The association of blood transfusion with mortality after cardiac surgery: cause or confounding?

O R I G I N A L A R T I C L E

The association of blood transfusion with mortality after cardiacsurgery: cause or confounding?_3697 1..9

Barry Dixon, John D. Santamaria, David Reid, Marnie Collins, Thomas Rechnitzer,

Andrew E. Newcomb, Ian Nixon, Michael Yii, Alexander Rosalion, and Duncan J. Campbell

BACKGROUND: Bleeding into the chest is a life-threatening complication of cardiac surgery. Bloodtransfusion has been implicated as an important causeof harm associated with bleeding, based largely onstudies demonstrating an independent associationbetween transfusion and mortality. These studies didnot, however, consider the possibility that bleeding mayin itself be harmful, inasmuch as drains are inefficient atclearing blood from the chest and retained blood maycompromise cardiac and lung function.STUDY DESIGN AND METHODS: We undertook amultivariate logistic regression analysis of the riskfactors associated with mortality in 2599 consecutivepatients undergoing cardiac surgery. Unlike previousstudies the risk factors examined included the volumeof chest tube drainage at 24 hours. A stratified analysiswas also undertaken that compared the adjusted risk ofdeath for patients exposed or not exposed to a postop-erative blood transfusion.RESULTS: Blood transfusion was not an independentpredictor of mortality (p = 0.4). Chest tube drainagewas the strongest independent predictor of mortality(p < 0.001). In the stratified analysis, chest tube drain-age remained an independent predictor of mortality forpatients not exposed to a blood transfusion (p < 0.01).Furthermore, the risk of death of these patients was nodifferent from patients exposed to a blood transfusion(p = 0.7 for interaction).CONCLUSIONS: Our results argue that for patientsundergoing cardiac surgery bleeding contributes tomortality through mechanisms unrelated to bloodtransfusion.

Every year an estimated 1 to 1.25 million patientsworldwide undergo cardiac surgery. For thesepatients bleeding into the chest remains acommon life-threatening complication.1 Blood

transfusion has been implicated as a major mechanism ofharm associated with bleeding after cardiac surgery, basedlargely on studies that demonstrated an independentassociation between blood transfusion and mortality.2-7

These studies did not, however, consider the possibilitythat bleeding may in itself be harmful, inasmuch as drainsare inefficient at clearing blood from the chest andretained blood may compromise cardiac and lungfunction.8-12

To investigate this hypothesis we undertook a multi-variate logistic regression analysis of the risk factors asso-ciated with mortality. Unlike previous studies the riskfactors also included the volume of chest tube drainage at24 hours. In addition, we undertook a stratified analysis tocompare the risk of death for patients that were or werenot exposed to a postoperative blood transfusion. Toassess whether retained blood in the chest may impaircardiac function we also investigated the relationshipbetween chest tube drainage and hemodynamic and res-piratory variables.

ABBREVIATIONS: ICU = intensive care unit; RCT(s) =randomized controlled trial(s).

From the Department of Intensive Care; St Vincent’s Institute of

Medical Research; the Department of Medicine, University of

Melbourne; the Department of Cardiothoracic Surgery, St Vin-

cent’s Hospital; and the Department of Mathematics and Statis-

tics, University of Melbourne, Melbourne, Australia.

Address correspondence to: Barry Dixon, Intensive Care, St

Vincent’s Hospital, 41 Victoria Pde Fitzroy, Melbourne, Victoria

3065, Australia; e-mail: [email protected].

This study was supported by departmental funds.

Received for publication January 4, 2012; revision received

March 27, 2012, and accepted March 28, 2012.

doi: 10.1111/j.1537-2995.2012.03697.x

TRANSFUSION **;**:**-**.

Volume **, ** ** TRANSFUSION 1

MATERIALS AND METHODS

Study populationThe study was undertaken at St Vincent’s Health, a largeinner-city tertiary university referral hospital in Mel-bourne, Australia. We analyzed data from 2599 consecu-tive patients who underwent cardiac surgery requiringcardiopulmonary bypass between January 1, 2002, andFebruary 12, 2008. Leukoreduction was gradually intro-duced from February 2007, but was not routinely used inall patients until August 2008. Approximately 5% ofpatients in our study received leukoreduced blood. Datawere retrieved from the patients’ electronic medicalrecord (CareVue, Philips, Eindhoven, the Netherlands)and the cardiac surgical databases. Patients undergoingsalvage surgery (undergoing cardiopulmonary resuscita-tion en route to theater, n = 7) and Jehovah’s Witnesspatients (n = 17) were excluded.

Study designThis was a retrospective study of patient data. The primaryend point was hospital death and was specified in advanceof data retrieval. The Human Research Ethics Committeeapproved the use of deidentified data for this study andwaived the need for individual patient consent. Theanesthetic, surgical, and intensive care management isdescribed in Appendix S1 (available as supporting infor-mation in the online version of this paper).

DefinitionsBlood transfusion was defined as administration of redblood cells (RBCs), platelets (PLTs), or plasma products inthe 24 hours after admission to the intensive care unit(ICU). Chest tube drainage was recorded as the chestdrain level at 24 hours after admission to the ICU. If thepatient was discharged from the ICU before 24 hours, thelast recorded level was used. Mortality was defined asdeath in hospital, before discharge. Type of surgery wasclassified as one of three categories: coronary arterybypass grafting, valve surgery (repair or replacement ofvalve), or complex surgery (multiple valve surgery or coro-nary artery bypass grafting with valve surgery or surgeryinvolving the aortic arch). Urgency of surgery was classi-fied as one of three categories: elective (the procedurecould be deferred without risk), urgent (surgery indicatedwithin 72 hr of angiography or of unplanned admission),and emergency (surgery required same day). Redo surgerywas defined by the patient having undergone cardiacsurgery on a previous admission. Pneumonia denotedclinical findings consistent with a chest infection associ-ated with positive cultures of respiratory secretions. Sep-ticemia was defined as positive blood cultures and at leasttwo of the following: fever, elevated granulocyte, elevatedC-reactive protein, or elevated erythrocyte sedimentationrate.

Statistical analysis

MortalityBinary logistic regression was used to investigate potentialunivariate predictors of mortality. Variables consideredincluded blood transfusion, chest tube drainage, Cana-dian Cardiovascular Society Score, the New York HeartAssociation Score, cardiopulmonary bypass time, operat-ing surgeon, antifibrinolytic agent used, urgency ofsurgery, type of surgery, valve (mitral, aortic, tricuspid),type of grafts, number of grafts, redo surgery, sex, age,height, weight, body mass index, preoperative creatinine,hemoglobin (Hb), left ventricle function, preoperativeanticoagulation, history of cerebrovascular accident,acute myocardial infarct, diabetes, hypertension, andsmoking. The univariate associations are provided inAppendix S1. Logistic regression was then used. Explana-tory variables were added to the model in three blocks. InBlock 1, known risk factors were fitted and retainedregardless of significance. These included age, sex, type ofsurgery, redo surgery, urgency of surgery, preoperativeplasma creatinine, and cardiopulmonary bypass time. InBlock 2, other potential predictors of hospital mortalitywere considered for inclusion into the model using aforward stepwise procedure; the p value for inclusion wasset at 0.05. In Block 3, blood transfusion and chest tubedrainage were entered. To further investigate potentialconfounding with regard to blood transfusion a stratifiedanalysis was also undertaken that compared the adjustedrisk of death for patients exposed or not exposed to a post-operative blood transfusion.

Cardiac impairmentThe relationship of chest tube drainage with decrease incardiac index, increase in pulmonary capillary wedgepressure and pulmonary artery pressure, inotropeadministration, and increase in ventilator peak inspira-tory pressure levels was assessed. For cardiac index,pulmonary capillary wedge pressure, pulmonary arterypressure, and ventilator peak inspiratory pressure themaximum change over the first 12 hours in ICU frombaseline (level on arrival) was assessed. The require-ment for inotrope administration in the ICU wasassessed. The Kruskal-Wallis test assessed associationsbetween chest tube drainage and continuous variables,Pearson’s chi-square test for categorical variables, andthe Spearman test assessed the correlation with bloodtransfusion.

RESULTS

Characteristics of patientsThe patient and operative characteristics are sum-marized in Table 1. Overall, 60 patients died in hospital(2.3%).

DIXON ET AL.

2 TRANSFUSION Volume **, ** **

Relationship between bleeding and volume ofblood transfusedChest tube drainage was correlated with the volume ofblood transfused over the first 24 hours after surgery(Spearman r = 0.42, p < 0.0001, Fig. 1).

Recognized bleeding complicationsDuring the first 24 hours in intensive care a total of 1071patients (41.6 %) were transfused a blood product (RBCs,fresh-frozen plasma products, or PLTs) and 1016 patients

(39.5%) were administered RBCs. Forpatients administered RBCs the meannumber was 2.3 units. Reoperation foracute cardiac tamponade or excessivebleeding was required in 84 patients(3.3%). The mean � SD chest tubedrainage at 4 hours was 351 � 400 mL(median, 250 mL), at 8 hours 487 � 523(median, 350 mL), at 12 hours625 � 600 mL (median, 460 mL), andat 24 hours 910 � 733 mL (median,750 mL).

MortalityBlood transfusion and chest tube drain-age were both significantly associatedwith mortality on univariate analysis(Appendix S1). However, after adjustingfor known risk factors of mortality andother significant explanatory variablesblood transfusion was found not to bean independent predictor of mortality(p = 0.4). Chest tube drainage was thestrongest predictor of mortality in themultivariate logistic regression model(p < 0.001, Table 2). For chest tubedrainage a dose-dependent relationshipwith mortality was present. Comparedwith the reference category (�500 mL),the adjusted odds ratios (ORs) for deathwere 2.1 (95% confidence interval [CI],0.8-5.6) for 501 to 1000 mL, 4.0 (95% CI,1.5-11.0) for 1001 to 1500 mL, 5.8 (95%CI, 1.7-19.2) for 1501 to 2000 mL, and16.3 (95% CI, 5.8-46) for more than2000 mL (Fig. 2).

A stratified multivariate analysiswas also undertaken that compared therelationship between chest tube drain-age and hospital death for both patientsexposed (n = 1071) or patients notexposed to a postoperative bloodtransfusion (n = 1504). For patients not

exposed to blood, chest tube drainage remained an inde-pendent predictor of mortality (p < 0.01). The multivariateanalysis was undertaken again, but only in patients thatwere exposed to blood. The interaction of blood transfu-sion on the risk of hospital death was then assessed. Bloodtransfusion had no statistical interaction with the rela-tionship between chest tube drainage and hospital death(p = 0.7 for interaction, Fig. 3), indicating that the relation-ship of chest tube drainage with hospital death was thesame for both patients exposed or not exposed to a post-operative blood transfusion.

TABLE 1. Characteristics of the patients*Characteristic Value (n = 2575)†

Age (years) 66 � 11Male sex 1868 (73)Body mass index (kg/m2) 28 � 5Hb (g/dL) 137 � 18Creatinine (mmol/L) 90 (80-110)Hypertension 1610 (63)Diabetes 691 (27)Ever smoked 2137 (83)Canadian Cardiovascular Society Class 3 or 4 1398 (54)New York Heart Association Class III or IV 1242 (48)Preoperative anticoagulation‡ 627 (24)Left ventricle function§

Normal 810 (31)Left ventricle hypertrophy 1053 (41)Mild impairment 493 (19)Moderate impairment 173 (7)Severe impairment 46 (2)

Surgical urgencyElective 1338 (52)Urgent 1029 (40)Emergency 204 (8)

SurgeryRedo 107 (4)Single valve 274 (11)Coronary artery bypass grafting 1785 (69)Complex|| 516 (20)Aortic valve 553 (22)Mitral valve 214 (8)Tricuspid valve 34 (1)

Distal graftsTotal 3.3 � 1.2Arterial 2.3 � 1.2Internal mammary artery 1.4 � 0.8Radial 0.8 � 0.8Vein 1.0 � 1.1

AntifibrinolyticAprotinin 1436 (58)e-Aminocaproic acid 747 (30)Tranexamic acid 301 (12)Cardiopulmonary bypass time (min) 122 � 38Cross-clamp time (min) 95 � 31

* Data are presented as mean � SD, number (%), or median (interquartile range).† Data for surgery urgency were missing for four patients, antifibrinolytic for 93 patients,

cardiopulmonary bypass time for 42 patients, and cross-clamp time for 59 patients.‡ Preoperative anticoagulation was managed with either heparin infusion or subcutane-

ous enoxaparin injections.§ Left ventricle function based on preoperative echocardiogram or angiographic assess-

ment of the ejection fraction (normal >50%, mild 35%-50%, moderate 20%-34%, andsevere impairment <20%).

|| Complex surgery was defined as multiple valve surgery or coronary artery bypassgrafting with valve surgery or surgery involving the aortic arch.

BLOOD SURGERY MORTALITY


The results of the multivariate analyses were notaffected by exclusion of the 84 patients who hadreoperation because of acute tamponade or excessivebleeding.

Chest tube bleeding and cardiac impairmentThe extent of chest tube drainage had a dose-dependentrelationship with the extent of decrease in cardiac index(p < 0.05), increase in left atrial pressure (p < 0.05), andincrease in pulmonary artery pressure (p < 0.001) over thefirst 12 hours in the ICU. In addition, the extent of chesttube drainage was associated with the requirement forinotropes while in ICU (p < 0.001). A dose-dependent rela-tionship was also present with the extent of increase inventilator peak inspiratory pressure levels over the first 12hours in the ICU (p < 0.001, Fig. 4).

Other adverse outcomesCompared with the reference category (�500 mL), theextent of chest tube drainage was significantly associatedwith other adverse outcomes including duration ofhospital and intensive care stay, duration of mechan-ical ventilation and rates of pneumonia, septicemia,hemofiltration, tracheostomy, reintubation, and read-mission to the intensive care after ward discharge(Table 3).

DISCUSSION

Blood transfusion has been implicated as an importantcause of harm in patients undergoing cardiac surgery,based largely on observational studies demonstrating anindependent association between blood transfusion andmortality.2-7 These studies did not, however, consider the

Fig. 1. Relationship between blood transfused and chest tube

drainage over the first 24 hours after admission to the inten-

sive care.

TABLE 2. ORs of variables included in theadjusted analysis of hospital death

Variable OR (95% CI) p value

Chest tube drainage (mL) <0.001501-1000 vs. �500 2.10 (0.78-5.61)1001-1500 vs. �500 3.99 (1.45-11.0)1501-2000 vs. �500 5.75 (1.72-19.2)>2000 vs. �500 mL 16.3 (5.78-46.0)

Radial grafts (per additional graft) 0.42 (0.25-0.71) 0.001Preoperative anticoagulation*

(yes vs. no)2.63 (1.31-5.26) 0.006

Cardiopulmonary bypasstime (per 10-min increase)

1.10 (1.00-1.20) 0.01

Tricuspid valve surgery (yes vs. no) 4.81 (1.34-17.2) 0.02Sex (female vs. male) 1.95 (1.03-3.66) 0.04Urgency of surgery 0.06

Urgent vs. elective 0.80 (0.38-1.66)Emergency vs. elective 2.02 (0.85-4.84)Emergency vs. urgent 2.54 (1.17-5.49)

Age (per 1-year increase) 1.03 (1.00-1.06) 0.09Type of surgery 0.09

Coronary artery bypass graftingvs. complex†

0.37 (0.14-0.94)

Coronary artery bypass graftingvs. single valve

0.97 (0.36-2.59)

Complex vs. single valve† 2.36 (0.85-8.13)Preoperative creatinine (per

1 mmol/L increase)3.52 (0.27-45.4) 0.3

Redo surgery (yes vs. no) 1.38 (0.42-4.54) 0.7

* Preoperative anticoagulation was managed with either heparininfusion or subcutaneous enoxaparin.

† Complex surgery was defined as multiple valve surgery orcoronary artery bypass grafting with valve surgery or surgeryinvolving the aortic arch.

Fig. 2. Adjusted OR for hospital death in relation to categories

of chest tube drainage. Chest tube drainage had a dose-

dependent relationship with death and the OR of death was

significantly higher for levels of more than 1000 mL. The ref-

erence category was not more than 500 mL. The dashed line

represents an OR of 1. The 95% CI is demonstrated. The y-axis

has a log scale.

DIXON ET AL.


possibility that bleeding may in itself be harmful, inas-much as drains are inefficient at clearing blood from thechest and retained blood may compromise cardiac andlung function.8-10

Unlike previous studies our analysis included chesttube drainage as a potential risk factor. Our multivariateanalysis found that blood transfusion was not an indepen-dent predictor of mortality, while chest tube drainage was,in fact, the strongest independent predictor of mortality.

Previous observational studies found a remarkableassociation between blood transfusion and mortality. Theadjusted odds of death increased by two- to fourfold forevery 2 units of blood given (which represents the meantransfusion given in our study).3,4 To further explore thenature of the relationship between blood transfusion andmortality, we also undertook a stratified multivariateanalysis. This analysis compared the relationship betweenchest tube drainage and hospital death for patientsexposed or not exposed to a postoperative blood transfu-sion. In this analysis, for patients not exposed to blood,chest tube drainage still remained an independentpredictor of mortality (p < 0.01). As these patients did notreceive blood, this finding suggests bleeding causes harmthrough mechanisms other than blood transfusion. The

Fig. 4. Association of chest tube drainage with cardiac insta-

bility and ventilator pressure levels. The values represent the

maximum change over the first 12 hours in the ICU from

baseline levels (measured on arrival). Inotropes represents the

percentage of patients administered an inotrope while in the

ICU. PCWP denotes pulmonary capillary wedge pressure,

which reflects left atrial pressure. Graphs with error bars rep-

resent median and interquartile range.

Fig. 3. Adjusted OR for hospital death in relation to categories

of chest tube drainage for patients exposed ( ) or not exposed

( ) to a postoperative blood transfusion. For patients not

exposed, chest tube bleeding remained an independent pre-

dictor of mortality (p < 0.01). Furthermore, the risk of death of

these patients was no different to patients exposed to blood

(p = 0.7 for interaction). The reference category was not more

than 500 mL. The dashed line represents an OR of 1. The

95% CI is demonstrated. The y-axis has a log scale. Blood

transfused—0 to 500 mL (n = 187), 501 to 1000 mL (n = 363),

1001 to 1500 mL (n = 265), and 1501 to 2000 mL (n = 256); not

transfused—0 to 500 mL (n = 552), 501 to 1000 mL (n = 669),

1001 to 1500 mL (n = 254), and 1501 to 2000 mL (n = 29);

overall blood transfused (n = 1071); and not transfused

(n = 1504).



multivariate analysis was again undertaken, but only inpatients that did receive blood. One would expect theoverall mortality for this group to be higher in comparisonto those not exposed to blood. Blood transfusion had nostatistical interaction with the relationship between chesttube drainage and hospital death (p = 0.7), indicatingthat the adjusted relationship of chest tube drainage withhospital death was the same for both patients exposed orpatients not exposed to a postoperative blood transfusion.These findings are important, as they suggest that theassociation between blood transfusion and mortalityreflects confounding and argue that bleeding contributesto mortality through mechanisms unrelated to bloodtransfusion.

It could be argued one reason we found patients notexposed to blood had the same adjusted risk of death aspatients exposed to blood was inadequate resuscitation inthe former group.We believe that inadequate resuscitationin an ICU setting is unlikely. All patients were managedusing the same intensive care protocols, these protocolsincluded continuous hemodynamic monitoring to main-tain a cardiac index of more than 2 L/min/m2 and a bloodtransfusion trigger of a Hb level of less than 80 g/dL.

Previous randomized controlled trials (RCTs) ofliberal versus conservative thresholds for transfusion aftercardiac surgery have been undertaken. These studiesfound lower thresholds were safe. These studies alsoprovide data to address the question of whether bloodtransfusion is harmful, as significantly more blood wastransfused in the liberal arms.4,13 The results of observa-tional studies that assessed the adjusted risks associatedwith blood transfusion suggest that marked increases inboth mortality and morbidity would be expected in theliberal arms of these RCTs.2-7 In a pediatric study 125patients were randomly assigned to liberal versus conser-

vative thresholds. The death rate was 3.2% for bothgroups. One could argue this study was underpoweredfor this endpoint, as death is an infrequent outcome.However, there was also no difference in ICU length ofstay, duration of mechanical ventilation, or severity ofpostoperative organ dysfunctions.13 An adult study ran-domly assigned 502 patients to liberal versus conservativethresholds. Mortality was the same in both groups. Inaddition, no difference was found in the rate of acute res-piratory failure, acute renal failure, or length of ICU andhospital stays.4 The results of these RCTs, therefore, do notsupport a causal relationship underlying the associationbetween blood transfusion and mortality and morbidity.

Another mechanism by which bleeding may contrib-ute to mortality is through the collection of blood in thechest causing a subclinical form of cardiac tamponade(i.e., a nonacute form of cardiac tamponade withoutobvious clinical signs).14 Animal studies have demon-strated that relatively small increases in pericardial pres-sure can cause a decrease in cardiac output and furtherincreases cause progressive deteriorations in cardiacoutput.15-17 Human studies also suggest relatively modestlevels of cardiac compression can cause tamponade, asdemonstrated by the development of tamponade inpatients with hiatus hernia.18,19 In addition, the meanvolume of blood causing tamponade after cardiac surgeryis relatively small, only 160 mL.11 It is unrealistic to expecta low cardiac output after cardiac surgery, due to a sub-clinical form of tamponade, to be routinely detectedas hemodynamic stability may be achieved throughincreased fluids and inotropes and the diagnosis oftamponade would generally therefore not be considered.Furthermore, transthoracic ECHO has been shown tobe unreliable, failing to detect up to 80% of cases oftamponade.11,20-24

TABLE 3. Adverse outcomes

Characteristic

Category of chest tube drainage (mL)

�500 501 to 1000 1001 to 1500 1501 to 2000 >2000p value(n = 739) (n = 1032) (n = 519) (n = 147) (n = 138)

Hospital stay (days)Median (IQR) 7 (6-9) 7 (6-9) 7 (6-9) 7 (6-10) 8 (7-13) <0.0001Mean 8.6 9.1 9.8 10.5 13.2

ICU stay (hr)Median (IQR) 22 (17-25) 22 (20-27) 24 (18-45) 25 (21-52) 47 (25-108) <0.0001Mean 35 39 50 63 102

Ventilation (hr)Median (IQR) 11 (8-15) 11 (8-17) 13 (9-19) 15 (11-30) 23 (16-70) <0.0001Mean 21 23 30 43 78Hemofiltration (%) 2.0 2.7 1.9 4.1 8.7 0.0002Pneumonia (%) 4.7 5.7 7.1 11.6 14.5 <0.0001Septicemia (%) 1.2 1.1 2.3 3.4 7.3 <0.0001Tracheostomy (%) 2.4 1.6 3.9 7.5 10.1 <0.0001Reintubation (%) 3.9 3.4 4.6 6.1 9.4 0.01Readmit to ICU (%) 2.2 2.5 3.1 4.8 6.5 0.04

IQR = interquartile range.

DIXON ET AL.


To investigate whether subclinical tamponade couldbe a mechanism of harm, we evaluated the associationbetween chest tube drainage and hemodynamicfeatures of tamponade over the first 12 hours inICU.16,22,25 We found that chest tube drainage wassignificantly associated with the extent of decrease incardiac index, increase in left atrial pressure, increasein pulmonary artery pressure, and extent of inotrope use.In addition, chest tube drainage was associated with theextent of increase in ventilator inspiratory pressurelevels, a finding potentially consistent with bloodcollecting in the chest limiting lung expansion. Overall,these associations were consistent with a dose-dependent relationship between the level of chest tubedrainage, the extent of retained blood clot in the chest,and the degree of tamponade. A recent study alsofound an association between the extent of chest tubedrainage and the risk of developing tamponade aftercardiac surgery.26

Our findings were unlikely to be explained by underresuscitation and hypovolemia, which would be associ-ated with a decrease in left atrial pressure and pulmonaryartery pressures and which, in any case, is unlikely todevelop in an intensive care setting with continuous inva-sive monitoring, including arterial and pulmonary arterycatheters. Overresuscitation could give rise to these find-ings and this cannot be excluded. Alternate mechanismsof cardiac failure, such as ischemia-reperfusion injuryor ischemia due to graft failure, could result in similarhemodynamic changes. These mechanisms would not,however, be expected to be associated with the extent ofchest tube drainage.

Chest tube drainage was associated with otheradverse outcomes including increased hospital and inten-sive care stays, increased duration of mechanical ventila-tion, and increased rates of pneumonia, septicemia,hemofiltration, tracheostomy, reintubation, and readmis-sion to the intensive care. We speculate that these adverseoutcomes could also be a consequence of retained bloodin the chest. While low cardiac output from subclinicaltamponade may be addressed with fluid and inotropes,adverse consequences can still develop. First, subclinicaltamponade may increase lung edema through raised leftatrial pressure. Second, additional fluid given to maintainadequate hemodynamics may promote lung edema.27

Third, blood clot retained in the chest triggers inflamma-tory responses to remove it (over a period of days toweeks), but these responses may further exacerbate lungedema, increase pleural fluid, and contribute to atelecta-sis.28 Consequently, blood in the chest may prolong theperiod of mechanical ventilation, which in turn increasespatients’ risk of life-threatening complications includingpneumonia and sepsis.29

Our results have a number of implications for surgi-cal practice. First, bleeding may be harmful, even in the

absence of a blood transfusion. Second, the dose-dependent association we found between chest tubedrainage and death suggests that there is no safelevel of bleeding. Third, more than 1000 mL of chest tubedrainage at 24 hours is independently associatedwith an increased risk of death. Changes in practice toreduce the proportion of patients with this level of chesttube drainage could reduce adverse outcomes andmortality. In our study 31% of patients had chest tubedrainage exceeding this level. The percentage is similarto highly regarded centers in the United States andEurope.30-33 Studies have demonstrated that markedreductions in chest tube drainage are possible with rela-tively simple changes to practice, including meticuloushemostatic surgical technique. In one study the volumeof chest tube drainage decreased by 44%.34 Case-controlstudies of Jehovah’s Witnesses patients also demon-strated reductions in chest tube drainage of approxi-mately 50%.35,36 Reducing chest tube drainage wouldhave other benefits, as bleeding is probably the mostimportant factor driving the use of blood products incardiac surgery. It is estimated that cardiac surgerypatients consume approximately 20% of the worldwideblood supply.37

Methodologic limitations and strengthsA significant limitation of the study was the absence ofan objective method to assess whether chest tube bleed-ing resulted in retained blood in the chest and whetherthis in turn contributed to subclinical tamponade. Thisassessment is, however, problematic as rethoracotomy isprobably the only definitive method to determine thesecomplications. Furthermore, our study was a retrospec-tive analysis of a large cardiac surgical database, andsuch databases may contain incomplete and inaccuratedata; caution is therefore required with interpretation.Finally, our study design does not allow us to determinecausation and therefore we can only speculate on themechanisms underlying the associations we found.Larger RCTs that compare transfusion thresholds mayprovide clearer evidence of whether or not blood trans-fusion is harmful.

Our study had a number of strengths. First, weadjusted for multiple factors, including establishedassociations with death. Second, the characteristics ofpatients in our cohort were typical of contemporarypractices and the extent of chest tube drainage andmortality were similar to published data from highlyregarded units.30-33 Finally, our conclusions have physi-ologic plausibility and were consistent with recent resultsof RCTs.4,13 In conclusion, our results argue that forpatients undergoing cardiac surgery, bleeding contrib-utes to mortality through mechanisms unrelated toblood transfusion.



CONFLICT OF INTEREST

The authors have no conflicts of interest to report.

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SUPPORTING INFORMATION

Additional Supporting Information may be found in theonline version of this article:

Appendix S1. Univariate associations with hospital death.

Please note: Wiley-Blackwell is not responsible for thecontent or functionality of any supporting materials sup-plied by the authors. Any queries (other than missingmaterial) should be directed to the corresponding authorfor the article.



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The association of blood transfusion with mortality after cardiac surgery: cause or confounding?