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Association between red blood cell storage duration and clinical outcome in patients undergoing off-pump coronary artery bypass surgery: a retrospective study...

Received: 4 June 2014
Accepted: 14 October 2014
Published: 21 October 2014

Abstract
Background
Prolonged storage of red blood cells (RBCs) leads to fundamental changes in both the RBCs and the storage media. We retrospectively evaluated the relationship between the RBC age and in-hospital and long-term postoperative outcomes in patients undergoing off-pump coronary artery bypass.

Methods
The electronic medical records of 1,072 OPCAB patients were reviewed and information on the transfused RBCs and clinical data were collected. The effects of RBCs age (mean age, oldest age of transfused RBCs, any RBCs older than 14 days) on various in-hospital postoperative complications and long-term major adverse cardiovascular and cerebral events over a mean follow-up of 31 months were investigated. Correlations between RBCs age and duration of intubation, intensive care unit, or hospital stay, and base excess at the first postoperative morning were also analyzed.

Results
After adjusting for confounders, there was no relationship between the RBCs age and in-hospital and long-term clinical outcomes except for postoperative wound complications. A significant linear trend was observed between the oldest age quartiles of transfused RBCs and the postoperative wound complications (quartile 1 vs. 2, 3 and 4: OR, 8.92, 12.01 and 13.79, respectively; P for trend?=?0.009). The oldest transfused RBCs showed significant relationships with a first postoperative day negative base excess (P?=?0.021), postoperative wound complications (P?=?0.001), and length of hospital stay (P?=?0.008).

Conclusions
In patients undergoing off-pump coronary artery bypass, the oldest age of transfused RBCs were associated with a postoperative negative base excess, increased wound complications, and a longer hospital stay, but not with the other in-hospital or long-term outcomes.

Keywords: RBC storage age; Old stored RBC; Postoperative outcome; Wound complication; Cardiac surgery
Background
Prolonged storage of red blood cells (RBCs) alters them and their storage media, causing changes referred to as ‘storage lesions’. Over time, intracellular adenosine triphosphate within the stored RBCs decreases, rendering the RBC membrane fragile and less deformable [1]. The breakdown of fragile RBCs releases free hemoglobin and microparticles which reduce nitric oxide bioavailability, leading to vasoconstriction, thrombosis, and inflammation [2,3]. Moreover, depleted 2,3 DPG decreases oxygen delivery to organs [4]. Numerous studies on various patient populations have investigated the clinical impact of RBC storage lesions. However, their impact is still debatable.

Several studies on cardiac surgery patients have investigated the association between clinical outcomes and the storage time of RBCs [5-9]. However, previous studies used heterogeneous populations that included patients who received open heart surgery for valvular heart disease or an on-pump coronary artery bypass. Valvular heart diseases have various cardiac pathophysiologies according to the disease type and severity. Moreover, cardiopulmonary bypass with hypothermia is associated with inflammatory, metabolic, and hematologic responses and various organ injuries, making elucidation of the effects of old stored blood in such patient populations more complex [10]. Although a few studies have investigated the clinical effects of transfusions of old stored blood in patients undergoing coronary artery bypass surgery with regard to vasoconstrictive, thrombotic, and inflammatory effects [3,5,7-9,11], to our knowledge, the effects of stored RBCs have not been investigated exclusively in patients undergoing off-pump coronary artery bypass (OPCAB) surgery.

Although the transfusion rate of RBCs in off-pump CABG surgery was lower than that in on-pump surgery, more than half of the OPCAB patients still needed RBCs transfusion [12]. In patients with coronary arterial disease, RBCs transfusion is essential for adequate oxygen delivery. Meanwhile, old blood transfusion is a concern in such patients because of the possible harmful vascular effects [2,3].

We hypothesized that prolonged storage of RBCs may be associated with adverse in-hospital and long-term postoperative outcomes in patients undergoing OPCAB. To evaluate this hypothesis, we retrospectively studied the relationship between the RBC storage duration and in-hospital clinical outcomes and long-term postoperative major adverse cardiovascular and cerebral events (MACCEs) in patients undergoing OPCAB.

Methods
The study protocol was approved by the institutional review board of our hospital (IRB No. 1302-052-465, Seoul National University Hospital). As this was a retrospective study using electronic medical records, individual informed consent was waived. We screened the computerized medical records of 1,113 patients who underwent OPCAB between December 2005 and May 2012 and identified patients who received RBC transfusions during their hospital stay. A total of 41 patients who had not received RBC transfusions were excluded. Therefore, the final study population included 1,072 patients.

Data collection
The electronic medical records of enrolled patients were reviewed and pre-, intra-, and postoperative data were collected by researchers who were not aware of the RBC transfusion information. The clinical follow-up concluded in September 2012, with a mean follow-up duration of 31 (inter-quartile range [IQR], 11–51) months.

To determine the quantity and age of RBCs, information about all RBC units transfused to enrolled patients during their hospital stay was obtained from the computerized database of our institutional blood bank with the aid of the hospital’s Medical Information Department. The storage time (in days) of RBCs was analyzed in three ways: (1) the mean age of transfused RBCs units, (2) the oldest age of transfused RBCs units, and (3) any transfusion of RBCs units older than 14 days as a categorical variable.

All RBCs units were provided by the Korean Red Cross Blood Services. The RBCs were stored in citrate phosphate dextrose adenine (CPDA)-1 and the storage temperature was 2–6°C. RBCs units in our institution’s blood bank are discarded after 35 days of storage. The perioperative coagulation management strategy was as follows: all patients took aspirin until the day of the surgery and resumed it as soon as possible after the surgery, usually one day postoperatively. During the surgery, the patients were given an initial dose of heparin (1.5 mg/kg) and periodic supplemental doses to maintain an ACT >300 sec. Heparin was neutralized at the end of the surgery to only one-third of the required protamine dose. The perioperative target hemoglobin level was 10 g/dl.

Study end points and definition
The primary endpoint was the in-hospital and long-term MACCEs, defined as a composite of death from cardiac causes, myocardial infarction (MI), coronary revascularization, and stroke. The long-term follow-up was initiated after hospital discharge and concluded in September 2012. The mean follow-up period was 31 months, with the range 0 to 80 months (median 29, inter-quartile range [IQR], 11–51 months). Other study endpoints were in-hospital postoperative adverse outcomes including all-cause mortality, new renal failure, respiratory complications, postoperative wound complications, a new arrhythmia requiring treatment, bleeding-related reoperations, and the length of ICU and hospital stay. Definitions of each in-hospital postoperative outcome are as follows; Death was considered to be of cardiac origin if attributed to myocardial infarction, cardiac arrhythmia, or heart failure caused primarily by a cardiac problem. MI or stroke diagnosis and coronary revascularization were confirmed by reviewing hospital records. Respiratory complications included prolonged ventilator support (>48 h) or postoperative pneumonia. The diagnosis of pneumonia was based on a combination of physical signs and a chest X-ray and often confirmed by microbiological tests. Postoperative new renal failure was defined as an increase of >50% in serum creatinine from the preoperative value or the requirement for new renal replacement therapy regardless of serum creatinine level. Postoperative wound complication was defined as any sternal wound complication after surgery such as superficial and deep sternal wound including mediastinitis. Arrhythmias other than atrial fibrillation were defined as a postoperative new arrhythmia requiring treatment, including frequent multifocal premature ventricular contractions, ventricular bigemini or quadrigemini, junctional rhythm, paroxysmal supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation and asystole. Bleeding-related reoperation was confirmed by reviewing hospital records.

Statistical analysis
Continuous variables are presented as the mean (SD) and categorical variables as numbers and percentages. Linearity assumptions in the continuous variables were examined using restricted cubic splines. After checking for violation of the proportional hazard assumption, Cox proportional hazards regression models were used to identify the univariate and multivariable covariates associated with long-term MACCEs. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each factor using Cox proportional hazards analysis. To assess the independent impact of each risk factor on various postoperative outcomes, univariate and multivariable logistic regression models were constructed.

Variables that included as risk factors for adverse postoperative outcomes were as follows: total number of transfused RBCs, patient’s age, sex, body mass index, presence of diabetes mellitus, hypertension, dyslipidemia, previous history of myocardial infarction, previous history of stroke, presence of renal failure, left ventricular dysfuction (LV ejection fraction less than 35%), chronic obstructive pulmonary disease, cardiac reoperation, perioperative IABP insertion, emergency operation and the duration of surgery. In the Cox regression model for MACCEs, perioperative use of statin, anesthetic agent, lowest values of intraoperative hemodynamic variables and lowest hematocrit were also included as covariates.

All adjusted models were constructed using the forward variable selection method and a forward selection criterion for model fit of P =0.1 was used. To determine the effect of RBC age on in-hospital and long-term clinical outcomes, we constructed each adjusted model including each RBC age as a covariate after forward variable selection although they showed insignificant results in the univariate analysis.

Pearson’s correlation or Spearman’s rank correlation coefficients were used as appropriate to analyze the relationships between RBC transfusion amount and some continuous variables such as postoperative base excess, total bilirubin, length of ICU and hospital stay. Partial correlation analyses were used to remove the effects of the number of transfused RBCs in the relationships between the three ages of RBCs and those continuous variables. A P value of <0.05 was considered to indicate statistical significance. Analyses were performed using SPSS 19.0 (SPSS, Chicago, IL).

Results
Baseline and operative characteristics of the 1,072 patients studied are shown in Table 1. Although there was a male dominance (71.6%), there was no sex-related difference in the transfused RBCs amounts. A total of 7,480 allogenic, non-leukoreduced RBC units were transfused in the 1,072 patients. The mean storage time of the transfused RBCs was 11.7 (5.2) days (range, 0–35 days); the distribution of the storage time of all transfused RBCs units is shown in Figure 1. The average number of transfused RBCs per patient was 7 (8) units and the distribution of the number of transfused RBCs and the average values of RBCs age according to the number of transfused RBCs units are shown in Figure 2. In all, 473 patients (44%) received at least one RBC unit that was older than 14 days.

http://www.biomedcentral.com/1471-2253/14/95