Outcomes of Patients Treated with Blood Transfusion in a Contemporary Tertiary Care Medical Center Intensive Cardiac Care Unit

Background: Acutely ill patients treated with blood transfusion (BT) have unfavorable prognoses. Nevertheless, data regarding outcomes in patients treated with BT admitted into a contemporary tertiary care medical center intensive cardiac care unit (ICCU) are limited. The current study aimed to assess the mortality rate and outcomes of patients treated with BT in a modern ICCU. Methods: Prospective single center study where we evaluated mortality, in the short and long term, of patients treated with BT between the period of January 2020 and December 2021 in an ICCU. Outcomes: A total of 2132 consecutive patients were admitted to the ICCU during the study period and were followed-up for up to 2 years. In total, 108 (5%) patients were treated with BT (BT-group) during their admission, with 305 packed cell units. The mean age was 73.8 ± 14 years in the BT-group vs. 66.6 ± 16 years in the non-BT (NBT) group, p < 0.0001. Females were more likely to receive BT as compared with males (48.1% vs. 29.5%, respectively, p < 0.0001). The crude mortality rate was 29.6% in the BT-group and 9.2% in the NBT-group, p < 0.0001. Multivariate Cox analysis found that even one unit of BT was independently associated with more than two-fold the mortality rate [HR = 2.19 95% CI (1.47–3.62)] as compared with the NBT-group, p < 0.0001]. Receiver operating characteristic (ROC) curve was plotted for multivariable analysis and showed area under curve (AUC) of 0.8 [95% CI (0.760–0.852)]. Conclusions: BT continues to be a potent and independent predictor for both short- and long-term mortality even in a contemporary ICCU, despite the advanced technology, equipment and delivery of care. Further considerations for refining the strategy of BT administration in ICCU patients and guidelines for different subsets of high-risk patients may be warranted.


Introduction
With advanced interventions and delivery of care, modern intensive cardiac care units (ICCUs) have changed from units primarily dedicated to managing patients with acute coronary syndromes (ACS) into units dealing with heterogeneous patients with different acute and chronic cardiovascular conditions [1,2]. Consequently, the prevalence of ischemic heart disease patients has decreased, whereas the proportion of patients with other cardiac comorbidity conditions such as valvular heart disease, heart failure (HF), malignant arrythmias and venous thromboembolism [3] increased. Moreover, not uncommonly, patients with chronic cardiovascular comorbidities presenting with acute noncardiac conditions, such as sepsis and kidney injury, are also managed in the ICCU [2,4]. Anemia commonly affects critically ill patients and is associated with increased morbidity and mortality [5]. The management of low hemoglobin levels frequently includes blood transfusions (BT), one of the most common treatments in the intensive care setting [6]. However, the benefits of liberal BT in hemodynamically stable trauma patients and critically ill patients with anemia are debatable [7][8][9][10][11]. Conversely, patients with pre-existing coronary lesions and limited flow reserve may experience a higher rate of adverse events due to the additional risk of myocardial ischemia and infarction as a result of anemia [12]. In the recently published REALITY trial, evaluating patients with acute myocardial infarction (MI) and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of major adverse cardiac events (MACE) after 30 days [13]. Despite being a potentially lifesaving therapy, BT may be associated with fatal adverse events including transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury, which are associated with non-neglectable mortality, apart from other infectious and non-infectious transfusion reactions including transfusion-associated immunosuppression and allosensitization, which is known as transfusion-related immune modulation (TRIM) [12,[14][15][16][17][18]. Despite several clinical practice guidelines for transfusion, none fully addresses the relevant subgroups of ICCU patients [18][19][20]. Available evidence supports a restrictive BT approach for non-bleeding, critically ill, general ICU patients with hemoglobin (Hb) level <7 g/dL. In patients with coexisting cardiovascular disease and planned cardiac surgery, the cut-off is higher at Hb level of <8 g/dL [15,18,[21][22][23][24][25]. Hence, the aim of the current study was to examine mortality rates and outcomes in patients treated with BT in a contemporary tertiary ICCU.

Methods
All patients admitted to the ICCU at a tertiary care medical center between January 2020 and December 2021 were included in the study and were followed-up for up to 2 years. Restrictive transfusion strategy was adopted at out center, where BT was indicated if Hb level was ≤7-8 g/dL or if there was evidence of active bleeding with signs of hemodynamic instability [13,26,27]. Hemodynamic instability was defined as persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥65 and serum lactate level greater than 2 mmol/L in the absence of hypovolemia at the time of transfusion [28].

Data Collection
Data were anonymously submitted and prospectively documented into an electronic case report form and then were checked for accurateness and out-of-range values by a local coordinator. Demographic data, comorbidity conditions and clinical diagnoses were systematically recorded as well as laboratory and imaging data. Overall mortality rates were determined from the Israeli Ministry of Internal Affairs data.
The study was approved by the SZMC Institutional Review Board (approval number 0233-19-SZMC) with the exemption from informed consent.

Study Outcomes
The primary outcome was overall mortality rates, assessed at 1 year from time of index hospitalization. The study secondary outcomes were in-hospital complications during the index hospitalization and length of stay.

Statistical Analyses
For categorical variables, characteristics were expressed as numbers and percentages, and for continuous variables, as means, standard deviations or medians with interquartile ranges. Chi-square and Fisher's exact tests were used to analyze relationships between categorical variables. Through the use of Student's t-and Mann-Whitney tests, the impact of categorical variables on continuous measurements was examined. The distribution of the continuous variable determined whether a parametric or nonparametric test should be used. By using a stepwise backward Cox proportional hazards model adjusted for blood transfusion groups for age, sex, prior cardiac intervention and different cardiac risk factors, the mortality rate was examined. All tests were two-sided, and statistical significance was set at p < 0.05. Version 25.0 of SPSS Statistics for Windows was used to conduct the analyses (IBM Corp, Armonk, NY, USA).

Patient Characteristics
Two thousand one hundred and thirty-two patients were admitted to the ICCU during the study period. The mean age was 66.9 ± 16 years old and 650 (30.5%) were female. One hundred and eight (5%) patients were treated with BT (BT-group) during their hospitalization, with a total of 305 packed cells (PCs) transfusions. Of them, 31.4% of patients received a single PC, 29.6% received two PCs and 39% received ≥ three PCs, as shown in Figure 1. Patients who received BT were more likely to be elderly, female, have lower body mass index (BMI) and suffer more from hypertension, coronary artery disease (CAD), congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary hypertension, anemia and chronic kidney disease (CKD), compared with the non-BT group. Of note, ninety-five percent of PC transfusions were of standard unmodified packed red blood cells, whereas leukocyte reduced or irradiated and leuko-reduced packed red blood cells were documented in 5% of the PC transfusions. (Table 1). and for continuous variables, as means, standard deviations or medians with interquartile ranges. Chi-square and Fisher's exact tests were used to analyze relationships between categorical variables. Through the use of Student's t-and Mann-Whitney tests, the impact of categorical variables on continuous measurements was examined. The distribution of the continuous variable determined whether a parametric or nonparametric test should be used. By using a stepwise backward Cox proportional hazards model adjusted for blood transfusion groups for age, sex, prior cardiac intervention and different cardiac risk factors, the mortality rate was examined. All tests were two-sided, and statistical significance was set at p 0.05. Version 25.0 of SPSS Statistics for Windows was used to conduct the analyses (IBM Corp, Armonk, NY, USA).

Patient Characteristics
Two thousand one hundred and thirty-two patients were admitted to the ICCU during the study period. The mean age was 66.9 ± 16 years old and 650 (30.5%) were female. One hundred and eight (5%) patients were treated with BT (BT-group) during their hospitalization, with a total of 305 packed cells (PCs) transfusions. Of them, 31.4% of patients received a single PC, 29.6% received two PCs and 39% received ≥ three PCs, as shown in Figure 1. Patients who received BT were more likely to be elderly, female, have lower body mass index (BMI) and suffer more from hypertension, coronary artery disease (CAD), congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary hypertension, anemia and chronic kidney disease (CKD), compared with the non-BT group. Of note, ninety-five percent of PC transfusions were of standard unmodified packed red blood cells, whereas leukocyte reduced or irradiated and leuko-reduced packed red blood cells were documented in 5% of the PC transfusions. (Table 1).

Diagnosis on Admission and Blood Transfusion
The most common diagnosis for admission was ACS; almost all ACS patients underwent coronary angiography, and the majority also underwent percutaneous coronary intervention (PCI). Nevertheless, there was no increased rate of BT in this subgroup ( Table 2). Patients presenting with shock, whether cardiogenic or septic, CHF exacerbation and post trans-catheter aortic implantation (TAVI) were all more likely to receive BT during their admission, as presented in Tables 3 and 4. Interestingly, patients admitted due to other cardiac interventions, such as mitral clip, electrophysiologic study and implantation of a pacemaker, intracardiac defibrillator (ICD) or cardiac resynchronization therapy (CRT), were less likely to receive BT during their admission.

Mortality Rate
The crude mortality rate was 29.6% in the BT-group and 9.2% in the NBT-group, p < 0.0001, as shown in Figure 2. Multivariate Cox analysis for female gender, previous TAVI, cardiac intervention, pacemaker implantation, CHF, sepsis, pulmonary hypertension and low hemoglobin levels found that BT as compared with NBT was independently associated with more than two-fold the mortality rate [HR = 2.19, 95% CI (1.47-3.62), p < 0.001] as shown in Table 5. Multivariate analysis ROC curve was plotted and showed an AUC of 0.

Mortality Rate
The crude mortality rate was 29.6% in the BT-group and 9.2% in the NBT-group, p < 0.0001, as shown in Figure 2. Multivariate Cox analysis for female gender, previous TAVI, cardiac intervention, pacemaker implantation, CHF, sepsis, pulmonary hypertension and low hemoglobin levels found that BT as compared with NBT was independently associated with more than two-fold the mortality rate [HR = 2.19, 95% CI (1.47-3.62), p < 0.001] as shown in Table 5. Multivariate analysis ROC curve was plotted and showed an AUC of 0.

Discussion
The optimal strategy of BT in ICCU remains controversial, with an increasing number of studies supporting a more restrictive transfusion strategy. Although several studies have tried to address BT in specific situations, such as ACS [13], CHF or post CABG [29], very few have specifically addressed BT in ICCU patients. The present study evaluated the impact of BT on outcomes in a tertiary care center ICCU all-comers population. Our main findings were: (1) Patients treated with BT were older with a higher proportion of females, concurrent comorbidities and in-hospital complications; (2) Patients diagnosed with shock, CHF exacerbation and post TAVI were more likely to receive BT during their admission. Conversely, patients admitted for other cardiac interventions were less likely to receive BT; (3) Even one unit of BT was independently associated with more than twofold the risk of death; (4) BT was associated with longer length of hospital stay.
Our findings are in accordance with previous studies that found an increased likelihood of BT in elderly patients [26] and females [27]. In a study including patients with non-ST elevation myocardial infarction (NSTEMI) [26], patients of 75 years of age or more had a three-fold increased likelihood of BT than patients <55 years old. Another study evaluating patients with acute coronary syndrome reported that transfused patients were more likely to be elderly and females [27]. Patients undergoing TAVI do not uncommonly require peri-procedural blood transfusion [30]. The multicenter Transfusion Require-

Discussion
The optimal strategy of BT in ICCU remains controversial, with an increasing number of studies supporting a more restrictive transfusion strategy. Although several studies have tried to address BT in specific situations, such as ACS [13], CHF or post CABG [29], very few have specifically addressed BT in ICCU patients. The present study evaluated the impact of BT on outcomes in a tertiary care center ICCU all-comers population. Our main findings were: (1) Patients treated with BT were older with a higher proportion of females, concurrent comorbidities and in-hospital complications; (2) Patients diagnosed with shock, CHF exacerbation and post TAVI were more likely to receive BT during their admission. Conversely, patients admitted for other cardiac interventions were less likely to receive BT; (3) Even one unit of BT was independently associated with more than two-fold the risk of death; (4) BT was associated with longer length of hospital stay.
Our findings are in accordance with previous studies that found an increased likelihood of BT in elderly patients [26] and females [27]. In a study including patients with non-ST elevation myocardial infarction (NSTEMI) [26], patients of 75 years of age or more had a three-fold increased likelihood of BT than patients <55 years old. Another study evaluating patients with acute coronary syndrome reported that transfused patients were more likely to be elderly and females [27]. Patients undergoing TAVI do not uncommonly require peri-procedural blood transfusion [30]. The multicenter Transfusion Requirements in Transcatheter Aortic Valve Implantation (TRITAVI) registry reported an RBC transfusion rate of 16% in a transfemoral TAVI population [31]. The relative high transfusion rate in our cohort may be attributed to more complex and elderly patients admitted in the ICCU, a sizeable number of procedures performed via alternative vascular access site and thus associated with higher bleeding rates and treating high-risk patients prone to vascular complications.
The independent increased risk of mortality associated with BT has been documented across multiple "real world" cohorts and randomized trials [32][33][34], including ICU [35] and ICCU [36] populations, as in our study. Although considered generally safe and effective, BT can potentially carry considerable risks due to adverse events such as electrolyte disturbances, volume overload and transfusion reactions [37][38][39][40]. However, in high-risk populations, several factors, such as impaired oxygenation, reduced deformability of stored red blood cells, prothrombotic effects due to increased release of procoagulant factors, and transfusion-associated immunosuppression and allosensitization which is known as transfusion related immune modulation(TRIM), have been proposed to explain the association between blood transfusions and poor prognosis [17,34]. Furthermore, BTs are often administered in response to bleeding events, which themselves confer additional risk [26]. Our findings further support the available data, including the evidence of the detrimental effects of BT seen from the very first administered RBC unit.
The potentially harmful effects of BT have led to the adoption of a more cautious transfusion approach, with current guidelines recommending a restrictive BT strategy [i.e., limiting the transfusion of packed red blood cells to hemodynamically stable patients with a Hb value <7 g/dL] in non-bleeding, critically ill patients [22,41]. The restrictive transfusion strategy was found to be non-inferior to a liberal blood administration approach, also in patients with acute MI and Hb level < 8 g/dL [13]. However, proper implementation of recommendations onto specific subsets of high-risk populations is still rather challenging and often requires a personalized approach [42].
Finally, despite all precautionary measures including fluoroscopy-and US-guided vascular punctures, smaller gauge needles used for vascular access, activated clotting time (ACT) monitoring and experienced interventional cardiologists and ICCU intensivists, iatrogenic vascular complications leading to bleeding and anemia are not uncommon. Unfortunately, a recent study reported no benefit of US-guided arterial access used for cardiac interventions in reducing bleeding or vascular complications [43]. Consequently, additional strategies to make vascular access safer are needed.
Limitations: Our study had several limitations; first, we did not stratify patients according to the BT indication. Hence, the mortality rate recorded in our cohort may underestimate the true fatality rate in patients receiving BT following acute bleeding compared with BT administered following other indications. Second, it is a single-center study with its inherent biases; nevertheless, our study consists of a large number of consecutive patients in a real life setting of a tertiary care center ICCU. Third, the causes of death have not been systematically collected. Lastly, we investigated only RBC transfusions. The administration of other blood products has not been studied.
Conclusion: In a contemporary tertiary ICCU delivering guidelines-oriented care, even a single BT remains an independent strong predictor for poor outcomes. Thus, guidelines for further refining the strategy of BT administration in the ICCU setting, including different subsets of high-risk patients, may be warranted.

Conflicts of Interest:
The authors declare no conflict of interest.