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Specific Etiologies Associated With the Multiple

Organ Dysfunction Syndrome in Children: Part 2

Jeffrey S. Upperman, MD1; John C. Bucuvalas, MD2; Felicia N. Williams, MD3; Bruce A. Cairns, MD3;
Charles S. Cox Jr., MD4; Allan Doctor, MD5; Robert F. Tamburro, MD, MSc6

Objective: To describe a number of conditions and therapies asso- Data Extraction: Moderated by an expert from the field, issues rel-
ciated with multiple organ dysfunction syndrome presented as part evant to the association of multiple organ dysfunction syndrome
of the Eunice Kennedy Shriver National Institute of Child Health with a variety of conditions and therapies were presented, dis-
and Human Development Multiple Organ Dysfunction Workshop cussed, and debated with a focus on identifying knowledge gaps
(March 26–27, 2015). In addition, the relationship between burn and the research priorities.
injuries and multiple organ dysfunction syndrome is also included Data Synthesis: Summary of presentations and discussion sup-
although it was not discussed at the workshop. ported and supplemented by relevant literature.
Data Sources: Literature review, research data, and expert opinion. Conclusions: Sepsis and trauma are the two conditions most
Study Selection: Not applicable. commonly associated with multiple organ dysfunction syndrome
both in children and adults. However, many other pathophysi-
ologic processes may result in multiple organ dysfunction syn-
Division of Pediatric Surgery, Children’s Hospital Los Angeles, Keck
School of Medicine, University of Southern California, Los Angeles, CA. drome. In this article, we discuss conditions such as liver failure
Department of Pediatrics, University of Cincinnati, Cincinnati Children’s and pancreatitis, pathophysiologic processes such as ischemia
Hospital Medical Center, Cincinnati, OH. and hypoxia, and injuries such as trauma and burns. Addition-
Department of Surgery, University of North Carolina, North Carolina ally, therapeutic interventions such as medications, blood trans-
Jaycee Burn Center, Chapel Hill, NC. fusions, transplantation may also precipitate and contribute to
Department of Pediatric Surgery, UT-Health, Children’s Memorial multiple organ dysfunction syndrome. The purpose of this article
Hermann Hospital, Houston, TX.
is to describe the association of multiple organ dysfunction syn-
Departments of Pediatrics and Biochemistry, Washington University in
Saint Louis, Saint Louis, MO. drome with a variety of conditions and therapies in an attempt to
Pediatric Trauma and Critical Illness Branch, Eunice Kennedy Shriver identify similarities, differences, and opportunities for therapeutic
National Institute of Child Health and Human Development, National intervention. (Pediatr Crit Care Med 2017; 18:S58–S66)
Institutes of Health, U.S. Department of Health and Human Services, Key Words: liver failure; multiple organ dysfunction syndrome;
Bethesda, MD.
pancreatitis; transfusion; trauma and burns
This information or content and conclusions are those of the authors and
should not be construed as the official position or policy of, nor should
any endorsements be inferred by, the National Institutes of Health, the
U.S. Department of Health and Human Services, or the U.S. government.

Drs. Upperman, Bucuvalas, and Doctor received support for article research here are a number of pathophysiologic processes that
from the National Institutes of Health (NIH). Dr. Cairns received funding
from GlaxoSmithKline. Dr. Doctor’s institution received funding from the
may result in the multiple organ dysfunction syndrome
NIH (National Institute of General Medical Sciences R01GM113838), (MODS) in children. To begin, underlying diagnoses
Department of Defense, and Children’s Discovery Institution. His institu- such as cancer and congenital heart disease as described in
tion received funding from the NIH, Department of Defense, and Chil-
dren’s Discovery Institution. Dr. Tamburro’s former institution received part 1 of this article, as well as inborn errors of metabolism,
funding from U.S. Food and Drug Administration Office of Orphan Product rheumatologic diseases, and various others have been associ-
Development Grant Program and from Ony (provided the calfactant free ated with a predisposition to the syndrome. Similarly, acute
of charge for the above grant which assessed the efficacy of exogenous
surfactant in pediatric hematopoietic stem cell transplant patients with conditions such as sepsis, acute respiratory distress syndrome,
acute lung injury). He received funding from Springer Publishing for serv- acute kidney injury (AKI), liver failure, and pancreatitis have
ing as an editor on a Pediatric Critical Care Study Guide: Text and Review, also been associated with the process. Additionally, patho-
and he disclosed government work. The remaining authors have disclosed
that they do not have any potential conflicts of interest. physiologic processes such as hypoxia (of any source) can be
For information regarding this article, E-mail: robert.tamburro@nih.gov potent triggers of MODS as observed following cardiopul-
Copyright © 2016 by the Society of Critical Care Medicine and the World monary arrest. Further, acute insults such as multiple trauma
Federation of Pediatric Intensive and Critical Care Societies and thermal injuries have also been found to result in MODS.
DOI: 10.1097/PCC.0000000000001051 Conversely, numerous treatments and therapeutic regimens

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MODS Supplement

such as antineoplastic therapies, blood transfusions, hemato- with vasodilatation and complications of portal hypertension.
poietic, and solid organ transplantation have all been reported With ACLF, bacterial translocation across the intestine occurs
to elicit MODS. Given the breadth of these various topics, any in the setting of decreased immunosurveillance of the innate
attempt to provide a comprehensive review of the many etiolo- and adaptive immune systems. This bacterial infection is asso-
gies of MODS would be grossly insufficient, and thus that is ciated with worsening systemic hemodynamics and MODS.
not the intent of this article. Conditions commonly associated Transplant-free mortality is increased five-fold in adults with
with MODS such as inborn errors of metabolism, brain injury ACLF (51%, 90-day mortality) compared with acute decom-
and neurological insults, and rheumatologic disorders are not pensation of cirrhosis (10%, 90-day mortality). The number
addressed in this, or its accompanying article. The available lit- of organ failures is directly related to the risk of mortality, and
erature contains a host of publications and reviews addressing disease severity tools for liver disease (i.e., MELD, PELD) do
these individual topics and their association with MODS. The not accurately reflect risk.
purpose of this article, in conjunction with part 1, is simply to
encourage investigators to consider the topic from the perspec- Acute Liver Failure
tive of other disciplines to hopefully identify the areas of com- Acute liver failure is a devastating condition which may com-
monality, enhance the body of knowledge of other disciplines, monly be associated with MODS including renal, bone mar-
and identify the opportunities for future study. row, and central nervous system failure (4). The primary
etiology is not established in almost 50% of children (5). Liver
HEPATIC FAILURE/SOLID ORGAN transplantation can serve as directed therapy for patients with
TRANSPLANTATION acute liver failure when treatment fails to rescue the patient
MODS is a critical problem for patients who receive solid from clinical deterioration. Although liver transplantation may
organ transplantation, as well as those with disease processes be life-saving, the decision to proceed with transplantation is
that put them at risk for requiring a transplant such as acute irreversible and has profound consequences, both on organ
and chronic liver failure. As with other causes of MODS, dis- allocation and on long-term challenges faced by the patient
ordered regulation of the immune system and endothelial dys- and family. Patients who receive transplantation for pediatric
function play a central role in these processes. Consequently, an acute liver failure have increased short-term and long-term
understanding of the clinical phenotypes and/or mechanisms mortality risk compared with those with chronic liver dis-
of injury associated with MODS in patients with acute and/or ease. Death in the immediate post-transplant period is usually
chronic liver failure or in solid organ transplant recipients may attributed to MODS, sepsis, or cerebral edema. Patients with
help inform MODS in other disease processes. indeterminate acute liver failure have excess late mortality risk
most commonly related to sepsis; they are also at increased risk
Cirrhosis for developing aplastic anemia.
In cirrhosis, vasodilatation occurs in the systemic vasculature As part of the pediatric acute liver failure effort (U01
and in the splanchnic vascular bed in response to liver fibrosis as DK072146 Squires), markers of immune activation were mea-
portal hypertension results in poor clearance of vasoactive pep- sured in 77 children with acute liver failure (6). The normalized
tides which promotes endothelial dysfunction. This endothelial serum soluble interleukin-2 receptor alpha (sIL2Rα) level was
dysfunction, in turn, decreases afterload and promotes excessive higher in patients who died (p = 0.02) or underwent liver trans-
myocardial contractility. As a result, systolic function is not only plant (p = 0.01) than that in those who survived with native liver
disproportionately high, but diastolic function, or relaxation (7). Of the 15 subjects with markedly high sIL2Rα levels (≥ 5,000
becomes compromised (1, 2). Such alterations in cardiac func- IU/mL), five survived with their native liver, two died, and eight
tion may be clinically silent, until made evident by intercurrent underwent liver transplant (7). The investigators subsequently
stress. Furthermore, dilatation of the pulmonary vasculature in analyzed serum inflammatory mediators and found that liver
cirrhosis may result in hepatopulmonary syndrome secondary transplant recipients had a biomarker pattern more similar to
to right to left shunting of blood through pulmonary angiomas. spontaneous survivors than those of nonsurvivors (8). If con-
Further, the renin-angiotensin-aldosterone system is activated in firmed, such findings might allow for the use of immunomodu-
response to the dilatation of the systemic vascular bed resulting latory therapy to improve outcomes and potentially decrease the
in the release of vasopressin and an increased risk for hepatore- use of liver transplants (Table 1).
nal syndromes types I and II. Each of the pulmonary and renal
changes is associated with pretransplant morbidity and justi- Solid Organ Transplantation
fies Model for End-Stage Liver Disease (MELD) and Pediatric Thrombotic microangiopathy (TMA), recognized as a cause of
End-Stage Liver Disease (PELD) exception points. In the end, all morbidity and mortality in stem cell transplant recipients (part 1),
changes directly or indirectly reflect altered endothelial function. is increasingly detected in solid organ transplant recipients (9, 10).
TMA results from dysregulation of complement activation. With
Acute on Chronic Liver Failure (ACLF) solid organ transplant recipients, endothelial injury and micro-
Acute decompensation of cirrhosis versus ACLF is distin- angiopathy are likely multifactorial reflecting ischemia reperfu-
guished by the presence of organ failure (1, 3, 4). In the for- sion injury associated with transplant, infections, inherited or
mer, increased fibrosis and portal hypertension are associated acquired complement dysregulation, and injury from exposure to

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Table 1. Identified Knowledge Gaps and Potential Opportunities for Study

Current disease stratification tools of acute and chronic liver failure are inadequate, and therefore, it is difficult to effectively predict
which patients are at risk or how risk evolves over time. Understanding the pathobiology and the development of risk stratification
using molecular and computational techniques would potentially guide risk stratification, permit trials targeted to mitigate injury,
improve organ allocation, and decrease mortality.
A better understanding of serum inflammatory mediators and biomarker patterns in acute liver failure might help distinguish
spontaneous survivors from nonsurvivors and allow for the use of immunomodulatory therapy to improve outcomes and
potentially decrease the use of liver transplants.
There appears to be a need for the validation in children of criteria used in adults to diagnose acute pancreatitis including
prospective studies that standardize etiological classifications.
The natural history of pancreatitis in children needs to be better established in order to understand factors predicting disease
severity, complications, and the progression to MODS.
A better understanding of the molecular details associated with acute pancreatitis and their relationship to MODS needs to be
The mechanisms by which acute kidney injury precipitate dysfunction in other organs are not clearly established; conversely, the
mechanisms by which the kidney is secondarily injured as part of MODS are also not well understood.
An expansion of the understanding of the manner by which the hyperdynamic metabolic and catabolic responses associated with
major pediatric burn contribute to the risk of MODS may result in better outcomes.
Further work assessing the genomic and proteomic profiles associated with burn injury may help to improve morbidity and mortality
and reduce the occurrence of MODS in this patient population.
A better understanding of the inflammatory and counter-inflammatory changes associated with major trauma is needed; such
insight might afford opportunities to intervene and mitigate the occurrence and severity of associated MODS.
The natural history of trauma associated coagulopathy in children needs to be better delineated and understood in the context
of injury severity. The role of thromboelastography-driven resuscitation protocols in decreasing the morbidity and mortality
associated with pediatric trauma warrants investigation.
A decision-making structure is needed to guide RBC transfusion both in terms of timing and amount based upon outcome-linked
physiologic O2 delivery targets.
The ability to quantify O2 delivery and consumption measurements, to relate these measurements to O2 sufficiency and reserve at
the whole body, organ, and tissue levels, and to attribute these variables to anemia must be developed.
MODS = multiple organ dysfunction syndrome.

medications such as calcineurin inhibitors. As a result of uncon- there has been a rising trend in the number of patients pre-
trolled complement activation, patients with TMA have hemolytic senting with acute pancreatitis in the past decade (12). With
anemia, pulmonary hypertension, and renal insufficiency with this increase, there has also been an increase in the number
evidence of gastrointestinal and central nervous system injury. of patients who are developing MODS in the setting of acute
The risk of death is related to the number of involved organs. pancreatitis. However, the reasons that drive a subpopulation
Early data suggest that blockage of terminal steps in complement of patients with pancreatitis to develop MODS and the process
activation with ecluzimab may mitigate injury (11). by which acute pancreatitis transitions to MODS are not well
understood (Table 1). Some experts are unsure whether pan-
Summary creatitis is a primary driver or a byproduct of MODS.
MODS is a critical problem with acute and chronic liver failure In recent years, the pathophysiology of pancreatitis has
and for those who receive solid organ transplant. It appears that been the focus of multiple laboratories throughout the world.
immune dysregulation and endothelial dysfunction play a central Still, the molecular details of the events that lead to pancreatitis
role in the pathogenesis of MODS. Current disease stratification remain uncertain. A number of hypotheses have been offered
tools are inadequate, and therefore, we cannot effectively predict (12–14). Many center on the premature activation of tryp-
which patients are at risk or how risk evolves over time. Under- sinogen within the acinar cell. Other models invoke excessive
standing the pathobiology and the development of risk stratifica- activation of the unfolded protein response, which results in
tion tools using molecular and computational techniques would activation of cell-death pathways. In each case, the damage to
guide risk stratification, permit trials targeted to mitigate injury, acinar cells triggers an inflammatory response and the release
improve organ allocation, and decrease mortality. of digestive enzymes into the circulation.
Some experts speculate that the increased levels of pancre-
PANCREATITIS atic digestive enzymes in the bloodstream may lead to an imbal-
In addition to liver disease, other disease processes of the gas- ance in cytokines resulting in MODS (12, 15). Others propose
trointestinal tract may be associated with MODS. For example, that MODS develops as a result of a robust local inflammatory

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MODS Supplement

response (15). Still others suggest that MODS occurs primarily Not surprisingly, the presence of MODS has been associ-
in the setting of infected pancreatic necrosis and sepsis (16). ated with increased mortality among children who receive
Regardless of the trigger, patients with MODS present with a continuous RRT (CRRT) for any indication (26). The use of
systemic inflammatory response syndrome (SIRS) and/or a CRRT associated with MODS is frequently in the setting of
compensatory anti-inflammatory response syndrome (CARS) sepsis. In the surviving sepsis management guidelines, CRRT
(14, 17). In the case of SIRS, there is an activation of the vas- is suggested to facilitate fluid management in hemodynami-
cular endothelium, neutrophils, and biological defenses, which cally unstable septic patients and specifically for children to
results in early phase complications and morbidity, eventually prevent greater than or equal to 10% fluid overload (27). The
resulting in the occurrence of MODS (13). In CARS, there is indication for CRRT commencement in this setting is often
an excessive anti-inflammatory response and compromised for hypermetabolic syndrome associated with fluid overload.
immune function, which leads to late-phase complications In this clinical condition, CRRT may facilitate effective fluid
such as infected pancreatic necrosis and abscess formation. management removing sufficient fluid to prevent symptom-
The data supporting these models are sparse. It is important to atic overload and allowing for the provision of adequate nutri-
gain a better understanding of the pathophysiologic changes at tion and necessary medications. Temperature control is also
the level of the pancreas that incite the downstream effects that effectively achieved and maintained with the use of CRRT.
culminate in MODS. Although the true benefit of CRRT in this setting remains to
In addition, there would appear to be an immediate need for be clearly established, some data suggest benefit with its use
the validation in children of criteria used in adults to diagnose among children with multiple organ failure (28). A miniatur-
acute pancreatitis including prospective studies that standard- ized Cardio-Renal Pediatric Dialysis Emergency Machine has
ize etiological classifications (12, 17). Additionally, multicenter been developed and published case reports suggest its benefit
studies on the natural history of this disease in children would in neonates with MODS (29, 30).
also appear needed in order to understand factors predicting
disease severity and complications (12). Finally, it would seem BURN PATIENTS
important for a better understanding of the molecular details In addition to medical conditions, MODS has also been associ-
of acute pancreatitis to be attained (Table 1). The development ated with a host of external injuries including multiple trauma
of better research models, particularly to elucidate the mecha- patients and burn victims. Although not discussed as a sepa-
nisms of genetic risk factors, would seem essential to facilitat- rate topic at the Workshop, this section is included given the
ing such an understanding. prevalence of burn injuries in children and their association
with MODS. For example, a recent, relatively large single cen-
AKI ter trial reported MODS to occur in 19% of children with a
AKI occurs between 20% and 60% of children and neonates burn area that encompassed at least 30% of the body surface
admitted to critical care units (18). This wide range likely reflects, area (31). Furthermore, pediatric burn patients represent a
to some degree, the variability in definitions used to identify and unique group with a profound and poorly understood dys-
diagnose AKI. Over the past decade, the use of the Risk, Injury, functional immune, metabolic, and catabolic response com-
Failure, Loss, End-Stage Renal Disease (RIFLE), pediatric RIFLE, mensurate to the original size of the thermal injury (32).
Acute Kidney Injury Network, and Kidney Disease: Improving Physiologically, the post burn response is manifested by meta-
Global Outcomes guidelines has been created to give a more bolic rates well above normal, increased cardiac work, muscle
definitive ranking of the degree of AKI based on a rising serum protein catabolism, profound lipolysis, insulin resistance and
creatinine level and/or diminishing urine output (19). Addition- liver dysfunction (33). Virtually every organ system is affected
ally, biomarkers (e.g., neutrophil gelatinase-associated lipocalin, by major burn injury with perturbations mediated by surges in
kidney injury molecule-1, interleukin [IL]-18) are being used as catecholamines, cortisol, glucagon and pro- and anti-inflam-
research tools to identify “subclinical” AKI (20). Prior to these matory cytokines (33). In one study, MODS was found to be
various tools, the literature-based definition of AKI was often associated with the size of the burn, full thickness burns, and
simply the need for renal replacement therapy (RRT) (21). Data an associated inhalational injury. Not surprisingly, the occur-
suggest that the need for RRT is associated with a greater risk rence of MODS was associated with a longer length of ICU
of death (22). In fact, the presence of AKI is associated with stay, a greater number of major infections, and a substantially
increased mortality in children; recent data reveal that early AKI higher mortality.
is associated with a seven-fold increase in mortality (23). Among Research over the last fifty years has focused on defining
children with acute decompensated heart failure, the presence of the clinical challenges encountered from the onset of thermal
worsening renal function (defined as a serum creatinine increase injury: the resuscitation, the acute hospitalization, and the reha-
≥ 0.3 mg/dL) was associated with a 10-fold increase in the com- bilitation. Encouragingly, substantial gains in the understand-
bined endpoint of either death or the need for mechanical cir- ing of the clinical response have resulted in improvements in
culatory support (24). Among children with sepsis and MODS, morbidity and mortality. Current standards of care underscore
the development of AKI is a discouraging prognostic sign (25) these advances and awareness: early excision and grafting, early
As with other organ injuries, AKI may be the precipitant of enteral nutrition, and environmental thermoregulation (33).
MODS or one of the organs injured as part of the syndrome. As knowledge is gained and care informed, new and deeper

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questions arise that must be addressed. For example, the hyper- admitted to a PICU with an injury severity score greater than
dynamic metabolic and catabolic response associated with nine (56). Much of that morbidity would appear to be asso-
major pediatric burn clearly contributes to the risk of MODS ciated with traumatic brain injury (TBI) as the incidence of
(Table 1). To address these concerns and attenuate the pervasive MODS in pediatric trauma patients decreases substantially
growth retardation after severe burns, early enteral nutrition, when TBI patients are excluded from analysis (57). The patho-
based on metabolic carts has become standard (33). Other strat- genesis of MODS associated with pediatric trauma is just
egies, such as increased ambient temperatures in the operating beginning to be elucidated, but would appear to emanate from
and hospital room successfully limit metabolic rates and sub- a variety of potential causes including inflammation, immune
stantially improve gains associated with early enteral nutrition dysfunction, endothelial injury, secondary infection and hem-
(33). However, as composition of standard tube feedings change, orrhage. Data suggest that IL-6 levels are elevated in critically
maintaining the balance between increasing lean body mass and injured children with some data suggesting an association
fat gain has been a challenge. It is not definitively established between these levels and the occurrence of MODS (56, 58).
whether supplementation with arginine, high dose glutamine, Additionally, immunoparalysis has also been reported in criti-
or other amino acids will benefit this patient population (34). cally injured pediatric trauma patients using ex vivo lipo-
Additionally, propranolol administration during acute hos- polysaccharide-induced tumor necrosis factor α production
pitalization has been found to mitigate the marked tachycardia capacity assessments (58). Furthermore, nosocomial infections
and increased cardiac work observed in severely burned chil- appear to be more common in the trauma patients who have
dren (35–43). Benefits associated with propranolol use include this documented impediment in their immune response.
decreased metabolic rates, lean body mass gains, and more effi- In addition to the inflammatory changes and perturba-
cient myocardial oxygen consumption. However, the definitive tions, hemorrhage, the associated coagulopathy and the use of
role of propranolol in this population is still not fully known, transfusion may also contribute to the promulgation of MODS
and multicenter study is ongoing to best delineate its value. among the pediatric trauma population (Table 1). For example,
Further, oxandrolone has been found to decrease whole body among the 8–10% of pediatric trauma patients who require
catabolism, and counter the decreased strength and growth transfusion under current Advanced Trauma Life Support
retardation observed in large burns. However, the long-term guidelines, mortality is reported to approximate 30% (59).
effects of this agent need to be demonstrated, both alone and Recent data suggest that 30–77% of pediatric trauma
in combination with other anti-catabolic agents such as pro- patients have some degree of coagulopathy upon admis-
pranolol (43–48). Insulin resistance has been noted in severely sion, with a higher occurrence rate and severity in patients
burned pediatric patients starting during the acute hospitaliza- with a concomitant traumatic brain injury (59–61). Many
tion and lasting for three years. Better blood glucose control adult trauma centers have recognized this “trauma associated
has led to better outcomes in some populations, but optimal coagulopathy” (TAC), and early balanced ratio transfusion/
management of hyperglycemia and insulin resistance in these resuscitation protocols have been implemented. Typically,
children remains unknown (49–52). these protocols use 1:1:1 ratios of packed RBCs, fresh frozen
Given the magnitude of the physiologic response to major plasma, and platelets, or some variation initially—followed by
burn injury, there is a need to understand the role of genetics thromboelastography-driven component transfusions. Such
in the response, whether it be in the response to resuscitation an approach has not gained widespread acceptance among the
or in the development of hypertrophic scars. Several groups are pediatric community. The natural history of TAC in children
focusing on the genomic and proteomic response to burn injury needs to be better delineated and understood in the context of
in children and identifying the genotypes and phenotypes of injury severity. The role of thromboelastography-driven resus-
survivors and nonsurvivors in order to evaluate treatment algo- citation protocols in decreasing the morbidity and mortality
rithms and/or predict outcomes (53–55). Specifically, groups associated with pediatric trauma including the occurrence
are looking at genomic and proteomic profiles to try to deter- of MODS should be established. Given the body of evidence
mine who is a risk for developing MODS in order to improve suggesting an association between transfusion and organ dys-
morbidity and mortality (31). In one small, multicenter study function, a better understanding of the optimal approach to
of burn victims, proteomic analysis revealed differences in the transfusion therapy in pediatric trauma patients may result in
level of acute phase reactants, proteins of inflammation, com- improved outcomes.
plement, hepatic signaling proteins, and proteins associated
with insulin resistance that distinguished survivors from non- RBC TRANSFUSION THERAPY
survivors. In particular, among the cytokines assessed, nonsur- The association of RBC transfusion as well as native RBC dys-
vivors were characterized by higher serum levels of granulocyte function with organ failure progression in the setting of MODS
macrophage colony-stimulating factor, IL-8, IL-4, and mono- has been broadly reported and is an active field of investiga-
cyte chemotactic protein-1 (p < 0.05) (53). tion (62). The principle RBC function is to enable oxygen (O2)
delivery, the maintenance of which is fundamental to support-
TRAUMA ing those with critical illness and is an integrated function of
Pediatric major trauma patients are also at risk for MODS; blood O2 content and flow. It is essential to note that blood flow
data suggest that MODS occurs in as many as 12% of children (rather than O2 content) is the focus of physiologic control in

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MODS Supplement

O2 delivery homeostasis (63). O2 content varies within a fairly improved understanding of vascular signaling and gas transport
narrow range, whereas flow is scalable by several orders of by RBCs (67, 69, 95), and of the full array of defects comprising
magnitude. Thus, the volume and distribution of blood flow the RBC “storage lesion” (75, 83), it is now appreciated that this
vary to maintain coupling between O2 delivery and demand strategy must be balanced by consideration that (1): donor and
(64–66). In addition to conventionally appreciated features of recipient RBCs do not exhibit similar physiology and (2) RBC
RBC physiology influencing O2 delivery (O2 affinity and rheol- transfusion may cause harm (beyond transfusion reactions and
ogy), mounting evidence supports an expanded paradigm for transmission of infection)—and that this harm appears pro-
O2 delivery homeostasis based on coordinated gas transport (O2, gressive with transfusion volume, frequency and donor expo-
carbon dioxide [CO2], and nitric oxide [NO]) which is linked sure. Consequently, newer “restrictive” hemoglobin thresholds
to vascular signaling by RBCs (67, 68). Thus, it has come to be for transfusion (approximately 7 gm/dL) are now appreciated
understood that the trapping, processing and delivery of NO by to be at least noninferior (and in many cases, superior) to more
RBCs has emerged as a conserved mechanism through which “liberal” hemoglobin thresholds (approximately 9 gm/dL) for
regional blood flow is linked to biochemical cues of perfusion a broad array of conditions (96–102), even in actively bleeding
sufficiency (69, 70). By coordinating vascular signaling in a fash- patients (103). While traditional transfusion thresholds are cur-
ion that links O2 and NO flux, RBCs couple small vessel caliber rently undergoing a broad “reset,” a comprehensive paradigm
(and thus blood flow) to O2 need in the tissues (71–74). Mal- shift is emerging in the approach to the critically ill, with re-
function of this signaling system is implicated in a wide array consideration of the “hemoglobin trigger” strategy. Clearly, it is
of pathophysiologic processes and may be explanatory for the not feasible to define specific hemoglobin boundaries across the
dysoxia frequently encountered in the critical care setting (62). complex interaction of developmental-, condition- and stress-
Furthermore, it is now recognized that donor RBCs are fun- specific situations in the ICU. Ideally, the decision to transfuse
damentally altered during processing and storage in a manner should be based upon individual and context-specific consid-
that both impairs O2 transport efficacy and introduces addi- erations of the degree to which anemia contributes to tissue
tional risk by perturbing both immune and coagulation sys- O2 delivery lack (and/or reserve) (104–107). This distinction is
tems in transfusion recipients (75–80). The protean biophysical exemplified by employing “physiologic” triggers (e.g., transfus-
and physiologic changes in RBC function arising from storage ing only to rectify abnormal measures of perfusion sufficiency
are termed the “storage lesion”; many have been understood [or reserve]), rather than to maintain a specific hemoglobin
for some time. For example, it is known that the O2 affinity concentration, irrespective of context (108, 109). In order to do
of stored blood rises during the storage period and that intra- so, it is necessary to identify the specific physiologic goal(s) most
cellular allosteric regulators, notably 2,3-disphosphoglyceric linked to outcome as well as to determine appropriate thresholds
acid and adenosine triphosphate, are depleted during stor- for putative goals. An enhanced ability to assess the functionality
age (78, 81). The appreciation of other storage lesion features of the circulating RBC mass and its specific relationship to tissue
has emerged with improved understanding of coagulation, oxygen delivery is pivotal to such determinations.
immune, and vascular signaling systems (75). Recent data Transfusion decisions, particularly among the critically
further implicate RBC processing and storage in disturbance ill, should maintain hemoglobin levels above thresholds that
of key RBC signaling regulating the linkage between regional limit O2 delivery. Historically, normal values were presumed
blood flow and regional O2 consumption (by regulating necessary during stress. There is now a better appreciation of
the bioavailability of key vasoactive mediators in plasma as anemia tolerance and donor RBC impairment; consequently,
described above). In summary, RBC transfusion always results conservative transfusion approaches are emerging, based
in an increased arterial O2 content, but the signaling distur- upon noninferiority trials of permissive anemia (e.g., restric-
bance and the compensatory mechanisms to anemia described tive hemoglobin-based thresholds). However, there is a lack of
above may explain the surprising lack of efficacy for transfu- decision-making structure that identifies specific individuals
sion in improving O2 delivery in critically ill patients with ane- for whom permissive anemia is unsafe and guides transfusion
mia (82–89). The failure of RBC energetics and antioxidant both in terms of timing and amount based upon outcome-
systems is emerging as a likely mechanism for both the ‘storage linked physiologic O2 delivery targets. Prior to implemen-
lesion’ and the acquired dysfunction of endogenous RBCs in tation of this approach, the ability to quantify O2 delivery/
the setting of MODS (90, 91). consumption and sufficiency/reserve relationships (global/
Although RBC transfusion increases hemoglobin concen- organ/tissue) and the ability to specifically attribute these val-
tration, and thereby blood O2 content, it does not necessarily ues to anemia must be developed (Table 1).
follow that O2 delivery is likewise increased unless blood O2
content is rate-limiting in the transfer of O2 from lung to tissue. CONCLUSIONS
The current approaches to transfusion decision-making in the In summary, there are a number of medical conditions, exter-
critical care setting are to maintain an “adequate” RBC mass well nal injuries and therapeutic interventions that are associated
above a threshold that may limit tissue O2 delivery. Historically, with multiple organ dysfunction and the MODS. The intent
“normal” values have been presumed necessary for “adequate of this article was to highlight a handful of those conditions,
reserve” during stress, although awareness of the tolerance injuries and therapies in an attempt to identify areas of com-
for anemia in this population is developing (92–94). With an monality, areas of difference, and opportunities for further

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Upperman et al

study and intervention; it was not to present an exhaustive list 17. Suzuki M, Sai JK, Shimizu T: Acute pancreatitis in children and ado-
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ACKNOWLEDGMENT 21. Bunchman TE, McBryde KD, Mottes TE, et al: Pediatric acute renal
We thank the Eunice Kennedy Shriver National Institute of failure: Outcome by modality and disease. Pediatr Nephrol 2001;
Child Health and Human Development and their Office of Sci-
22. Rewa O, Bagshaw SM: Acute kidney injury-epidemiology, outcomes
ence Policy, Analysis and Communications for their support of and economics. Nat Rev Nephrol 2014; 10:193–207
this workshop. 23. Sanchez-Pinto LN, Khemani RG: Development of a prediction model
of early acute kidney injury in critically ill children using electronic
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