Adverse Blood Transfusion Outcomes: Establishing Causation

doi:10.1016/j.tmrv.2010.11.001

Transfusion Medicine Reviews

Volume 25, Issue 2, April 2011, Pages 89-101

https://doi.org/10.1016/j.tmrv.2010.11.001 Get rights and content

The transfusion of allogeneic red blood cells (RBCs) and other blood components is ingrained in modern medical practice. The rationale for administering transfusions is based on key assumptions that efficacy is established and risks are acceptable and minimized. Despite the cliché that, “the blood supply is safer than ever,” data about risks and lack of efficacy of RBC transfusions in several clinical settings have steadily accumulated. Frequentist statisticians and clinicians demand evidence from randomized clinical trials (RCTs); however, causation for the recognized serious hazards of allogeneic transfusion has never been established in this manner. On the other hand, the preponderance of evidence implicating RBC transfusions in adverse clinical outcomes related to immunomodulation and the storage lesion comes from observational studies, and a broad and critical analysis to evaluate causation is overdue. It is suggested in several circumstances that this cannot wait for the design, execution, and conduct of rigorous RCTs. We begin by examining the nature and definition of causation with relevant examples from transfusion medicine. Deductive deterministic methods may be applied to most of the well-accepted and understood serious hazards of transfusion, with modified Koch's postulates being fulfilled in most circumstances. On the other hand, when several possible interacting risk factors exist and RBC transfusions are associated with adverse clinical outcomes, establishing causation requires inferential probabilistic methodology. In the latter circumstances, the case for RBC transfusions being causal for adverse clinical outcomes can be strengthened by applying modified Bradford Hill criteria to the plethora of existing observational studies. This being the case, a greater precautionary approach to RBC transfusion is necessary and equipoise that justifying RCTs may become problematic.

Section snippets

Drivers for an Evidence-Based Approach to Transfusion Practices and the Transition to Patient-Focused Blood Management

A fresh and comprehensive look at transfusion medicine in light of the available evidence rather than the assumptions has been long overdue. We believe that shifting the focus in transfusion medicine from supply centered to patient centric is essential, and it is being driven by 4 key factors.

Tackling the Association—Causation Challenge in Transfusion Medicine

To analyze the benefits and potential adverse outcomes of transfusions, it is important to first define “causation” as a scientific term.⁵⁵ A cause is commonly defined as something that is necessary and/or sufficient to determine a specific outcome. This definition refers to what is known as deductive deterministic causation. Deterministic causation is historically based on Koch's postulates and applies in circumstances when transfusions are clearly and directly implicated. It should be noted

Applying Bradford Hill Criteria to Observational Data to Support a Causal Association Between RBC Transfusion and Adverse Clinical Outcomes

It is not questioned that allogeneic blood transfusions have risks and can cause serious adverse events. However, notwithstanding the cases of profound anemia and hemorrhage with impaired oxygen delivery to tissues, we argue that in most patients who are currently considered to be transfusion candidates, blood transfusions do not improve the outcomes and, conversely, cause worse clinical outcomes. The evidence comes from a multitude of mostly observational studies comparing the outcomes of

Problem-Based Transfusion Medicine

From the patient's perspective, the primary responsibility of clinicians is to manage the patient's own blood as a precious and unique resource that should not be wasted and to only consider allogeneic blood component therapy when there is no other option. This review, addressing issues surrounding the safety and efficacy of RBC transfusions for treating anemia, challenges dogmas long embedded in clinical practice regarded as standard of care. Central to problem-based transfusion medicine, in

Conclusions

We believe that it is no longer acceptable to maintain a laissez faire approach and assume the benefits and accept the risks of allogeneic blood transfusion. Evidence has accumulated questioning RBC transfusion efficacy and establishing transfusion as a contributing risk factor for adverse clinical outcomes in many clinical settings. Acknowledging that most available data are observational and that rigorous evidence to establish risks and benefits is needed, we should no longer accept

Conflicts of interest statements

James Isbister: Lecturing/consulting honoraria/travel support in last 5 years: NovoNordisk, CSL Bioplasma, Amgen Australia, Pall Australia. Chair: Haemostasis Register, Monash University Department of Epidemiology, unrestricted grant funding from NovoNordisk Chair: Advisory Committee and Board Member. Australian Red Cross Blood Service. Australian National Blood Authority: Member: Steering committee on blood measures and patient blood management.

Aryeh Shander: Consultant: Bayer, Luitpold,

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Patient Blood Management (PBM) is a multidimensional approach that seeks to optimize the use of blood and its components in patients. This matter emerged as a response to the need to reduce unnecessary exposure to blood transfusions and their potential risks. In the past, blood transfusion was often overused resulting in complications and high costs. The advent of Patient Blood Management has caused a paradigm shift, highlighting anemia prevention, bleeding control and maximizing the production of blood cells by the organism itself. Patient Blood Management guidelines include the early identification of anemia, strategies to minimize blood loss during surgery, intraoperative blood conservation techniques, preoperative hemoglobin optimization and evidence-based approaches to the rational use of blood transfusions. Aiming to improve clinical outcomes, decrease transfusion-related complications and reduce associated costs, this multidisciplinary approach counts on doctors, nurses, pharmacists and other healthcare professionals. Based on research and clinical evidence, Patient Blood Management continues to evolve thereby promoting safer, more effective patient-centered practices. Its implementation has proven beneficial in various medical contexts thereby contributing to improvements in the quality of care provided to patients. Our goal with this Consensus is to present readers with a broad and diverse view of Patient Blood Management so that they have the building blocks to implement this new technique.
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Perioperative care in open aortic vascular surgery: A consensus statement by the Enhanced Recovery After Surgery (ERAS) Society and Society for Vascular Surgery
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Physiological measure: Blood transfusion thresholds and associated posttransfusion complications (morbidity, mortality, length of stay, infections, etc) of the published articles.
Adult spine surgery patients.
A systematic review of the literature using the PubMed, Google Scholar, and Web of Science electronic databases was made according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Focus was set on papers discussing thresholds for blood transfusion in adult surgical spine patients, as well as complications associated with transfusion after acute surgical blood loss in the operating room or postoperative period. Publications discussing pediatric cases, blood type analyses, blood loss prevention strategies and protocols, systematic reviews and letters to the editor were excluded.
A total of 22 articles fitting our search criteria were reviewed. Patients who received blood transfusion in these studies were older, of female gender, had more severe comorbidities except for smoking, and had prolonged surgical time. Blood transfusion was associated with multiple adverse postoperative complications, including a higher rate of superficial or deep surgical site infections, sepsis, urinary and pulmonary infections, cardiovascular complications, return to the operating room, and increased postoperative length of stay and 30 day readmission.
Analysis of transfusion thresholds from these studies showed that a pre-operative hemoglobin (Hb) of > 13 g/dL, and an intraoperative and post-operative Hb nadir above 9 and 8 g/dL, respectively, were associated with better outcomes and fewer wound infections than lower thresholds (Level B Class III). Additionally, it was generally recommended to transfuse autologous blood that was < 28 days old, if possible, with a limit of 2 to 3 units to minimize patient morbidity and mortality.
Blood transfusion thresholds in surgical patients may be specialty-specific and different than those used for critically-ill medical patients. For adult spine surgery patients, red blood cell transfusion should be avoided if Hb numbers remain > 9 and 8 g/dL in the intraoperative and direct post-operative periods, respectively.
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Citation Excerpt :
These direct risks are clearly identified by a definitive medico-legal evaluation as would be the case in criminal law where the determination of the causal link requires a high level of scientific and well-reasoned credibility and certainty. According to the current scientific evidence, as in criminal law, correlation cannot attribute causation to the indirect or statistical risks of transfusion as the probability of causation is based in large part on epidemiological studies [26]. It flows that from the point of view of litigation for medical professional liability is thus in the field of civil law, where the causal assessment is normally obtainable with different rigor, ie balance of probabilities.
In advanced health systems it is increasingly important to offer effective medical services that have high quality and safety standards. We present an overview of the direct hazards and the indirect hazards associated with blood transfusions. Our aim is to focus on the potential medico-legal impacts of these hazards in the context of clinical risk management, incorporating the accumulating evidence from Patient Blood Management programs. The direct or deterministic hazards of transfusion refer to scenarios where the mechanisms for post transfusion damage are clearly traceable to the blood transfused in a 1:1 cause and effect manner. The indirect hazards can be defined as probabilistic and are associated with transfusion through epidemiological studies. The implementation of Patient Blood Management programs demonstrates that the use of a blood transfusion is not always necessary or unavoidable but can be considered modifiable. Review of the literature confirms that transfusion should not be the default option to manage anemia or blood loss. Instead, accumulating evidence demonstrates that a patient-centred, proactive approach to managing a patient’s own blood is the new standard of care. It thus follows, an adverse transfusion event, where the transfusion was avoidable through the application of patient blood management, may constitute a profile for medical professional medical negligence.
In an effort to maximise patient safety, transfusion medicine practice culture needs to shift towards a patient blood management approach, with hospitals implementing it as an important tool to minimize the risks of allogeneic blood transfusion.
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View full text

Adverse Blood Transfusion Outcomes: Establishing Causation

Section snippets

Drivers for an Evidence-Based Approach to Transfusion Practices and the Transition to Patient-Focused Blood Management

Tackling the Association—Causation Challenge in Transfusion Medicine

Applying Bradford Hill Criteria to Observational Data to Support a Causal Association Between RBC Transfusion and Adverse Clinical Outcomes

Problem-Based Transfusion Medicine

Conclusions

Conflicts of interest statements

Acta tropica

Lancet

Transfus Apheresis Sci

J Am Coll Cardiol

New Sci

J Am Coll Surg

Am Heart J

J Proteomics

Resuscitation

Transfus Apheresis Sci

Best Pract Res Clin Anaesthesiol

Transfus Clin Biol

Transfus Med Rev

Toxicology

Rev Esp Cardiol

Curr Opin Immunol

Cancer Lett

Cell

Blood Rev

Transpl Immunol

Blood Rev

Transfus Med Rev

Best Pract Res Clin Anaesthesiol

A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care

N Engl J Med

Clinicians as gatekeepers: What is the best route to optimal blood use?

Dev Biol (Basel)

Blood management

Arch Pathol Lab Med

Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery

Circulation

Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting

Crit Care Med

Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes

JAMA

Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer

Arch Intern Med

Anemia, blood loss, and blood transfusions in North American children in the intensive care unit

Am J Respir Crit Care Med

The effect of erythrocyte blood transfusions on survival after surgery for hip fracture

J Trauma

Intraoperative red blood cell transfusion during coronary artery bypass graft surgery increases the risk of postoperative low-output heart failure

Circulation

Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery

Curr Opin Anaesthesiol

Deleterious clinical effects of transfusion immunomodulation: Proven beyond a reasonable doubt

Transfusion

Allogeneic blood transfusion increases the risk of postoperative bacterial infection: A meta-analysis

J Trauma

Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literature

Crit Care Med

Red blood cell transfusions and nosocomial infections in critically ill patients

Crit Care Med

Intraoperative transfusion of 1 U to 2 U packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and sepsis in general surgery patients

J Am Coll Surg

Timing and incidence of postoperative infections associated with blood transfusion: Analysis of 1,489 orthopedic and cardiac surgery patients

Surg Infect

Early packed red blood cell transfusion and acute respiratory distress syndrome after trauma

Anesthesiology

Transfusions result in pulmonary morbidity and death after a moderate degree of injury

J Trauma