anesthesia and Intensive Care Unit, IRCCS Policlinico S. Donato, Milan, Italy
b Department of Cardiac Surgery, IRCCS Policlinico S. Donato, Milan, Italy
c Scientific Directorate, IRCCS Policlinico S. Donato, Milan, Italy
Accepted for publication July 30, 2009.
* Address correspondence to Dr Ranucci, Department of Anesthesia and Intensive Care, IRCCS Policlinico S. Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy (Email: cardioanestesia{at}virgilio.it).
| Cardiothoracic anesthesiology:
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentReferences |
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Methods: A consecutive series of 3,003 patients was analyzed. They had all undergone isolated coronary operations without receiving blood transfusions during their hospital stay. The preoperative hematocrit and the lowest hematocrit on cardiopulmonary bypass were analyzed in a multivariable model as predictors of major morbidity and operative mortality.
Results: After adjustment for the other explanatory variables, both the preoperative hematocrit and the lowest hematocrit on cardiopulmonary bypass were found to be independent risk factors for major morbidity, but not for operative mortality. However, low values of preoperative hematocrit were not associated with an increased morbidity, provided that the lowest hematocrit on cardiopulmonary bypass was maintained above 28%. Median values of the lowest hematocrit on cardiopulmonary bypass below 25% were associated with an increased major morbidity rate.
Conclusions: Excessive hemodilution during cardiopulmonary bypass is a risk factor for major morbidity even in the absence of blood transfusions. Techniques that aim to reduce the fall in hematocrit during cardiopulmonary bypass, including blood cardioplegia, may be useful, especially in patients with a low preoperative hematocrit.
In recent years, many articles have identified the value of the lowest hematocrit (HCT) on cardiopulmonary bypass (CPB) to be a determinant of morbidity and mortality after cardiac operations [1–9]. Among the various postoperative complications related to this, acute renal failure seems to be the most prevalent [3–6, 8], but a higher incidence of stroke [3, 9], low cardiac output [3, 7], and other organ dysfunction [1–3] were also found to be associated with the degree of hemodilution during CPB. However, the lowest HCT on CPB is closely dependent on the preoperative HCT and the degree of intraoperative hemodilution. Preoperative anemia is an independent risk factor for morbidity and mortality after cardiac operations, and specifically for coronary operations [10–14].
The consequence of low values of HCT before or during the operation is, of course, a higher risk of receiving allogeneic blood products during or after the operation. In fact, the preoperative HCT is the major determinant of transfusions in cardiac surgery [15–18]. Allogeneic blood transfusions are associated with an increased morbidity and mortality after cardiac operations [19–22].
Because of the correlation between the preoperative HCT, the lowest HCT on CPB, and the higher rate of transfusions, the specific role of each of the three factors in independently determining a poor outcome after cardiac operations is still unclear. The majority of the relevant studies did not account for the preoperative HCT as a determinant of the lowest HCT on CPB. Moreover, separating the role of anemia from the impact of allogeneic blood products is a difficult exercise, and although some authors applied sophisticated statistical techniques to account for this interaction [3, 7, 8, 14], clear conclusions are, as yet, unavailable.
The present study aims first, to verify if the preoperative HCT and the lowest HCT on CPB are independent risk factors for morbidity and mortality after isolated coronary operations, and second, to assess the relative contribution of the two factors in determining morbidity and mortality.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Clinical Management
All the patients were operated on under moderate hypothermia (34°C) and alpha-stat pH management. Roller or centrifugal pumps were used, with standard or biocompatible (heparin or phosphorylcholine treated) circuits and hollow-fiber oxygenators; the CPB circuit was primed with colloid solutions at variable volumes, ranging from 900 mL to 1,200 mL. No retroprime was used. Pump flow was set between 2.0 and 2.8 L · min-1 · m-2, according to the core temperature. Cardiac arrest was achieved with antegrade cold crystalloid cardioplegia or blood cardioplegia for patients with an ejection fraction less than 0.3. Hemofiltration during CPB was used to correct low values of HCT whenever feasible. During the operations in patients treated with conventional open CPB circuits, pericardial blood was collected into a reservoir and reinfused into the patient without being processed; conversely, this blood was not readmitted to the circulation in the patients treated with closed circuits, unless previously processed by a cell-saving device. After the operation and during the intensive care unit stay, mediastinal blood collected into a reservoir was not reinfused to the patients.
Data Collection
Two outcome variables were identified for the study: major morbidity, defined according to The Society of Thoracic Surgeons (STS) national database risk stratification subcommittee (one of the following: mechanical ventilation longer than 48 hours, surgical reoperation, mediastinitis, renal dysfunction or failure, stroke) and operative mortality (death in hospital or within 30 days of the operation after discharge). The renal morbidity endpoint was defined as acute postoperative renal insufficiency resulting in one or more of the following: an increase of serum creatinine to more than 2.0; 50% or greater increase in creatinine over baseline preoperative value; a new requirement for dialysis. Mortality after discharge was identified by a phone contact with the rehabilitation center accepting the patient, or with the patient or relatives when the patient was back home, after 30 days from the operation. The preoperative HCT (%) and the lowest HCT (%) on CPB were recorded and tested for any associations with the outcome variables.
Other variables collected were: age (years), sex, weight, body surface area, left ventricular ejection fraction (%), recent (within 90 days before surgery) myocardial infarction, unstable angina, serum creatinine value (mg/dL), chronic obstructive pulmonary disease, diabetes mellitus (on medication), previous cerebrovascular accident, previous vascular surgery, previous cardiac surgery, urgent procedure, CPB duration (minutes), lowest temperature (°C) on pump, use of blood cardioplegia, and use of ultrafiltration during CPB. Patients were stratified for mortality risk according to the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (23), and for transfusion risk according to the Transfusion Risk and Clinical Knowledge (TRACK) score (18).
Statistics
The univariate associations between the outcome variables and the preoperative and intraoperative risk factors were explored using a logistic regression analysis, producing an odds ratio (OR) and a 95% confidence interval (CI). Factors associated with the outcome variables (p < 0.1) were entered into a multivariable logistic regression analysis (stepwise forward) to identify the independent risk factors for major morbidity and mortality. The Hosmer-Lemeshow goodness-of-fit test was used to assess the calibration properties of the models. Correlation between continuous variables were assessed using a linear regression analysis with r2 correlation coefficient.
For graphical purposes, the patient population was divided into deciles according to the values of preoperative HCT and lowest HCT on CPB; spline curves were used for the graphical representation of the relationship between the predictors and the outcome variables.
To address the respective role of the preoperative HCT and the lowest HCT on CPB, a subgroup analysis was performed by dichotomizing the above variables according to the median value of the patient population.
Data in tables and figures are presented as the number (%), mean (SD), or median (interquartile range [IQR] and absolute range). All tests were two-sided. A p value less than 0.05 was considered to be significant for all statistical tests. Statistical calculations were performed using a computerized statistical program (SPSS 11.0, SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The postoperative outcome is reported in Table 2. There was a major morbidity rate of 2.3% and an operative mortality rate of 0.7%. Patients with major morbidity (70 cases) had a preoperative HCT of 38.9 ± 4 and a lowest HCT on CPB of 26.6 ± 3.5; patients with operative mortality (21 cases) had a preoperative HCT of 38.7 ± 4.8 and a lowest HCT on CPB of 26.5 ± 3.8; the other patients (2,933 cases) had a preoperative HCT of 40.4 ± 4 and a lowest HCT on CPB of 27.8 ± 3.5.
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The graphical relationship between the two predictors (preoperative HCT and lowest HCT on CPB) and the major morbidity rate is reported in Figures 1 and 2, for each decile of distribution of the independent variables, with spline curves.
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To address the respective effects of the preoperative HCT and the lowest HCT on CPB, four groups were created by dividing the patient population according to the median value. The resulting four groups were group I (preoperative HCT > 40% and lowest HCT > 28%), group II (preoperative HCT 
40% and lowest HCT > 28%), group III (preoperative HCT > 40% and lowest HCT 28%), and group IV (preoperative HCT 40% and lowest HCT 28%). Because 112 patients were lacking the lowest HCT on CPB value, the total number of patients for this analysis is 2,891, not 3,003. Major morbidity and operative mortality rates are shown in Figure 3. There was no between-groups difference for operative mortality; major morbidity significantly (p = 0.021) differed between groups, with group IV having a significantly higher major morbidity rate than group I (p = 0.018). There was a significant difference (p < 0.001) between groups for the preoperative HCT and the lowest HCT on CPB; the difference between the two (delta HCT) was significantly different for group II versus the others and group III versus the others (see Table 5). No differences between any of the groups were detected for priming volume, CPB duration, and use of ultrafiltration during CPB. Patients in groups I and II received blood cardioplegia at a significantly higher rate than patients in groups III and IV (group I, 92 patients, 10%; group II, 40 patients, 11%; group III, 26 patients, 5%; group IV, 67 patients, 7%; p = 0.001 between groups I–II and III–IV). Other preoperative and operative factors were investigated for association with the degree of intraoperative hemodilution (delta HCT). The delta HCT was negatively associated with the body surface area, male sex, and left ventricular ejection fraction. These factors were entered into a multivariable model (logistic regression) to identify whether the group classification based on preoperative HCT and lowest HCT on CPB was independent predictor of major morbidity. After adjustment for these confounders, patients belonging to group IV still had a significant higher rate of major morbidity than patients in group I (p = 0.008) and group II (p = 0.045).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Our results demonstrate that the deleterious effects of preoperative anemia and hemodilution during CPB are independent of the possible interaction with allogeneic blood products transfusions. This information is relevant, as no clear conclusion can be drawn to date from the existing literature. Some of the first authors [1, 2] who highlighted the association between the lowest HCT on CPB and morbidity and mortality failed to consider transfusions within their models. Others [4] included the number of packed red cells transfused within their logistic regression model, and concluded that, despite the fact that transfusions and lowest HCT on CPB were intercorrelated, the lowest HCT on CPB remained an independent risk factor for an increase in peak postoperative creatinine value. This is a sound statistical approach, but the nature of the outcome variable (peak postoperative creatinine value) does not allow to clearly identify whether a serious postoperative renal dysfunction was present. Karkouti and coworkers [6] analyzed the more relevant renal outcome data represented by acute renal failure (necessitating renal replacement therapy). They demonstrated an increased risk of acute renal failure when values of the lowest HCT on CPB were either lower than 21% or higher than approximately 25%. In their analysis, a lowest HCT on CPB below 21% (severe hemodilution) was an independent risk factor for acute renal failure, in a model adjusted for excessive perioperative blood loss (five or more units of blood transfused on the day of the operation). Unfortunately, they limited their analysis to the transfusions on the day of the operation (which was less than 10% of their patient population), whereas the acute renal failure could have occurred at any postoperative point in time. Therefore, transfusions after the first day may have had a confounding effect. A similar potential bias can be found in the study of Habib and associates [3], who only considered intraoperative transfusions in their risk model. So, as the investigators admitted, the role of transfusions was not fully elucidated in their study, and the use of a more liberal transfusion policy during CPB is cited as a possible measure to limit the deleterious effects of hemodilution. However, in another study from the same group [8], the investigators could demonstrate that transfusions are not the answer to hemodilution, and may even worsen the problem. Recently, we performed a study addressing the roles of the lowest HCT on CPB and the lowest oxygen delivery on CPB on the development of acute renal failure (5). In this study, we identified the lowest HCT on CPB value of 26% as an independent risk factor for acute renal failure. However, after adjustment for transfusions (at any point in time), the lowest HCT on CPB lost significance in a multivariable model.
We believe that, despite statistical attempts to separate the consequences of a low HCT from those of transfusions, these two factors remain tightly correlated; moreover, it is difficult to analyze the time-related association between transfusions and the onset of the outcome event. Consequently, we decided to eliminate this complex interaction by only including nontransfused patients in our analysis. This approach allowed us to demonstrate that a low HCT before and during CPB is a risk factor per se for major morbidity.
There are many hypotheses that could interpret this result. Fundamentally, they are related to the link between poor oxygen delivery and organ dysfunction. A low oxygen delivery rate may be dangerous for many organs, such as the brain, heart, liver, kidneys, and gut. The kidney seems to be particularly prone to ischemia: severe hemodilution may induce renal injury by augmenting the local renal inflammatory response subsequent to an ischemia-reperfusion phenomenon, particularly in the hypoxic environment of the renal medulla [4]. In-vitro studies [24, 25] have demonstrated that a slight fall in renal oxygen delivery may cause ischemic injury in susceptible areas of the kidney. This could be offset by an increased renal blood flow in the presence of severe hemodilution, leading to increased work and oxygen needs, and a decrease in plasma oncotic pressure, leading to fluid accumulation in the interstitial space, capillary closure and reduced oxygen delivery [6].
Similar mechanisms can be hypothesized for other complications, including ischemic cerebral events. Indeed, damage to the brain and kidney has been repeatedly associated with severe hemodilution during CPB, and our major morbidity index includes stroke and acute renal failure.
The analysis of the respective roles of the preoperative HCT and the lowest HCT on CPB in determining a major morbidity offers further insights and clinical considerations. The only group that demonstrateds a significantly higher rate of major morbidity was group IV. The median value of the lowest HCT in this group was 25%. This value was previously identified as the cut-off for acute renal dysfunction [5, 6]. Patients in group III did not experience a significantly higher rate of major morbidity: in this group, the median value of lowest HCT on CPB was higher (27%) than in group IV. This finding leads to the conclusion that preoperative anemia may not cause major morbidity, provided that the lowest HCT on CPB was maintained at an acceptable value.
Patients with a preoperative HCT of 40% or less had rates of major morbidity similar to those of patients with a preoperative HCT greater than 40% when the lowest HCT on CPB was maintained above 28%. This information highlights the concept of hemodilution during CPB: patients in group II could avoid severe hemodilution during CPB because the delta HCT was significantly lower than in the other groups (8.2% versus 12% to 16%). Therefore, preoperative anemia could not be a risk factor provided that adequate measures were taken to avoid excessive hemodilution on CPB. These measures may include minimization of the priming volume of the circuit and oxygenator, a restrictive policy of fluid administration before and during CPB, the use of retroprime, the use of ultrafiltration during CPB, the use of blood cardioplegia, and the use of miniaturized, closed circuits.
There are some limitations to the present study. The first is strictly related to the study design: including only nontransfused patients means selecting a population at low-medium mortality risk. Consequently, the morbidity and mortality rates are low. It is possible that both the preoperative HCT and the lowest HCT on CPB had no impact on mortality because of the limited number of events observed. A second limitation is that all our patients received a low priming volume (a policy that we have adhered to over the last 15 years). Therefore, extreme levels of hemodilution during CPB were rare events. It is possible that the inclusion of a higher number of these cases may result in different levels of significance, and may have a clear impact on mortality. There were very few women in the sample, so these results may not apply to female patients. Finally, owing to the retrospective nature of our data, it is impossible to identify all the factors that led to different values of delta HCT. Because the CPB technique was the same in all patients in terms of priming volume, it is likely that other factors may have played a role, namely, the fluid management before and during CPB, possibly due to the different working practices and expertise of the anesthesiologists and perfusionists. Moreover, and again owing to the retrospective nature of the study, we could find associations, but we cannot claim causations.
In conclusion, the preoperative HCT is a morbidity risk factor in coronary operations only if it triggers a low value of HCT on CPB. The adoption of adequate measures to contain the intraoperative decrease of the HCT seems advisable, and it is important to comment that the use of blood cardioplegia produced a protective effect in our patient population.
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