Hyperkalaemia Following Blood Transfusion–a Systematic Review Assessing Evidence and Risks
Introduction
Hyperkalaemia following blood transfusion has been described in the literature but a causative relationship between the two has not been conclusively established. Generally defined as potassium (K+) concentration >5.5 mmol/L [1], hyperkalaemia is associated with adverse effects, most seriously a decrease in resting membrane potential of cardiac myocytes leading to progressive electrocardiographic changes and reduced cardiac contractility. As K+ concentrations rise, life-threatening cardiac arrhythmias and cardiac arrest can occur [2].
In transfusion medicine, hyperkalaemia has been postulated as being associated with infusion of RBCs with supernatant K+ concentrations above the physiological concentration in human plasma [3,4]. Supernatant K+ concentrations rise in RBC units during cold storage due to K+ leaking from red cells. All red cells have a small K+ leak, compensated in vivo by the sodium/K+ -ATPase pump (Na+/K+-ATPase). However, in cold-storage, the Na+/K+-ATPase is nonfunctional, and extracellular K+ rises [3]. RBCs can be stored for 35 to 49 days following donation, and supernatant K+ levels rise significantly with length of storage time [4]. This can be exacerbated by processes applied after RBC manufacturing, such as cryopreservation [5] or irradiation [6]. RBC irradiation is known to compromise RBC membrane integrity, affecting Na+/K+-ATPase function and accelerating K+ leakage [7]. Supernatant K+ rises more quickly after irradiation, at a similar rate regardless of storage age at irradiation [6,8]. It should be noted that the actual K+ concentration in transfused RBC units will be lower than measured in the supernatant alone due to the presence of RBCs.
Despite the easily demonstrable in vitro rise in RBC supernatant K+ concentration, evidence for RBC transfusion causing clinically significant hyperkalaemia and associated adverse events is less convincing. Most evidence that suggests a causal link between transfusion and hyperkalaemia is derived from case reports and small studies [9], [10], [11], [12], [13]. Additionally, a recent review summarised transfusion associated hyperkalaemic cardiac arrest (TAHCA) events in neonates and older children and highlighted their physiological susceptibility to electrolyte imbalances [14].
The risk of clinical hyperkalaemia, which may be transient, theoretically increases with quantity of K+, and therefore RBC storage time, irradiation and volume, infused. This places patients receiving large volume transfusions (LVT) at higher potential risk [13]. The rate of transfusion might also contribute, with greater risk with rapid transfusions through central venous access devices [12,13]. However, patients receiving rapid LVT in acute settings frequently have other risk factors for hyperkalaemia, such as hypotension with acidosis, tissue injury, hypothermia, or renal insufficiency [12,13]. Additionally, LVT can have other significant effects such as hypocalcaemia or even hypokalemia, resulting in difficulty in interpretation of causation of adverse clinical sequelae [15].
Concerns about the possible effect of hyperkalaemia following transfusion have led to the development of several potential mitigating procedures for vulnerable patients. These include washing of RBCs [16,17], RBC ultrafiltration [18], use of K+ filters [19], and use of short-storage RBCs (eg, <5 days from donation, within 24 hours of irradiation) for neonatal and infant LVT [20].
A detailed literature review in 2011 [12] summarised the evidence surrounding hyperkalaemia and transfusion, including potential risk factors and mitigation strategies. However, lack of good quality evidence meant that no causative relationship between transfusion and hyperkalaemia could be conclusively established.
Section snippets
Objectives
We planned a systematic review (SR) to critically analyse all evidence published following the review by Vraets et al. [12], to investigate the relationship between hyperkalaemia and RBC transfusion, including associated clinical adverse events, and whether mitigating strategies should be considered.
Methods
The protocol for this review was prospectively registered on PROSPERO [PROSPERO 2021 CRD42021252981], and the review was carried out in accordance with PRISMA guidelines [21].
Study Selection
After removal of duplicates, we screened 1671 references based on title and abstract, and excluded 1382 (Figure 1). We screened 289 articles at full text and excluded 253 (Figure 1 and Supplementary Material S1, App.2): 72 narrative or systematic reviews were hand-searched for additional references.
In deviation from our protocol, noncomparative studies were excluded due to availability of a significant number of comparative, higher-level studies (Figure 1 and Supplementary Material S1, App.2).
Discussion
Our SR is an update of a thorough, nonsystematic review conducted in 2011 [12]. Vraets et al suggested multiple risk factors for hyperkalaemia, but the authors were unable to fully answer several questions. These included whether transfusions cause hyperkalaemia, whether there is a transfusion rate that increases the risk, and what the most effective preventative strategies might be.
To our knowledge this is the first SR of comparative studies investigating hyperkalaemia following RBC
Conclusion
Overall, our SR found that the recent comparative evidence is too weak to support identification of groups most at risk of hyperkalaemia from transfusion, to support recommendations on the use of short-storage RBC, or to further define ‘short-storage’ in this context. For other commonly used risk mitigations for hyperkalaemia, the (very-low certainty) evidence was either conflicting or not supportive. Studies were often conducted in situations where significant K+ increase was unlikely and were
Contributions of Authors
Julia Wolf: clinician; developed the protocol, screened all titles, full texts, and performed hand-searching, extracted and quality appraised the data (risk of bias), wrote the manuscript of the review. Louise Geneen: systematic reviewer and methodologist; developed and registered the protocol, screened all titles and full texts, quality appraised the data (risk of bias and GRADE), undertook analyses, wrote the manuscript of the review. Athina Meli: principal scientist; developed the protocol,
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgments
Thanks to Dr Ka Ling Mak, who performed translation of Chinese to English and to Dr Mia Kahvo, who performed translation of French to English.We also thank Dr Joan Cid, Dr Pavel Trakhtman, and Dr Arvind Bishnoi for providing additional data from their studies.
Declaration of Competing Interest
No known conflicts of interest,
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