MINI REVIEW

published: 29 October 2021

doi: 10.3389/fped.2021.765306

Transfusion-Associated
Hyperkalemic Cardiac Arrest in
Neonatal, Infant, and Pediatric
Patients
Morgan Burke 1 , Pranava Sinha 2,3,4 , Naomi L. C. Luban 2,5,6 and Nikki Gillum Posnack 2,4,7,8*
1
School of Medicine, George Washington University, Washington, DC, United States, 2 Department of Pediatrics, School of
Medicine, George Washington University, Washington, DC, United States, 3 Division of Cardiac Surgery, Children’s National
Hospital, Washington, DC, United States, 4 Children’s National Heart Institute, Children’s National Hospital, Washington, DC,
United States, 5 Department of Pathology, School of Medicine, George Washington University, Washington, DC,
United States, 6 Division of Hematology and Laboratory Medicine, Children’s National Hospital, Washington, DC,
United States, 7 Department of Pharmacology & Physiology, School of Medicine, George Washington University, Washington,
DC, United States, 8 Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Hospital, Washington, DC,
United States

Red blood cell (RBC) transfusions are a life-saving intervention, with nearly 14 million
RBC units transfused in the United States each year. However, the safety and efficacy
of this procedure can be influenced by variations in the collection, processing, and
administration of RBCs. Procedures or manipulations that increase potassium (K+ )
Edited by: levels in stored blood products can also predispose patients to hyperkalemia and
Begum Atasay,
Ankara University Medical
transfusion-associated hyperkalemic cardiac arrest (TAHCA). In this mini review, we
School, Turkey aimed to provide a brief overview of blood storage, the red cell storage lesion,
Reviewed by: and variables that increase extracellular [K+ ]. We also summarize cases of TAHCA
Tuuli Metsvaht,
and identify potential mitigation strategies. Hyperkalemia and cardiac arrhythmias
University of Tartu, Estonia
Simone Pratesi, can occur in pediatric patients when RBCs are transfused quickly, delivered directly
Careggi University Hospital, Italy to the heart without time for electrolyte equilibration, or accumulate extracellular
*Correspondence: K+ due to storage time or irradiation. Advances in blood banking have improved
Nikki Gillum Posnack
[email protected]
the availability and quality of RBCs, yet, some patient populations are sensitive to
transfusion-associated hyperkalemia. Future research studies should further investigate
Specialty section: potential mitigation strategies to reduce the risk of TAHCA, which may include using fresh
This article was submitted to
Neonatology,
RBCs, reducing storage time after irradiation, transfusing at slower rates, implementing
a section of the journal manipulations that wash or remove excess extracellular K+ , and implementing restrictive
Frontiers in Pediatrics
transfusion strategies.
Received: 26 August 2021
Accepted: 29 September 2021 Keywords: transfusion, hyperkalemia, cardiac arrest, pediatric, neonate, red blood cell storage lesion, red
Published: 29 October 2021 blood cell

Citation:
Burke M, Sinha P, Luban NLC and
Posnack NG (2021)
INTRODUCTION
Transfusion-Associated Hyperkalemic
Cardiac Arrest in Neonatal, Infant, and Of the nearly 14 million blood transfusions in the United States each year, over 400,000 of
Pediatric Patients. these were administered to pediatric patients (1, 2). A recent multicenter study found that 79%
Front. Pediatr. 9:765306. of children in the intensive care unit for cardiac conditions received at least one red blood
doi: 10.3389/fped.2021.765306 cell (RBC) transfusion during their stay (3). Neonatal and pediatric patients are physiologically

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Burke et al. Transfusion-Associated Hyperkalemic Cardiac Arrest

different from adults, and as such, transfusion indications and The latter highlights the risk of electrolyte disturbances in
clinical management can present unique challenges (4, 5). For transfused patients. Irradiation further exacerbates RBC K+
example, younger patients are more susceptible to electrolyte leak, as increases in oxidative stress and red cell permeability
and metabolic consequences of transfusions (e.g., hyperkalemia, result in a two-fold increase in [K+ ] following blood product
hypocalcemia), since the amount of blood given during surgery irradiation (27–29). Upon transfusion, an acute spike in serum
or massive transfusion can equal the total blood volume of a [K+ ] can shift the myocardial resting membrane potential and
neonate, and the glomerular filtration rate of newborns does not trigger lethal arrhythmias (30). Indeed, transfusion-associated
reach maturity until near the first year of life (4, 6, 7). Moreover, hyperkalemic cardiac arrest (TAHCA) is a recognized transfusion
many children’s hospitals follow a dedicated donor strategy, complication (31).
wherein a single-donor unit is split into multiple pediatric packs
for use in a designated patient (8–10), up to the date of expiration.
This practice reduces the risk of multiple donor exposures,
but with the consequence that older RBCs are then used ADMINISTRATION OF RBC
for subsequent transfusions. Additionally, institutions that lack TRANSFUSIONS
irradiation facilities may procure RBCs that are already irradiated
off-site, which prolongs the time from irradiation to transfusion Both the RBC storage lesion and the method used to transfuse
and increases the risk of transfusion-associated hyperkalemia. RBCs can contribute to transfusion-associated complications.
Accordingly, the collection, processing, and administration of RBC transfusions are administered to neonatal, infant, and
RBC transfusions can influence the safety and efficacy of pediatric patients via a variety of methods, including: intravenous
transfusions and contribute to adverse events (11). Indeed, a (IV) catheter, handheld syringe infusion, or extracorporeal
recent multicenter study found that nearly 1% of pediatric circulation (32–34). Conventionally, RBC transfusions are
patients experience transfusion-associated hyperkalemia, which performed using a catheter, of variable bore size, placed
coincides with a 20% 1-day mortality rate (7) – thus, further peripherally in an accessible vein or via a central line (35).
highlighting the importance of additional study. Accordingly, the route of administration can influence electrolyte
homeostasis and the safety margin of this procedure. For
instance, central lines are more commonly associated with
THE RED BLOOD CELL STORAGE LESION hyperkalemia and cardiac arrest (25, 36). Whereas peripheral IV
infusions provide ample time for transfused blood to ionically
RBCs develop storage-induced damage and undergo a series equilibrate and redistribute K+ with surrounding tissues before
of biochemical, metabolic, and structural changes that are reaching the heart (35). Notably, patients with low cardiac output
collectively termed “the RBC storage lesion” [previously reviewed may still present with clinical hyperkalemia even in instances of
(12–14)]. Briefly, prolonged RBC storage results in glucose peripheral venous administration (35, 37).
depletion and a reduction in ATP production, which impairs The flow rate of the transfusion can also influence the
RBC membrane stability and increases hemolysis. Storage lesion likelihood of developing transfusion-associated hyperkalemia
severity can result in downstream physiological consequences and/or TAHCA. Transfusions with rapid flow rates can increase
that diminish both the safety and efficacy of RBC transfusions red cell hemolysis (32, 38) and also elevate K+ levels quickly
(12, 15–18). Accordingly, numerous biomarkers have been with inadequate time for equilibration. Miller et al., observed
identified to monitor the pathobiological changes that red that hemolysis increases with handheld syringes, resulting in
cells undergo during storage, including (but not limited to) a serum K+ concentration that exceeds the threshold for
measurements of free hemoglobin and non-transferrin bound arrhythmogenicity (32). While there are guidelines for the
iron, microvesicle production, 2, 3-diphosphoglyceric acid, maximum transfusion rate in pediatrics, in clinical practice, the
lactate, and extracellular [K+ ] (14, 19–23). Although metabolic rate of infusion is largely determined by the rate of blood loss and
processes are slowed during refrigeration, hypothermic indication for transfusion. In the operating room or emergency
storage impairs cation transporters which alters the electrolyte setting, the use of handheld syringes is a common practice for
composition of the RBC unit. As an example, Na+ /K+ ATPase neonatal and infant transfusions (32, 38), but can introduce
dysfunction results in K+ leak and accumulation within the considerable variability in the speed of administration compared
extracellular solution of stored RBC units. Extracellular K+ to automated pumps. Emergency circumstances that require fast
levels increase linearly at a rate of approximately 1 mEq/L rates of transfusion also decrease the allowable time for K+
each day during refrigerated storage – until an equilibrium redistribution, which further increases the risk of TAHCA (37).
point is reached at ∼ 60 mEq/L (24). Experimental studies by Transfusion-associated complications can also occur in
Bennett-Guerrero et al., reported a 376% increase in extracellular pediatric populations following large volume RBC transfusions.
[K+ ] within 3-weeks of storage, exceeding the maximum level Pediatric patients with congenital cardiac malformations often
of instrument detection (20 mmol/L) (14). Clinical studies undergo reconstructive surgery that requires the use of
have also observed high [K+ ] in RBC units stored for longer extracorporeal membrane oxygenation (ECMO). Although adult
periods of time, including a case report on the death of an patients can usually accommodate the volume of blood required
infant after cardiac surgery that involved the rapid transfusion to prime an ECMO circuit, this volume can exceed the total
of a 32-day RBC unit with high K+ levels (60 mEq/L) (25, 26). blood volume of a neonatal or infant patient. Consequently,

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Burke et al. Transfusion-Associated Hyperkalemic Cardiac Arrest

pediatric ECMO patients receive large volumes of RBCs (42–

105 ml/kg/day), which increases the risk of circulatory overload
and hyperkalemia (34, 39). Parshuram et al., reported a case in
which a 3-week old ECMO patient experienced TAHCA within
a few min of infusing RBC’s irradiated 10 days prior as part of
the circuit prime; a blood gas measurement denoted 9 mmol/L
[K+ ] at the time of cardiac arrest (40). Hyperkalemia has also
been observed in cardiopulmonary bypass (CPB) procedures,
especially when irradiated blood products are used in smaller
patients (<5kg) (41, 42). Indeed, a single RBC transfusion
can double an infant’s plasma [K+ ] (26, 43). Further, both
ECMO and CPB circuits place additional mechanical stress
on circulating RBCs from the tubing, connectors, cannulas,
and/or roller pump. This mechanical stress can alter the
membrane properties of RBCs, by increasing red cell fragility
and hemolysis (44–47). A study by the Naval Blood Research
Laboratory found that 15% of red cells were damaged within
24-h of extracorporeal circulation (47). Saline washing of
RBC’s is yet another form of mechanical stress that has
been shown to increase hemolysis and osmotic fragility (48).
Accordingly, fresh RBCs are preferred for neonatal and infant
patients undergoing cardiac surgery, ECMO, or an exchange
transfusion (49–51).

CONSEQUENCES OF
TRANSFUSION-ASSOCIATED
HYPERKALEMIA
Blood transfusions are life-saving procedures; nevertheless, RBC
transfusions are associated with a wide range of complications.
The latter includes increased postoperative complications and
infections, impaired postoperative recovery, longer hospital stay,
and increased morbidity following cardiac surgical procedures
(52–60). As previously discussed, RBC transfusions can also
FIGURE 1 | Transfusion-associated hyperkalemia can precipitate cardiac
precipitate hyperkalemia (26), as the extracellular solution of
electrical disturbances, which can present with peaked T-waves in the
stored RBC units can reach 40–70 mM [K+ ] (19, 25). Indeed, electrocardiogram. Further increase in serum [K+] can result in cardiac arrest.
more than 75% of critically ill (adult) patients and 18–23% Graphic generated in BioRender. ECG traces kindly provided by Dr.
of trauma (pediatric) patients experience elevated serum K+ Elizabeth Sherwin.
following RBC transfusion (61, 62). Upon transfusion, high K+
levels can shift the myocardial resting membrane potential and
precipitate adverse electrophysiological outcomes, from a short-
lasting atrial flutter to protracted ventricular fibrillation (30, 63). Recently, our laboratory conducted the first experimental
An acute increase in serum [K+ ] can delay electrical conduction study to show a direct correlation between red cell storage
in the atrioventricular node, His bundle, and Purkinje system, duration, hyperkalemia, and cardiac electrophysiology (69).
which manifests as a prolonged PR interval and widened Using intact heart preparations and human induced pluripotent
QRS complex (64). Hyperkalemia also predisposes the heart stem cell-derived cardiomyocytes, we reported that RBC
to pathological conditions, including ventricular tachycardia, storage age was associated with increased extracellular [K+ ],
ventricular fibrillation, atrioventricular block, and asystole (30, reduced cardiac automaticity, and slowed electrical conduction.
63, 64). In some cases, cardiac electrical instabilities may be Notably, cardiac electrophysiology parameters remained stable
detectable in electrocardiogram recordings (65, 66) before the following exposure to fresh RBC units, but older products
onset of severe events (Figure 1), such as cardiac arrest that precipitated bradycardia, impaired sinus node function, and
require immediate intervention (25, 67). As highlighted above, delayed atrioventricular conduction. The latter suggests that the
risk factors for TAHCA may include the volume and rate of storage age of blood products may be a modifiable risk factor for
RBC transfusion, storage age of blood products, and irradiation hyperkalemic cardiac arrest and warrants further investigation.
of red cells – although the perceived risk of TAHCA remains Although TAHCA is an adverse event that is anticipated
debated (68). by anesthesiologists, it can still prove difficult to manage.

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Burke et al. Transfusion-Associated Hyperkalemic Cardiac Arrest

In a simulation study (70), only one-fourth of anesthesia A number of clinical case reports have documented TAHCA
residents suspected hyperkalemia as an underlying cause of in patients receiving large volume transfusions, although we
pulseless electrical activity, and only one-third of residents have also highlighted reports of TAHCA following rapid, small
correctly resuscitated patients using the correct pediatric dose volume transfusions of older and/or irradiated blood products
of epinephrine. Further, a separate case series found that serum (66, 67, 82, 84, 88, 89, 91). Inoue et al., observed peaked T-waves
[K+ ] during or immediately after cardiac arrest ranged from 5.9– immediately after administering 10 mL of blood via handheld
9.2 mEq/L and that TAHCA had poor in-hospital survival of syringe to a 1.4kg newborn (82). In this specific case, blood was
only 12.5% (71). To improve patient outcomes, it is important administered via a central venous catheter, which can facilitate
to examine and understand how the composition of transfused the delivery of a higher K+ load to the heart without allowing
blood product(s), the method of transfusion administration, adequate time for redistribution. Similarly, Taylor et al., reported
and patient demographics (31, 72) can increase susceptibility that an infant developed hyperkalemia and cardiac arrhythmia
to TAHCA. Unfortunately, transfusion recipients often have after administering 5-day old blood in small 10 mL aliquots (91).
several comorbidities, which may result in underreporting of One possible explanation for developing clinical hyperkalemia
transfusion-associated adverse events (73). after small volume injections is the higher rate of hemolysis
when smaller needles are used and/or fast rates of transfusion
(32, 93). Other cases included transfused patients who received
fresh blood without incident, but later developed TAHCA after
TAHCA IN NEONATAL, INFANT, AND the administration of older and/or irradiated RBCs that were
PEDIATRIC PATIENTS stored for >24 h (25, 78, 79, 91). As an example, Hall et al.
reported the successful transfusion of 4 units of fresh blood to
The prevalence of transfusion-associated hyperkalemia and/or a 2-week-old male undergoing cardiac surgery without incident;
TAHCA is currently unknown, as reports are limited to case upon transfusion of 60 mL of 32-day old blood delivered via
studies and case reports. Nevertheless, hyperkalemia from blood a central line, the patient suddenly developed cardiac arrest
transfusion is the second most common cause of perioperative and died (25). In this case, the older blood products were
cardiac arrest in neonates, infants, and children as documented administered due to a shortage of fresh units. Similarly, Buntain
by the perioperative cardiac arrest registry, second only to et al., reported successful transfusion of 1.5 units of RBCs in
hypovolemia from blood loss (74). In Table 1, we have a craniofacial surgery, but, later the patient developed cardiac
summarized 24 case studies and reports of TAHCA in neonatal, arrest following the administration of 60 mL of 22-day old blood
infant, and pediatric patients – with data reported as indicated that had been irradiated 14-days prior (78). Kim et al., reported
in the original article (25, 37, 39, 40, 66, 67, 71, 75–92). We a case of a 9-month old patient with severe hypoxia receiving
also highlight a case report in which TAHCA was avoided ECMO support without incident for several days (39). In this
by pre-transfusion K+ filtration (87). Briefly, our literature case, the ECMO circuit was primed with RBCs <24 h post-
search identified TAHCA case reports and case series using the irradiation. However, after an oxygenator failed, a new ECMO
following search query: “hyperkalemia or hyperkalemic” AND circuit was primed with donor blood that had been stored 3-
“transfusion” AND “cardiac arrest” AND “neonate OR neonatal days post-irradiation. Immediately after restarting ECMO, the
OR infant OR pediatric” in both PubMed and Google Scholar patient went into cardiac arrest. ECMO is the equivalent of a
databases. Only reports on patients <18 years old were included. massive transfusion for pediatric patients, who are vulnerable to
Studies were excluded if transfusion-associated hyperkalemia was large fluctuations in electrolyte concentrations; moreover, in this
not explicitly associated with cardiac arrest, or if cardiac arrest clinical case a catheter was inserted directly into the right atrium
was attributed to another condition. A manual search of the cited of the patient, which minimized the diffusion potential of the
references was also performed. K+ load. In each of the described clinical cases, prolonged blood
Within the identified TAHCA case reports, patient’s age storage time (with or without irradiation) may have contributed
ranged from 1 h to 18 years old; with 24 patients <1 to the development of TAHCA, as the extracellular [K+ ] within
year old, and 16 reports of TAHCA in neonatal patients. the RBC unit increases linearly with time and doubles 24-h post-
Roughly half of these studies included transfusions that were irradiation (27).
carried out during surgical procedures such as cardiac surgery, We also noted clinical practices to avoid TAHCA using
trauma, spinal surgery, hip surgery, organ transplant, and pre-transfusion manipulations. Nakagawa et al., reported the
tracheoesophageal fistula repair. The remaining studies included avoidance of a hyperkalemic event by using a K+ adsorption
medical transfusions such as ECMO and exchange transfusion. filter (87). In this case, a 10-month old patient was undergoing
Fifteen reports included transfusions that were initiated centrally a liver transplant that required a massive transfusion, which was
through a venous catheter and thirteen reports included initiated with an in-line filter to reduce the [K+ ] from 16.3 to 1.9
transfusion via a peripheral vein. As observed in Table 1, there mEq/L. Additionally, Sohn et al., demonstrated the applicability
was a non-uniform method of reporting lab values between case of a continuous autotransfusion system (CATS) to reduce the
studies and reports. In the case of Morray et.al., the authors K+ level in donor blood before transfusion (90). In this case,
reported that there were three cases of TAHCA, but did not the patient received 1 unit of non-irradiated blood, followed
provide any additional details beyond two of the three patients by another unit of blood that was 5-days post-irradiation. The
suffering fatal arrhythmias (86). patient went into cardiac arrest shortly after the transfusion. After

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Burke et al.
TABLE 1 | Pediatric cases of transfusion-associated hyperkalemia cardiac arrest.

Patient age, genetic Transfusion volume, Blood storage age & [K+] in [K+] in patient Patient response Patient References
sex, weight, method of delivery irradiation unit (mmol/L) before and after outcome
procedure transfusion (mmol/L)

2-month-old, female, The patient received 120 mL Blood storage age: 6 55.3 Before: 4.1 Patient went into cardiac arrest Survived Baz et al., (67)
weight not reported. of RBCs. days After: 6.3 10 min into transfusion. (Lebanon)
Cardiac surgery. Central venous line. Irradiation: 48 h prior to Patient received CPR and
infusion cardiac defibrillation.
72-h-old, male, The patient received 500 mL Blood storage age: 9.55 Before: not reported Patient went into cardiac arrest Survived Bolande et al., (75)
∼3.5 kg. of RBCs. <21 days old After: 5.16 during the transfusion. (United States)
Exchange transfusion. Umbilical vein. Irradiation: not reported Resuscitation measures were
not reported.
<72-h-old, male, The patient received 485 mL Blood storage age: 22.7 Before: 5.4 Patient went into cardiac arrest Survived
∼3.5 kg. of RBCs. <21 days old After: 5.3 during the transfusion.
Exchange transfusion. Umbilical vein. Irradiation: not reported Resuscitation measures were
not reported.
<72-h-old, female, The patient received 500 mL Blood storage age: 21.1 Before: 3.95 Patient went into cardiac arrest Deceased
∼3.5 kg. of RBCs. <21 days old After: 6.55 shortly after the transfusion.
Exchange transfusion. Umbilical vein. Irradiation: not reported Resuscitation measures were
not reported.
<72-h-old, genetic sex The patient received 320 mL Blood storage age: 20.5 Before: 3.75 Patient went into cardiac arrest Deceased
not reported, ∼3.5 kg. of RBCs. <21 days old After: 7.75 shortly after the transfusion.
Exchange transfusion. Rapid injection via Irradiation: not reported Resuscitation measures were
5

umbilical vein. not reported.

2-day-old, genetic sex 1 RBC unit to prime Blood storage age: 5 28.1 Patient before: not Patient went into cardiac arrest Survived Bolton et al., (76)
not reported, 2.26kg. the circuit. days reported at the start of ECMO. (United Kingdom)
Venoveno ECMO. Right internal jugular vein Irradiation: yes After: 9.7 Patient received external
central venous catheter. cardiac massage.
9-year-old, male, Transfusion of 1L of RBCs Blood storage age: 10.2, 7.5, and Before: not reported Patient received 500 mL of 10% Deceased Bostic and Duvernoy
weight not reported. rapidly followed by 500 mL units were 13, 13, and 13.0, respectively After: not reported glucose in water with 15 units of (77)
Pulmonary laceration of RBCs slowly. 14 days old regular insulin. (United States)
after trauma. Method of delivery was respectively
not reported. Irradiation: not reported

Transfusion-Associated Hyperkalemic Cardiac Arrest

6-month-old, genetic Volume not reported. Blood storage: 13 days Not reported Before: 4.2 Patient developed ventricular Outcome not Brown et. al., (37)
sex not reported, 7 kg. The patient received rapid old After: 9.6 tachycardia intraoperatively reported (Canada)
Unspecified surgery. administration of Irradiation: not reported during RBC transfusion. Patient
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reconstituted whole blood received epinephrine,

via large bore bicarbonate and CPR.
intravenous access.
1.5-year-old, genetic Volume not reported. Blood storage: 13 days Not reported Before: 5.0 Patient went into cardiac arrest Outcome not
sex not reported, 7 kg. The patient received rapid old After: 7.3 intraoperatively during reported
Unspecified surgery. administration of Irradiation: not reported RBC transfusion. Patient
reconstituted whole blood received CPR.
via large bore
intravenous access.

(Continued)
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Burke et al.
TABLE 1 | Continued

Patient age, genetic Transfusion volume, Blood storage age & [K+] in [K+] in patient Patient response Patient References
sex, weight, method of delivery irradiation unit (mmol/L) before and after outcome
procedure transfusion (mmol/L)

1-year-old, genetic sex Volume not reported. Blood storage: 13 days Not reported Before: 3.1 Patient developed ventricular Outcome not
not reported, 8 kg. The patient received rapid old After: 7.5 tachycardia intraoperatively reported
Unspecified surgery. administration of Irradiation: not reported during RBC transfusion.
reconstituted whole blood Patient received epinephrine
via large bore and CPR.
intravenous access.
2-year-old, genetic sex Volume not reported. Blood storage: 21 days Not reported Before: 4.3 Patient developed asystole Outcome not
not reported, 11 kg. The patient received rapid old After: 12.3 intraoperatively during reported
Unspecified surgery. administration of Irradiation: not reported RBC transfusion.
reconstituted whole blood Patient received CPR.
via large bore
intravenous access.
2-year-old, genetic sex Volume not reported. Blood storage: >17 Not reported Before: 5.0 Patient went into cardiac arrest Outcome not
not reported, 12 kg. The patient received rapid days old After: 9.0 intraoperatively during reported
Unspecified surgery. administration of Irradiation: not reported RBC transfusion.
reconstituted whole blood Patient received epinephrine
via large bore and CPR.
6

intravenous access.
17-year-old, genetic Volume not reported. Blood storage: >18 Not reported Before: 5.3 Patient went into cardiac arrest Outcome not
sex not reported, 33 kg. The patient received rapid days old After: 7.3 intraoperatively during reported
Unspecified surgery. administration of Irradiation: not reported RBC transfusion.
reconstituted whole blood Patient received CPR.
via large bore
intravenous access.
13-year-old, genetic Volume not reported. Blood storage: 7 days Not reported Before: 3.4 Patient went into cardiac arrest Outcome not
sex not reported, 70 kg. The patient received a rapid old After: 6.4 intraoperatively during reported
Unspecified surgery. transfusion of RBC Irradiation: not reported RBC transfusion.

Transfusion-Associated Hyperkalemic Cardiac Arrest

concentrate diluted in Patient received CPR.
250mL of normal saline.
12-month-old, male, 1.5 units of RBCs over 2 h, Blood storage age: 3, 8.2, 30.1, >40, Before: 3.1 Patient went into cardiac arrest Survived Buntain and Pabari (78)
7.85 kg. then 2 units of RBCs over 17, 21, and 22 days and >40, After: 10.1 15 min after 20 mL of RBC via (Australia)
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Craniosynostosis 45 min, finally 20 mL old, respectively respectively syringe was administered.

repair. of RBCs. Irradiation: The first unit The patient received external
Peripheral venous line, final was not irradiated, the chest compressions, adrenaline
20mL was delivered via last three units were 1mg, atropine 0.4mg, calcium
handheld syringe. irradiated 14 days prior chloride 10% 25ml, Calcium
to transfusion Gluconate 10% 5ml, and
Sodium Bicarb 8.4% 20 ml.

(Continued)
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Burke et al.
TABLE 1 | Continued

Patient age, genetic Transfusion volume, Blood storage age & [K+] in [K+] in patient Patient response Patient References
sex, weight, method of delivery irradiation unit (mmol/L) before and after outcome
procedure transfusion (mmol/L)

7-year-old, female, 15 units of RBC over 4 h, Blood storage age: Not reported Before: 3.7 Patient went into cardiac arrest Deceased Chen et al., (79)
20 kg. then 100 mL of whole blood Whole blood was 16 After: 10.3 10 min after 100 ml of whole (Taiwan)
Hip surgery. over 10 min. days old. Age RBC blood was transfused.
The method of delivery was units not reported. Patient received external Cardiac
not reported. Irradiation: not massage CaCl2, NaHCO3, and
reported. regular insulin.
Fetus, genetic sex not Volume not reported. Blood storage age: 24.7 mmol/L Not reported Not reported Not reported Galligan, et al., (80)
reported, weight not Transfusion directly into the four-day-old gravity (Saudi Arabia)
reported. left ventricle of the heart. sedimented packed
Intracardiac cells
transfusion. Irradiation: not reported
2-week-old, male, 2 units of RBC < 5 days old Blood storage age: 2 32-day old unit ∼ Before: 4.2 Patient went into cardiac arrest Deceased Hall et al., (25)
3.2 kg. during CPB, 2 units of RBC units of RBC < 5 days 60 30 min before immediately after the second (United States)
Cardiac surgery. < 5 days old over 3 h post old during CPB, 2 units transfusion of transfusion of 32-day old blood.
op, then 60 mL RBC 32 of RBC < 5 days old, 32-day-old blood: 4.0 Patient received a
days old over 10 min. 60 mL RBC 32 days During cardiac arrest: cardiac massage.
7

Central venous catheter. old. 8.9 mmol/L

Irradiation: not reported After: not reported
7-month-old, female, 3 units of RBCs in mannitol- Blood storage age: Not reported Before: not reported CPR Survived Inaba, et al., (81)
weight not reported. adenine-phosphate. stored 8–10 days post After: 10.6 mEq per L. (Japan)
Ventricular septal Extracorporeal circuit irradiation
defect repair. Irradiation: yes
1-day-old, female, Two doses (10mL each) of Blood storage age: 8.0 Before: not reported Cardiac arrest shortly Deceased Inoue et al., (82)
1.4 kg. fresh umbilical cord blood. fresh After: 5.0 after transfusion. (Japan)
Left pneumonectomy. Handheld syringe. Central Irradiation: not reported Patient treated with 0.5mL of
venous catheter. 8.5% calcium gluconate.

Transfusion-Associated Hyperkalemic Cardiac Arrest

4-month-old, female, 320 mL of RBCs. Blood storage: not Not reported Before: 4.3 Patient went into cardiac arrest Survived Ivens et. al., (83)
6.65 kg. Cardiopulmonary reported After: 10.2 after the surgery while still (Belgium)
Surgical correction for bypass circuit. Irradiation: not reported on CPB.
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anomalous origin of left Resuscitation measures included

coronary artery. sodium bicarbonate, glucose,
insulin, and calcium chloride.
2 h old, male, 3.23 kg. 35 mL of RBCs. Blood storage age: not Not reported Before: >9.0 Patient went into cardiac arrest Survived Kavčič et al., (84)
Anemia. Method of delivery was reported After: 9.8 and an exchange transfusion (Slovenia)
not reported. Irradiation: not reported was initiated.

(Continued)
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Burke et al.
TABLE 1 | Continued

Patient age, genetic Transfusion volume, Blood storage age & [K+] in [K+] in patient Patient response Patient References
sex, weight, method of delivery irradiation unit (mmol/L) before and after outcome
procedure transfusion (mmol/L)

5-month-old, male, 60 mL of RBCs over 2.5 h. Blood storage age: 3-4 Not reported Before: 3.8 Cardiac arrest 1 h after start Survived Kang et al., (66)
3.6 kg. Arterial line. days After: 4.9 of transfusion. (United States)
Surgical repair of Irradiated 60 min prior Patient was treated
H-type with furosemide.
tracheoesophageal
fistula.
9-month-old, female, Extracorporeal volume of an Blood storage age: not 35 Before: not reported Cardiac arrest immediately after Survived TAHCA, Kim, et al., (39)
0.7 kg. ECMO circuit (∼260 ml). recorded After: 9.0 starting ECMO. but later died of (Korea)
ECMO. Catheter inserted directly 3-days post gamma CPR performed, calcium condition
into right atrium via irradiation gluconate treatment.
pulmonary artery (16Fr), and
(12F) venous
drainage cannula.
11-year-old, female, 1 unit of RBCs. Blood storage age: 9 >20.0 During cardiac arrest: Patient went into cardiac arrest Survived Martin et al., (85)
49 kg. Cardiopulmonary days old 9.9 shortly after the transfusion. (Peru)
Mitral valve bypass circuit. Irradiation: not reported After cardiac arrest: 4.9 Resuscitation measures included
replacement. Furosemide and
sodium bicarbonate.
3 patients, Volume reported as Blood storage age: not Not reported Not reported Not reported (1) Survived; Morray, et al., (86)
8

<18-years-old, weight “massive transfusion” reported (2) Deceased (United States)

not reported. Method of delivery Irradiation: not reported
Unspecified surgery. not reported.
10-month-old, female, 665mL of RBCs. Blood storage age: not Before Before: not reported Patient did not go into cardiac Survived. Nakagawa et al., (87)
7.3 kg. Method of delivery was reported filtering: 16.9 After: not reported arrest because of potassium (Japan)
Liver transplant. not reported. Irradiation: yes After filtering: 1.9 filter.
3-week-old, male, 8 kg. 146 mL of blood Blood storage age: 21 14.3 Before: 4.0 Patient went into cardiac arrest Survived Parshuram and Cox
Venovenous primed CVVH. days old After: 9.0 during initiation of blood (40) (Canada)
hemofiltration. Central venous catheter. Irradiation: 10 days primed CVVH.
prior to transfusion Patient received 3 boluses of 0.1

Transfusion-Associated Hyperkalemic Cardiac Arrest

mg/kg Epinephrine, 100% O2,
200 mg/kg CaCl2, and 3
mmol/kg NaHCO3.
October 2021 | Volume 9 | Article 765306

Neonate, male, weight 350 mL of RBCs. Blood storage age: Not reported Before: not reported Patient went into cardiac arrest Survived Pew (88)
not reported. Peripheral venous access. <24 h old After: 4.5 shortly after RBC administration. (United States)
Exchange transfusion. Irradiation: not reported Patient received a
cardiac massage.
28-h-old, male, 1.1 kg. 160 mL of RBCs. Blood storage age: 13.0 Before: 4.6 Patient went into cardiac arrest Deceased Scanlon and Krakaur
Exchange transfusion Method of delivery <48 h old After: 12.0 during the conclusion of the (89)
for disseminated not reported. Irradiation: not reported exchange transfusion. (United States)
intravascular
coagulation.

(Continued)
Frontiers in Pediatrics | www.frontiersin.org

Burke et al.
TABLE 1 | Continued

Patient age, genetic Transfusion volume, Blood storage age & [K+] in [K+] in patient Patient response Patient References
sex, weight, method of delivery irradiation unit (mmol/L) before and after outcome
procedure transfusion (mmol/L)

14-year-old, male, 3 units of RBCs Blood storage age: not Not reported Before: 4.6 Patient developed pulseless Survived Smith, et al., (71)
weight not reported reported After: 7.9 electrical activity. (United States)
Resection of spinal Irradiation: not reported Patient received chest
cord tumor. compressions and epinephrine.
9-year-old, female, 5 units of RBCs Blood storage age: not Not reported Before: 4.1 Patient developed pulseless Survived
weight not reported. reported After: 7.9 electrical activity.
Anterior spine Irradiation: not reported Patient received chest
instrumentation for compressions, atropine,
severe scoliosis. and epinephrine.
12-year-old, male, 6 units of RBCs Blood storage age: not Not reported Before: 3.9 Patient developed asystole. Deceased
weight not reported. Method of delivery was reported After: 7.1 Patient received chest
Anterior spine not reported. Irradiation: yes compressions and epinephrine.
instrumentation for
severe scoliosis.
2-day-old, male, 2.7 kg. 350 mL of RBC. Blood storage age: not Not reported Before: 3.6 Patient developed asystole. Deceased
Craniotomy for Arnold Method of delivery was reported After: 5.9 Patient received chest
Chiari III in premature not reported. Irradiation: yes compressions and epinephrine.
infant.
17-year-old, male, 39 units of RBCs Blood storage age: not Not reported. Before: 3.1 Patient developed asystole. Deceased
weight not reported. Method of delivery was reported After: >8 Patient received chest
9

Trauma. not reported. Irradiation: not reported compressions, epinephrine,

bicarbonate, and calcium.
1-month-old, male, 28 units of RBCs. Blood storage age: not 19.9 Before: 3.7 Cardiac arrest shortly after rapid Deceased Sohn et al., (90)
3.1 kg. Double lumen (4Fr) venous recorded After: 14.2 injection of 80 ml RBCs. (Korea)
Surgical repair of catheter in the right Irradiation: 5-days post Patient treated with 10 U insulin,
hemorrhagic mass in subclavian vein. 50 ml of 50% dextrose, multiple
left posterior fossa. doses of epinephrine, 0.1 mg
atropine, 30 mg CaCl2 and
chest compressions.

Transfusion-Associated Hyperkalemic Cardiac Arrest

1-h-old, female, 384 mL of RBCs during the Blood storage age: >20.0 Before: 4.3 The first cardiac arrest happened Deceased Taylor et al., (91)
2.22 kg. first exchange, then 6 h later Third unit was 7 days After: 12 a few moments after the second (Canada)
Exchange transfusion. received another 290 mL of old, the other units age volume exchange. The second
RBCs. That 22 h received was not reported. cardiac arrest occurred 32
October 2021 | Volume 9 | Article 765306

yet another 70 mL of 7-day Irradiation: not reported minutes after the third exchange.
old blood. Patient received 2 mL of Calcium
Peripheral venous access. glucoheptonate each time.
1-h-old, male, 2.16 kg. 185 mL of RBCs in 15 Blood storage age: 5 Third exchange Before: 6.9 Patient went into cardiac arrest Survived
Exchange transfusion. mL aliquots. days old unit: 9.7 After: 7.6 immediately after the injection of
Peripheral venous access. Irradiation: not reported the aliquots. Patient received
1.5 mL calcium gluconate.
16-year-old, male, 9 units of RBC over 90 min. Blood storage age: not Not reported Before: not reported Patient went into cardiac arrest Survived Woodforth (92)
29.6 kg. Peripheral venous access. reported After: 12.0 9 h into the surgery. (Australia)
Anteroposterior spine Irradiation: not reported Patient received
fusion. chest compressions.
Burke et al. Transfusion-Associated Hyperkalemic Cardiac Arrest

restoring normal cardiac function, the surgical team utilized irradiated blood products are transfused, and when blood
CATS to prevent TAHCA during the transfusion of another 26 products are administered via a central line vs. a peripheral site
RBC units. These strategies may be useful in situations where (25, 36, 71). Further, the use of handheld syringes with small
fresh RBC units are in short supply. bore needles can increase hemolysis at the injection site and
is a potential cause of transfusion-associated hyperkalemia in
POTENTIAL MITIGATION STRATEGIES TO emergency situations (32, 38). Although there is debate around
whether transfusion-associated hyperkalemia causes cardiac
REDUCE THE INCIDENCE OF
arrest and increases the incidence of TAHCA, there is no doubt
HYPERKALEMIA that an increased serum [K+ ] can exacerbate a precarious
physiological state in transfused patients (26, 83). While the
Strategies to reduce the incidence of TAHCA include the use
prevalence of TAHCA is not known and may be underreported
of fresh blood products, reducing storage time post-irradiation,
(73); we have highlighted 24 case reports and case series that
slower rates of transfusion, and other manipulation techniques.
identify potentially fatal outcomes if appropriate precautions
Current standard of practice dictates that blood units <5 days
are not taken to remedy electrolyte imbalance. TAHCA is not
old and within 24 h of irradiation are employed in massive
unique to neonatal and pediatric populations (61, 71), but
transfusion (50, 94); although older RBC units are administered
these patients have increased susceptibility due to their unique
if fresh units are not readily available. Fresh RBC units are
physiology. There is a 20% 1-day mortality rate in pediatric
also preferred for neonatal and pediatric cardiac surgery (95).
patients who experience TAHCA (7), and hyperkalemia after
Fresh whole blood (<48 h) has been used for cardiac surgery
transfusion is the second most common cause of perioperative
at a few select institutions (96), although whole blood is not
cardiac arrest in neonates, infants, and children (74). Potential
routinely available to most transfusion services. For children
strategies to mitigate the risk of TAHCA include the use of
receiving ECMO, consensus panels recommend the use of fresh
fresh RBCs for pediatric cardiac surgery and ECMO, limiting
RBCs within 5-days of collection and irradiated RBCs are used
the duration of storage post-irradiation, washing RBCs and/or
within 24-h (50). This recommendation stems from the lack of
pre-bypass filtration to remove extracellular K+ , slower rates
evidence-based data required to reach consensus on the safety
of transfusion, and the use of specialized pre-transfusion filters
of older RBCs in the context of critically ill children (34, 97).
to reduce [K+ ] (42, 81, 87, 93, 101, 102, 104). To abrogate
Finally, blood sparing and blood conservation procedures are
TAHCA in the future, additional studies are warranted to
recommended to reduce the number and volume of RBCs
evaluate the safety and efficacy of these mitigation strategies
transfused to neonatal, infant, and pediatric patients (98).
and/or implementation of restrictive transfusion strategies
RBC washing with a non-plasma solution is another potential
(97, 105). Indeed, restrictive transfusion strategies can also
mitigation strategy, which reduces the extracellular [K+ ] to a
help to mitigate blood supply shortages that have resulted
physiologically-compatible level (99, 100). This strategy has been
from the COVID-19 pandemic, due in part to fewer blood
adopted in cardiac surgery cases requiring cardiopulmonary
donations (106).
bypass. Swindell et al., reported that pre-washing irradiated
RBCs reduced [K+ ] from >20 to 0.8 mmol/L (42). Further,
36% of patients receiving unwashed, irradiated RBCs had AUTHOR CONTRIBUTIONS
a serum [K+ ] >6 mmol/L during cardiopulmonary bypass
compared to 0% of patients receiving pre-washed RBCs. Pre- MB and NP performed a literature search and generated
bypass ultrafiltration can also normalize electrolyte levels and Table 1. MB, NP, NL, and PS drafted and approved the
reduce the risk of hyperkalemia. Delaney et al., reported that manuscript. All authors contributed to the article and approved
ultrafiltration significantly reduced [K+ ] from 10.9 to 6.0 mEq/L the submitted version.
in ECMO circuits primed with fresh RBCs (101). Utilization
of K+ adsorption filters to normalize electrolyte levels during FUNDING
extracorporeal support is another potential mitigation strategy,
as in-line filters can remove >90% of extracellular K+ while This work was supported by the National Institutes of Health
maintaining flow rates up to 50 mL/min (81, 87, 102). (R01HL139472 to NP), Children’s National Heart Institute,
Sheikh Zayed Institute for Pediatric Surgical Innovation, and the
CONCLUSION Children’s National Research Institute.

Transfusion-associated hyperkalemia is a recognized ACKNOWLEDGMENTS

complication of massive and rapid RBC transfusions in
neonates, infants, and children (103). Based on available case The authors gratefully acknowledge Devon Guerrelli and Dr.
reports, clinical hyperkalemia can occur when aged and/or Elizabeth Sherwin for assistance with Figure 1.

Frontiers in Pediatrics | www.frontiersin.org 10 October 2021 | Volume 9 | Article 765306

Burke et al. Transfusion-Associated Hyperkalemic Cardiac Arrest

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93. Harm SK, Raval JS, Cramer J, Waters JH, Yazer MH. Haemolysis and absence of any commercial or financial relationships that could be construed as a
sublethal injury of RBCs after routine blood bank manipulations. Transfus potential conflict of interest.
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94. New HV, Berryman J, Bolton-Maggs PHB, Cantwell C, Chalmers EA, Davies Publisher’s Note: All claims expressed in this article are solely those of the authors
T, et al. Guidelines on transfusion for fetuses, neonates and older children. Br and do not necessarily represent those of their affiliated organizations, or those of
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the publisher, the editors and the reviewers. Any product that may be evaluated in
95. New HV, Stanworth SJ, Engelfriet CP, Reesink HW, McQuilten ZK,
this article, or claim that may be made by its manufacturer, is not guaranteed or
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with use of fresh whole blood in pediatric cardiac surgical procedures. Ann Copyright © 2021 Burke, Sinha, Luban and Posnack. This is an open-access article
Thorac Surg. (2015) 99:1706–11. doi: 10.1016/j.athoracsur.2014.12.070 distributed under the terms of the Creative Commons Attribution License (CC BY).
97. Valentine SL, Bembea MM, Muszynski JA, Cholette JM, Doctor A, The use, distribution or reproduction in other forums is permitted, provided the
Spinella PC, et al. Consensus recommendations for RBC transfusion original author(s) and the copyright owner(s) are credited and that the original
practice in critically ill children from the pediatric critical care transfusion publication in this journal is cited, in accordance with accepted academic practice.
and anemia expertise initiative. Pediatr Crit Care Med. (2018) 19:884– No use, distribution or reproduction is permitted which does not comply with these
98. doi: 10.1097/PCC.0000000000001613 terms.

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