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Ann Thorac Surg 2006;82:13-20
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Persistent Effect of Red Cell Transfusion on Health-Related Quality of Life After Cardiac Surgery

Colleen Gorman Koch, MD, MS a , * , Farah Khandwala, MS b , Liang Li, PhD b , Fawzy G. Estafanous, MD c , Floyd D. Loop, MD d , Eugene H. Blackstone, MD b , d

a Department of Cardiothoracic Anesthesia, The Cleveland Clinic Foundation, Cleveland, Ohio
b Department of Quantitative Health Sciences, The Cleveland Clinic Foundation, Cleveland, Ohio
d Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
c Division of Anesthesia and Critical Care, The Cleveland Clinic Foundation, Cleveland, Ohio

Accepted for publication July 25, 2005.

* Address correspondence to Dr Koch, Department of Cardiothoracic Anesthesia (G-3), 9500 Euclid Ave, Cleveland, OH 44195 (Email: kochc{at}ccf.org).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Although red blood cell transfusion has been associated with an increase in early morbid outcomes and reduced long-term survival after cardiac surgery, its relationship to functional quality of life after surgery has not been previously explored. Our objective was to investigate the relationship between perioperative red blood cell and component transfusion and functional health-related quality of life 6 to 12 months after cardiac surgery.

METHODS: Of 12,536 patients undergoing cardiac surgical procedures between May 1995 and January 1999, 7,321 completed a self-administered Duke Activity Status Index (DASI) survey preoperatively and least one follow-up survey at nominally 6 or 12 months postoperatively. The influence of baseline DASI, preoperative risk factors, clinical status, laboratory values, operative events, and postoperative morbidities on follow-up DASI were examined with ordinal regression modeling.

RESULTS: After adjustment for preoperative DASI, demographic, cardiac and noncardiac comorbidity, type of surgery, postoperative complications, and interval between follow-up DASI, during which patients continued to improve (p < 0.0001), postoperative functional status after cardiac surgery was incrementally worse the more perioperative red cells (p < 0.0001) and platelets (p = 0.02) that had been transfused.

CONCLUSIONS: Red blood cell and platelet transfusion have an unintended persistently negative risk-adjusted effect on health-related quality of life after cardiac surgery that extends well beyond initial hospitalization. Reductions in functional recovery paralleled increasing units of red blood cells transfused.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Transfusion of packed red blood cells (PRBC) has been associated with increased in-hospital morbidity and mortality after cardiac surgery [1–5]. Additionally, transfusion of PRBC has been associated with reduced survival, well beyond the accepted postoperative recovery phase for cardiac surgical procedures [5]. Our objective was to examine the impact of perioperative PRBC and component transfusion on functional health-related quality of life in a large cohort of patients after recovery from cardiac surgery.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Population and Data Collection
From May 1, 1995, through January 1, 1999, 12,536 patients underwent isolated coronary artery bypass grafting, isolated valve repair or replacement, or a combination coronary artery bypass grafting and valve procedure at the Cleveland Clinic Foundation after completing a self-administered preoperative Duke Activity Status Index (DASI) survey. Perioperative variables were prospectively collected concurrently with patient care by dedicated individuals and entered into the Cleveland Clinic Foundation Department of Cardiothoracic Anesthesia Registry. The Cardiovascular Information Registry was used for additional variable information. The Social Security Death Index was queried to determine death status during the follow-up interval. Among these patients, 7,321 completed at least one of two follow-up surveys scheduled nominally at 6 and 12 months postoperatively. Because our institution is a large international referral center, 1,272 patients lacked a social security number and therefore it was not logistically feasible to obtain mortality information for comparison. Among nonresponders with social security numbers, 569 died within the 6-month follow-up interval and 679 died within the 12-month follow-up interval. Among patients who were available to respond to the follow-up survey, 79% responded and 2,695 (21%) of patients failed to respond to the follow-up DASI survey or refused to participate. If a patient was unable to complete the questionnaire independently, a research assistant administered it by reading the exact words of the survey questions. Postoperative follow-up DASI surveys were completed by means of telephone interviews. Institutional review board approval was obtained to perform research using these databases.

Duke Activity Status Index
Duke Activity Status Index is a disease-specific functional quality-of-life questionnaire validated for patients with cardiovascular disease [6, 7]. The 12-item instrument (see Table 1) measures activities of daily living, such as household tasks, ambulation, personal care, sexual function, and recreational activities [6]. Weight of each item was determined by measuring maximal oxygen consumption at the level of activity represented by each question. In its development, the Duke University investigators used multiple regression techniques both to select items most correlated with oxygen uptake at a given level of activity and to associate each selected item with a weight reflecting metabolic cost. The DASI score reflects one dimension of quality of life, physical functioning. Positive responses are summed to produce an aggregated score consisting of a limited set of numbers ranging from 0 to 58.2 [6]. Higher values represent better physical functioning.


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  		Table 1. The Duke Activity Status Index (DASI) [6]
 
Statistical Analysis
Preliminary Analysis
Tables 2 and 3 Go compare demographics, clinical history, symptomatic status, laboratory values, operative variables, and postoperative morbid events between those responders who received and did not receive a PRBC transfusion. Figures 1 and 2 Go depict the frequency distribution for PRBC and platelet transfusion.


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  		Table 2. Continuous Variables by Transfusion Status a
 

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  		Table 3. Categorical Variables by Transfusion Status
 

Figure 1
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  		Fig 1. Frequency histogram of red blood cell (RBC) units transfused.

 

Figure 2
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  		Fig 2. Frequency histogram of platelet units transfused.

 
Proportional Odds Regression
We initially focused on the association between the first follow-up DASI score at nominally 6 months after surgery and baseline risk factors. There were 7,283 patients who completed the survey between 5 and 9 months postoperatively.

Because the distribution of DASI scores were anomalous with, for example, a large number of observations at the highest attainable value and gaps in the distribution of responses, we first grouped the raw DASI scores into an ordinal scale using a data-driven approach. The grouping began with an initial ordinal logistic regression analysis treating each distinct score as its own group represented by a unique intercept term. Groups were then formed by consolidating similar intercept estimates to filter out redundancy. The groups were collapsed further so that each group had an adequate sample size. This yielded a five-group scale: 0 to 34.7, 34.7 to 42.7, 42.7 to 45.2, 45.2 to 58.2, and 58.2.

Bootstrap aggregation [8] was used to identify baseline characteristics, operative details, and postoperative morbid events that were associated with follow-up DASI scores. Two hundred bootstrap data sets were used with a p value for retention of 0.05. Variables selected more than 50% of the time were submitted to further logistic ordinal regression analyses. A score test and a goodness-of-fit test were used to check the proportional odds assumption. The influence of baseline DASI; preoperative risk factors; laboratory values; platelet, fresh frozen plasma, and cryoprecipitate transfusion; operative events; and postoperative morbidities associated with follow-up DASI were examined with ordinal regression modeling.

Responders Versus Nonresponders
Characteristics of the nonresponders were generally similar to responders except for a small group of 346 patients who had a low preoperative DASI, more comorbidity, different operations, more PRBC transfusions, and more postoperative morbidity. It is likely their follow-up DASI would have been lower than average, accentuating the findings of our study.

All statistical analyses were done using SAS 8.2 (SAS Institute, Cary, NC) and R (www.r-project.org).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Patients who received a perioperative PRBC transfusion had lower follow-up DASI scores at nominally 6 months compared with those who did not. Among the patients who received a transfusion, only 31% of patients achieved the highest follow-up score 58.2, whereas 42% of patients who did not receive a transfusion did so (Fig 3). Even after adjusting for variables known to be associated with functional recovery after cardiac surgery, PRBC units and platelet transfusion were associated with significantly reduced postoperative functional recovery (Table 4). These relationships are evident from the proportion of patients in each of the five follow-up DASI groups according to PRBC units transfused and platelet usage (Fig 4). As PRBC transfusion increased, more patients were in the lowest DASI score group (0 to 34.7) and fewer achieved the highest DASI score (58.2) group.


Figure 3
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  		Fig 3. Mirrored histogram displays nominally 6-month follow-up Duke Activity Status Index scores according to whether red blood cells had been transfused. (Blue bars = no blood transfusion; red bars = red blood cell transfusion.)

 

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  		Table 4. Factors Associated With Postoperative Functional Recovery for the Nominally 6-Month Follow-Up Duke Activity Status Index a
 

Figure 4
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  		Fig 4. Empiric probabilities of five grouped follow-up Duke Activity Status Index (DASI) groups at each number of packed red blood cell (RBC) units according to whether platelets were given (yes/no). The solid lines denote with platelet usage; the dashed lines represent no platelet usage.

 
The predicted probability of achieving the highest follow-up DASI by increasing age and transfusion status is shown in Figure 5. The depiction is based on a male patient, undergoing coronary artery bypass grafting with a left internal thoracic artery graft and with a preoperative DASI score of 50.7, a serum creatinine of 0.89 mg/dL, a bilirubin of 0.90 mg/dL, a hematocrit of 38%, and no other preoperative comorbidity or postoperative morbid events. The predicted probability of achieving the highest follow-up DASI category decreases with increasing age and is further decreased with the addition of a blood transfusion.


Figure 5
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  		Fig 5. Relationship between increasing age, recipient of blood transfusion (solid black line) or not (gray line), and the probability of being in the highest follow-up Duke Activity Status Index (DASI) functional category (58.2) based on a low-risk patient and the equation represented by Table 4. The dotted lines represent 95% confidence intervals.

 
Female sex, older age, history of chronic obstructive pulmonary disease, diabetes, stroke, peripheral vascular disease, higher preoperative serum creatinine, and occurrence of postoperative neurologic events were also associated with worse postoperative functional recovery. High baseline DASI score, use of an internal thoracic artery graft, and having an isolated valve procedure were associated with better postoperative functional recovery.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
Principal Findings
Although patient-centered outcomes have historically received little attention [9], they represent important end points with regard to assessing the success of an operation. We report that functional recovery after cardiac surgery is significantly reduced in patients who received PRBC transfusion perioperatively. Transfusion of PRBC remained a significant predictor for poor postoperative functional recovery even after maximal adjustment for baseline DASI, preoperative clinical status, comorbidities, hematopoietic system measurements, laboratory values, operative factors, surgical procedure, and postoperative morbid events. The model presented in Table 4 suggests that a transfusion of 4 PRBC units and a postoperative infectious or neurologic morbid event have equivalent effects on 6-month functional recovery; a similar comparison can be made between a 2-unit transfusion of PRBC and a preoperative history of chronic obstructive pulmonary disease.

In addition, there appeared to be a dose–response relationship, with incrementally poorer functional recovery with each unit of blood transfused. Figure 4 graphically depicts the increasing probability of achieving the lowest DASI functional score group (0 to 34.7) as the number of PRBC units increases. The probability of a patient achieving the highest DASI functional score group (58.2) dramatically decreases as the number of PRBC units transfused increases. The impact of platelet transfusion follows a similar graphical trend.

Increasing age was also associated with poorer functional health status postoperatively. Older patients' functional status was further reduced by the addition of PRBC transfusion. As Figure 5 depicts, the older the patient age, the less probability of achieving the highest functional DASI score group (58.2). For patients who then receive PRBC transfusion, further reductions in the probability of achieving the highest DASI (58.2) functional score group are noted.

Other Factors Related to Quality of Life After Cardiac Surgery
Several studies have examined preoperative predictors of quality of life after cardiac surgery with a variety of quality-of-life instruments [10–14]. Our findings of poorer functional recovery for women and for those with chronic obstructive pulmonary disease, diabetes, stroke, and peripheral vascular disease are similar to these investigations. We also report that higher baseline DASI scores were associated with higher functional quality of life postoperatively. Rumsfeld and colleagues [13] similarly reported on the importance of baseline health status on postoperative health status. Few investigations have examined the influence of operative factors and postoperative morbid events on quality of life after cardiac surgery. We found that patients who sustained postoperative neurologic and infectious morbid events not surprisingly had worse postoperative functional health status. Conversely, patients undergoing coronary artery bypass grafting who received an internal thoracic artery graft were 30% more likely than those patients who did not receive one to have a higher functional category as compared with the lower postoperative DASI functional categories.

Clinical Implications
Transfusion of PRBC has a strong association with reduced functional quality of life after cardiac surgery. These results have not been previously demonstrated in prior investigations on health-related quality of life after cardiac surgery. There are a number of studies that report on the negative impact of PRBC transfusion on morbid outcomes after cardiac surgery [1–5]. Many of these investigations, however, report on the impact of PRBC on immediate postoperative outcomes and few if any speculate on the causative mechanism. Persistent effects of PRBC transfusion beyond the initial hospitalization have been described in a variety of clinical settings [5, 15]. Engornen and colleagues [5] recently found that in addition to a short-term association of transfusion with early postoperative cardiac surgery mortality, the late hazard for death remained elevated for as long (5 years) as patients were followed.

No one currently knows the mechanism of adverse outcome observed with PRBC transfusion. Persistence of a deficit in functional recovery in patients receiving transfusion and the dose–response nature of the finding, coupled with at least an intermediate-term persistence of high hazard for death, has led us to speculate about possible reasons for these findings. From other settings, we speculate that our finding may be related to either an inflammatory response [16–19] or to the so-called second event that amplifies the effect of inflammation in a vulnerable window during the first few postoperative hours [20–23]. Our observation of platelet transfusion and reduced postoperative functional recovery may also be mediated through a similar mechanism [24, 25].

Although several variables associated with reduced postoperative quality of life are not modifiable, such as sex and age, transfusion of PRBC is a potentially modifiable variable. Furthermore, the ability to predict and potentially modify factors associated with poor functional health status after surgery represents an area to target for interventional measures. Many of the patients who received a transfusion received only 1 or 2 units of PRBC, amounts not associated with excessive perioperative blood loss, yet significantly associated with reduced functional recovery. Results of this study highlight the continued effort needed for implementation of blood-conservation techniques in cardiac surgery. Perioperative management strategies aimed at reducing transfusion requirements as well as the use of blood substitutes should be further pursued.

Limitations
This is an observational investigation in which patients were not randomized to perioperative PRBC or component transfusion. However, randomizing a patient to a specific number of units of PRBC is not possible. As in any observational study, unknown or unaccounted-for variables could have influenced our final results. We examined only short-term impact of PRBC transfusion on functional quality of life after cardiac surgery. Further studies are indicated to examine the adverse impact of PRBC and platelet transfusion on intermediate and long-term outcomes. Furthermore, the DASI instrument is reflective of the patient's functional quality of life and does not assess the patient's mental health status as does the commonly used 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36) [28, 29]. There have been reported associations between mental health status and poor health outcomes in patients with coronary artery disease [26, 27].

The strengths of this investigation are that this is one of the largest prospectively collected data set on functional quality of life in cardiac surgical patients. The DASI score is a validated quality-of-life instrument specifically designed for patients with cardiovascular disease. We acquired baseline quality-of-life measurements preoperatively, before surgical interventions. Furthermore, we modeled not only an extensive list of preoperative variables but also information on operative events, detailed prospectively collected blood utilization forms, and postoperative morbid events on follow-up quality of life.

Conclusion
Multiple variables affect a patient's quality of life after cardiac surgery. Transfusion of PRBC and blood components have unintended persistent effects on health-related quality of life after cardiac surgery even after maximal adjustment for variables known to be associated with postoperative quality of life. The nature of this persistent negative impact remains speculative and warrants further investigation. Improvement in quality of life is an expectation of patients who undergo cardiac surgery. The occurrence of and amount of PRBC transfused is a potentially modifiable risk factor contributing to reduced postoperative functional quality of life.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
We thank Beth Lieber from the Department of Biostatistics for programming the data set. We also thank the physician assistants in the Department of Thoracic and Cardiovascular Surgery for assisting in administrating the DASI instrument and the Department of Cardiothoracic Anesthesia Registry team for entering the information into the registry.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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