Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx

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Seminars in Fetal and Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Fluid management, electrolytes imbalance and renal management in

neonates with neonatal encephalopathy treated with hypothermia☆
Jeffrey L. Segar a, *, Valerie Y-L Chock b, Matthew W. Harer c, David T. Selewski d,
David J. Askenazi e, on behalf of the Newborn Brain Society Guidelines and Publications
Committee1
a
Department of Pediatrics, Medical College of Wisconsin, 999 North 92nd St, Suite C410, Milwaukee, WI, 53226, USA
b
Department of Pediatrics, Stanford University, Palo Alto, 750 Welch Road, Suite 315, CA, 94304, USA
c
Department of Pediatrics, University of Wisconsin-Madison, McConnell Hall, 4th Floor, 1010 Mound St., WI, 53715, Madison, USA
d
Department of Pediatrics, Medical College of South Carolina, North Charleston Medical Pavilion, 8992 University Boulevard, SC, 29406, Charleston, USA
e
Department of Pediatrics, University of Alabama-Birmingham, 1600 7th Ave south, Lowder Bldg 502, AL, 35223, Birmingham, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Kidney dysfunction and acute kidney injury (AKI) frequently accompanies neonatal encephalopathy and con­
Acute kidney injury tributes to neonatal morbidity and mortality. While there are currently no proven therapies for the treatment of
Hypoxic-ischemic encephalopathy AKI, understanding the pathophysiology along with early recognition and treatment of alterations in fluid,
Kidney support therapy
electrolyte and metabolic homeostasis that accompany AKI offer opportunity to reduce associated morbidity.
Newborn
Urine biomarkers
Promising new tests and technologies, including urine and serum biomarkers and renal near-infrared spectros­
copy offer opportunities to improve diagnosis and monitoring of neonates at risk for kidney injury. Furthermore,
recent advances in neonatal kidney supportive therapies such as hemofiltration and hemodialysis may further
improve outcomes in this population. This chapter provides an overview of disorders of fluid balance, electrolyte
homeostasis and kidney function associated with neonatal encephalopathy and therapeutic hypothermia. Rec­
ommendations for fluid and electrolyte management based upon published literature and authors’ opinions are
provided.

1. Introduction
The impact of ischemic-reperfusion injury to the kidney, which often
accompanies perinatal asphyxial events, presents a unique challenge to
both patients and clinicians. Acute kidney injury (AKI) is a common co-
morbidity in infants with neonatal encephalopathy (NE). Recent studies
demonstrated that AKI in this population is associated with increasing
morbidities and mortality. Currently, there are no specific therapies or
interventions approved for neonates experiencing AKI and kidney
dysfunction due to asphyxia. However, an understanding of the patho­
physiology of kidney injury as well as recognition of signs and markers
of AKI should aid clinicians in providing optimal care to these patients.
The goal of this chapter is to provide a brief background on the patho­
physiology of AKI in the setting of neonatal NE, highlight clinical issues
including diagnosis and recognition of AKI, fluid and electrolyte disor­
ders, and the use of medical technologies such as near infrared spec­
troscopy (NIRS) and various forms of kidney support therapy (KST,
including peritoneal dialysis, hemodialysis and hemofiltration) to
improve monitoring of this condition. Finally, we provide recommen­
dations regarding the clinical care of these infants pertaining to fluid and
electrolytes management and kidney health.

Abbreviations: AKI, acute kidney injury; CRRT, continuous renal replacement therapy; CVVH, continuous veno-venous hemofiltration; KDIGO, Kidney Disease:
Improving Global Outcomes; KST, kidney support therapy; NE, neonatal encephalopathy; NIRS, near infrared spectroscopy; SIADH, syndrome of inappropriate
production of antidiuretic hormone.
☆
Dr. Askenazi receives Grant support and/or consulting fees from Baxter Internations, CHF Solutions, Medtronic, Bioporto and the AKI Foundation.
* Corresponding author.
E-mail addresses: jsegar@mcw.edu (J.L. Segar), vchock@stanford.edu (V.Y.-L. Chock), mwharer@wisc.edu (M.W. Harer), selewski@musc.edu (D.T. Selewski),
daskenazi@peds.uab.edu (D.J. Askenazi).
1
Newborn Brain Society, PO Box 200783, Roxbury Crossing, MA 02120. Email: publications@newbornbrainsociety.org.

https://doi.org/10.1016/j.siny.2021.101261

Available online 12 June 2021

1744-165X/© 2021 Elsevier Ltd. All rights reserved.

Please cite this article as: N, Seminars in Fetal and Neonatal Medicine, https://doi.org/10.1016/j.siny.2021.101261
J.L. Segar et al.
2. Pathophysiology of ischemic-reperfusion kidney injury
Infants with NE often exhibit multiple risks factors for the develop­
ment of AKI. Recognizing factors such as concomitant severe infection
and exposure to nephrotoxic medications may contribute to AKI in these
patients, this section will focus on the proposed mechanisms and events
contributing to ischemic kidney injury.
Blood flow to the term neonatal kidney changes significantly after
birth, normally increasing from about 3 to 4% of cardiac output to 6% at
24 h and 10% at 1 week of age [1]. Because of this limited blood flow,
dependency upon normal physiological process to occur during the
immediate postnatal period, and the high metabolic activity of the
kidney, the newborn kidney may be uniquely susceptible to ischemic
injury [2]. Prolonged renal hypoperfusion or hypoxemia, resulting in
inadequate tissue oxygen delivery, leads to inadequate ATP production,
and ultimately injury to components of the renal tubules, glomeruli and
vasculature [3]. The straight proximal tubule segment (S3) appears most
vulnerable to ischemic injury because these segments are in lower ox­
ygen conditions at baseline and have decreased capacity of producing
energy under anaerobic conditions [4]. Ischemic-reperfusion injury
produces complex pathophysiology involving endothelial dysfunction,
programmed cell death, transcriptional reprogramming and activation
of innate and adaptive immune responses [5]. As tubular epithelial cells
lose their cytoskeletal integrity and polarity, there is mislocalization and
loss of function of membrane proteins, such as Na+/K+-ATPase [4]. With
necrosis or apoptosis, necrotic cellular debris are released into the lumen
[6]. The loss of epithelial barrier function causes leakage of glomerular
filtrate back into the interstitium [7]. With reperfusion, large amounts of
reactive oxygen species are produced, resulting in carbonylation of
proteins and lipid peroxidation, further disrupting cell membranes,
cytoskeleton and DNA. Additionally, there is activation of immune re­
sponses, including enhanced endothelium-leukocyte interactions, which
promote the production of cytokines and a proinflammatory state [8].
Renal blood flow and microcirculation is further impacted by release of
vasoactive agents, such as adenosine, angiotensin II and endothelin and
catecholamines [9]. Ischemia additionally induces a prothrombotic
state, resulting in microvascular dysfunction. Repair of AKI involves
chronic activation of macrophages that may ultimately contribute to
extracellular matrix deposition and fibrosis [4].
In adult animal models of ischemic-reperfusion kidney injury, acti­
vation of a large number of genes occurs [10]. Interestingly, many
specific proteins appear as a recapitulation of kidney development. For
example, several nephrogenic genes are re-expressed in regenerating
proximal tubule cells similar to that described during nephrogenesis
[11]. Whether expression of these proteins is altered with
ischemic-reperfusion injury in the neonatal kidney has, to our knowl­
edge, not been explored.
Studies of renal ischemic-reperfusion injury in newborn animal
models are limited. There is evidence that immature renal tubules are
more tolerant of oxygen deprivation and ischemia than mature tubules.
Cellular ATP levels are maintained at 2-fold higher levels during anoxia
in immature compares with mature tubules, though this does not appear
to be attributable to greater glycolytic capacity [12,13]. In vitro, hyp­
oxia and reoxygenation resulted in significant greater redistribution of
Na+/K+-ATPase from the membrane to cytoplasm (a marker of cellular
injury) in isolated, cultured rat renal proximal tubules from 40
d compared to 10 d old animals [14]. How these and other factors
impact the development of kidney dysfunction in infants with NE is
unclear. However, understanding the molecular mechanisms and path­
ways that modulate the ischemic-reperfusion injury response may yield
novel therapeutic targets to limit the severity of AKI in this population.
3. The incidence and impact of acute kidney injury in neonatal
encephalopathy
One of the most critical advances in the study of AKI across medicine
2
Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx
Table 1
Stages of neonatal acute kidney injury as defined by neonatal modified Kidney
Disease: Improving Global Outcomes (KDIGO) criteria [20].
Stage Neonatal
Serum Creatinine Urine Output*
1 ≥0.3 rise within 48 h or ≥1.5–1.9 × rise from baseline ≤1 ml/kg/h for
(previous lowest value) within 7 days 24 h
2 2.0–2.9 times baseline ≤0.5 ml/kg/h
for 24 h
3 ≥3 × rise from baseline or serum creatinine ≥2.5 mg/dl ≤0.3 ml/kg/h
or renal replacement therapy initiation for 24 h
over the last 30 years has been the implementation of a standardized
definition for AKI into clinical care and research [15]. This has allowed
clinicians and researchers to begin to understand the true epidemiology
and impact of AKI across populations. Investigators have moved away
from arbitrary definitions of neonatal AKI and adopted the staged def­
initions of AKI similar to those utilized in older patients. The strength of
the staged definition of AKI is allowing for the full description of the
spectrum of injury that occurs with AKI. The neonatal modified Kidney
Disease: Improving Global Outcomes (KDIGO) AKI definition is the
consensus definition agreed upon by experts at a 2013 National Institute
of Diabetes and Digestive and Kidney Diseases-sponsored neonatal AKI
workshop (Table 1). Using modern staged definitions of AKI, acute
kidney injury occurs in as high as 60% of neonates with NE (Table 2).
While the neonatal modified KDIGO definition remains the current
standard to be utilized in research and clinical practice, this definition is
imprecise, particularly in the first week after birth and will likely un­
dergo future refinement.
While directed hypothermia has been applied to limit ischemic
injury in kidney transplantation, and after cardiopulmonary resuscita­
tion, the impact of hypothermia on kidney injury and the development
of AKI in infants with NE is unclear. A meta-analysis of six trials
reporting the effects of hypothermia on renal impairment showed no
statistically significant difference in the rate of renal impairment in
cooled compared to non-cooled infants [16]. However, these studies
were performed prior to establishment of the KDIGO definition of AKI
and the definition of renal impairment varied among studies. More
recently, a single center randomized controlled trial of 120 term neo­
nates with NE suggested that therapeutic hypothermia may decrease the
incidence of AKI (32% versus 60%, p < 0.05) [17]. Because it is unlikely
further studies randomizing infants with moderate to severe NE to hy­
pothermia will be performed, the effect of cooling on kidney function
may remain unclear.
AKI is associated with detrimental impacts on other organs,
including the brain, lung, heart, and immune system. In evaluating the
impact of AKI in neonates with NE, there has been a clear association
with adverse outcomes, including length of stay, length of mechanical
ventilation, and increased mortality [17–21]. Additionally, there is a
growing body of evidence to suggest that AKI in neonates with NE may
be a risk factor for adverse long-term outcomes including neurologic
outcomes. Sarkar et al. evaluated the impact of AKI during therapeutic
hypothermia on the presence of abnormal brain MRI findings in a single
center retrospective study of 88 asphyxiated newborns [22]. Abnormal
brain MRI findings were more frequent in neonates with AKI than in
neonates without AKI (73% versus 46%, p = 0.012), which was
confirmed on multivariable analysis (adjusted OR 2.9; 95% confidence
interval 1.1–7.6) [22]. In a single center study evaluating the outcomes
in 101 neonates who received therapeutic hypothermia, AKI, which
occurred in 10% of the cohort, was associated with a poor neurologic
outcome at 24 months of age [19]. Further study of the impact of AKI on
long-term neurodevelopmental outcomes is warranted in this
population.
Recently, studies have begun to identify perinatal risk factors for the
development of AKI in this population including asystole at birth,
J.L. Segar et al.
Table 2
Citations reporting the incidence of acute kidney injury in neonates experiencing
hypoxic-ischemic encephalopathy treated with therapeutic hypothermia.
Studies listed chronological order with most recent first and represent publica­
tions known to authors that provide estimates of AKI utilizing a systematic
staged AKI grading system in infants with neonatal encephalopathy AND treated
with therapeutic hypothermia.
Study Therapeutic % Findings
Hypothermia (Yes or patients
No) with AKI
La Haye-Caty, Yes 5–12.5% Evaluated impact of
2020 (n = fluid and sodium
202) [29] restriction on several
outcomes. Restriction
fluid/sodium intake
resulted in significant
increase in AKI (p =
0.02)
Bozkurt, 2020 Yes 29.5% - Mortality was higher
(n = 166) in infants with AKI (41
[21] vs. 5%; p < 0.001)
- Risk factors for AKI
were: systole at birth (p
= 0.044), placental
abruption (p = 0.041),
outborn status (p =
0.041), vasopressor
support (p = 0.031),
bleeding tendency (p =
0.031), initial lactate
level (p = 0.015) and
12-h lactate level (p =
0.029)
Kirkley, 2019 Not Reported 41.6% - Secondary analysis of
(n = 113) multicenter AWAKEN
[28] study
- Risk factors for AKI
were: outside the
admitting institution
(OR 4.3; 95% CI
1.2–14.8), intrauterine
growth restriction (OR
10.3, 95% CI
1.1–100.5), and
meconium at delivery
(OR 2.8, 95% CI
1.04–7.7)
- On adjusted analysis
AKI was associated with
increased length of
hospitalization by an
average of 8.5 days
(95% CI 0.79–16.2
days; p = 0.03)
Cavallin, 2019 Yes 10% - AKI was associated
(n = 101) with increased
[26] likelihood or poor
outcome (death or
disability) at year
follow-up.
Chock, 2018 (n Yes 39% - Infants with AKI had
= 38) [27] higher renal saturations
measured by NIRS than
those without AKI.
Tanigasalam, Randomized trial 46% - The incidence of AKI
2016 (n = evaluating impact of was lower in the group
120) [25] therapeutic receiving therapeutic
hypothermia on the hypothermia (32% vs
incidence of AKI 60%, p < 0.05)
Sarkar, 2014 (n Yes 39% - AKI is independently
= 88) [30] associated with hypoxic
ischemic lesions on
brain MRI at 7–10 days
of life in infants with
HIE (aOR 2.9; 95% CI =
1.1–7.6.)
Yes 38%
3
Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx
Table 2 (continued )
Study Therapeutic % Findings
Hypothermia (Yes or patients
No) with AKI
Selewski, 2013 - AKI predicted:
(n = 96) [29] - Prolonged mechanical
ventilation
- Length of stay
placental abruption, vasopressor support, bleeding tendency, initial
lactate level and 12-h lactate level [18]. Strategies to prevent AKI
therefore include risk assessment and avoidance of known contributors
to renal injury, including hypotension, hypovolemia, anemia, hypox­
emia and nephrotoxic medications. While there are no known therapies
to prevent or mitigate AKI in neonates with NE, methylxanthines may
offer some renal protection (discussed later in chapter).
4. Management of fluid, electrolyte and mineral imbalances
Perinatal hypoxic ischemic kidney injury results in fluid, electrolyte
and metabolic derangements that impact clinical care. There remain
many unanswered questions about optimal fluid and electrolyte man­
agement and best monitoring strategies to detect and subsequently
minimize renal dysfunction. Current knowledge and ongoing in­
vestigations in this field provide the basis for recommendations pro­
vided below, however future efforts are essential to improve outcomes
for this at-risk population of infants.
Infants with NE are at high risk for fluid overload related to AKI and
the volume of fluids typically administered to maintain intravascular
volume, adequate preload and provide medications and nutrition.
Decreased metabolic demands associated with hypothermia and
decreased activity from encephalopathic states may contribute to pro­
gressive body edema and fluid overload. Oliguria (urine output < 1 ml/
kg/hour) is a frequent finding in infants who experience NE, occurring
in approximately 25% of infants enrolled in the six therapeutic hypo­
thermia trials reporting such data [16]. However, therapeutic hypo­
thermia itself had not consistent effect on the rate of oliguria in enrolled
infants, consistent with the apparent lack of effect on kidney injury
Furthermore, infants can maintain normal urine output (>1 ml/kg/h)
despite having significant kidney dysfunction. Non-oliguric AKI is
associated with maintained glomerular filtration rate but renal tubular
dysfunction resulting in the loss of water and electrolytes. In a retro­
spective analysis of asphyxiated term infants prior to therapeutic hy­
pothermia, acute renal failure, defined as serum Cr > 1.5 mg/dl
occurred in 61% of infants, over half of these being non-oliguric [23].
Animal studies suggest that many of the same pathogenetic factors
contributing to oliguric AKI operate to a lesser extent in non-oliguric AKI
accompanied by less morphologic damage [24].
Recommendations for fluid restriction were originally extrapolated
from the treatment of adults and children at risk for brain edema after
traumatic brain injury, and included consideration of decreased urinary,
respiratory, and transepidermal (evaporative) water loss during hypo­
thermia [25,26]. However, these limited data coupled with the unique
needs of a neonate after NE necessitate further studies of optimal fluid
intake in randomized, controlled trials. In one pilot study, 80 infants
with NE were randomized to receive normal fluid intake (60 ml/kg/d on
day 1 with increase by 20 ml/kg/d on each subsequent day) or restricted
intake (2/3 normal) in the first 4 days of life. Restricted fluid intake did
not reduce the composite outcome of death or neurodevelopmental
disability and was associated with a trend towards more hypoglycemia
and higher rates of shock, AKI, and adverse neurodevelopment
compared to the normal fluid group [27]. An initial fluid intake of
60–70 ml/kg/d as appropriate for neonates on the first day of life
may be considered, but fluid management should be individualized
to the patients’ needs. Systemic restriction of fluids should be
J.L. Segar et al.
avoided.
Careful assessment of fluid balance is critical in this population, and
includes the use of body weight, urine output, tracking of fluid intake
and the calculation of fluid balance. Close monitoring of urine output is
critical, particularly during the first 72 h while the infant is undergoing
therapeutic hypothermia for maintaining appropriate fluid balance.
While most AKI in infants with NE is non-oliguric, consideration should
be made for placement of a Foley catheter to better quantify urine
output, particularly if oliguria is noted [23]. Decreased urine output
may also be complicated by urinary retention from narcotic use during
cooling, which is typically administered for sedation to reduce shivering
discomfort. Assessment of bladder volume with point of care ultrasound
may be a useful bedside strategy to assess for urine retention as a cause
of oliguria. High output urine failure may also occur later in the course
of injury, further necessitating close monitoring of fluid balance. Stra­
tegies to improve urine output should be based on the potential etiology
and could include providing a bolus of fluid or blood products, use of
inotropic agent to increase cardiac output and blood pressure for better
kidney perfusion or use of theophylline or aminophylline for selectively
increasing renal perfusion. Diuretic therapy may be initiated after
establishment of hemodynamic stability and with subsequent increased
activity after rewarming to promote mobilization of edema. However,
the response to diuretics and evolving fluid needs must be closely
monitored.
Most neonates undergoing therapeutic hypothermia will have min­
imal oral intake due to clinical instability and concern of intestinal
ischemia. Intravenous fluid administration with adequate dextrose
concentration will be a mainstay of early nutrition, and for optimal brain
health, achieving consistent glucose levels is recommended.
Neonates with NE are at risk for hyponatremia related to AKI, iat­
rogenic fluid overload, syndrome of inappropriate production of anti­
diuretic hormone (SIADH), sepsis, and urinary sodium loss related to
decreased tubular sodium reabsorption [28]. Management strategies
depend upon identification of the contributing factors. In most infant
with NE, hyponatremia results from free water excess, and not sodium
depletion, and thus requires restriction of free water administration,
often to estimated insensible water loss plus urine output. Restricting
sodium intake has been associated with lower sodium concentrations (p
= 0.02) and increased AKI (p = 0.02) [29]. We therefore recommend
avoiding systematic restriction of sodium and individualizing the
approach based on daily monitoring of serum electrolytes at least
through the cooling period. It is important to note that AKI may result
in tubulopathies with excessive urine sodium losses. Monitoring urine
sodium losses, particularly during periods of high urine output, provides
additional information regarding total body sodium homeostasis and
facilitates the calculation of needed sodium intakes.
Clinicians need to address alterations in potassium homeostasis,
most commonly hypokalemia (serum potassium < 3.5 mEq/L). A review
of 5 therapeutic hypothermia trials reported approximately 42% infants
with NE experienced hypokalemia [16]. Although hypothermia results
in a shift of potassium to the intracellular space no statistical difference
in rates of hypokalemia between cooled and noncooled infants has been
reported [16,30]. Urine potassium losses may be high if non-oliguric AKI
is present. The presence of AKI, particularly during the rewarming phase
as potassium shifts to the extracellular space, places these infants at risk
for hyperkalemia, although data on the incidence of this complication is
unclear. We therefore recommend judicious potassium replace­
ment., maintaining serum potassium greater than 3.5 mEq/L.
Careful monitoring of serum potassium values is warranted through the
rewarming phase of therapy and until AKI is resolved.
Hypocalcemia is commonly seen in infants with neonatal encepha­
lopathy, likely related to ATP-dependent Na+/K+ pump failure, cellular
membrane depolarization and subsequent influx of calcium into the cell.
In a retrospective analysis, Prempunpong et al. described therapeutic
hypothermia improved calcium homeostasis, lowered the incidence of
hypocalcemia but increased the risk for hypercalcemia [31]. In this
4
Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx
retrospective study, normal serum calcium levels were maintained in
cooled infants with significantly lower daily calcium intakes than
non-cooled infants. However, combined results from the therapeutic
hypothermia trials failed to identity an effect of cooling on hypocalce­
mia, reporting a combined incidence of approximately 40% [16].
Because of the high incidence of serum calcium abnormalities
(hypocalcemia and hypercalcemia), frequent monitoring is sug­
gested. For infants receiving early parenteral nutrition, the initial
provision of approximately 50% of normal parenteral intake may
be warranted until the absence of hypercalcemia is assured. Acute
kidney injury may also contribute to the hyperphosphatemia and
acidosis seen in infants with neonatal encephalopathy.
5. Kidney support therapy in infants with acute kidney injury
Kidney support therapy (KST) in the form of continuous or inter­
mittent therapies have been used in neonates with encephalopathy and
resultant kidney injury for decades. As with any form of therapy (pro­
cedure or otherwise), the decision to initiate KST is based on multiple
factors, with focus on whether the probability for a desired outcome is
greater with the therapy than without. This necessitates weighing the
potential risks and benefits of the treatment in the context of the current
patient situation to make informed decisions. Historically, the use of KST
in critically ill neonates is much lower than other critically ill pop­
ulations, likely due to the complexity and complications arising from the
technological challenges of a neonate receiving KST with tools designed
for adults [32]. Furthermore, in a registry of pediatric centers which
enrolled children on continuous renal replacement therapy, small chil­
dren (<10 kg) had approximately half of the survival rate compared to
those who were >10 kg [33]. Now in 2021, the advent of novel ma­
chines and the adaption of existing machines with low extra-corporeal
volumes have dramatically reduced the hemodynamic instability that
historically occurred with circuit initiation. Clearly these machines
change the risk/benefit ratio and allow for safe and effective therapy in
neonates without major complications.
KST is indicated for patients in whom impending extra-renal organ
dysfunction is present or likely after attempts to maintain fluid and/or
metabolic homeostasis with medical management have failed. Fluid
overload is common in neonates with acute kidney injury and has been
shown to impact the function of multiple organs in various populations.
The most common manifestation is pulmonary edema, resulting in poor
lung function and need for ventilatory support. Heart, liver, intestine,
and kidney edema can also contribute to progressive multi-organs
dysfunction. Although a complete review of fluid overload is beyond
the scope of this chapter, a recent review and meta-analysis in pediatric
critical care patients highlighted the negative impact of fluid overload
on critically ill children [34]. Only recently have we begun identifying
the negative impact of fluid overload on clinical outcomes in neonates.
These studies again show, similarly to pediatric and adults patients, that
fluid overload is independently associated with worse pulmonary
function and prolonged requirement for kidney support [35]. When
clinicians are unable to maintain metabolic homeostasis through the
prescription of fluids, electrolytes, bases supplements and medications,
the provision of kidney support therapy should be considered.
The optimal time for KST initiation depends on the current and ex­
pected negative effects of fluid overload. Undeniably, in the resuscita­
tive phase of therapy, fluid provision is necessary; however, shortly after
the shock state resolves, goals of fluid management should change to­
ward maintenance of fluid balance (without progressive fluid overload).
A systematic, but deliberate attempt to maintain fluid homeostasis
should be developed, balancing the fluid needs from medications,
nutrition and blood products with the expected outputs from urine and
stool as well as metabolic consequences of kidney failure. Fluid overload
and body edema require addressing underlying medical problems (low
cardiac output, bladder obstruction, low oncotic pressure, high
abdominal pressure) and often a reduction in fluid intake. Provision of
J.L. Segar et al.
Fig. 1. Localization of kidney injury biomarkers. Depiction provides the different locations within the nephron from which specific biomarkers are released when
kidney injury occurs. Legend: NGAL, Neutrophil gelatinase-associated lipocalin; B2 Microglobulin, beta-2 microglobulin; KIM 1, Kidney injury molecule 1; L-FABP,
liver-type fatty acid-binding protein; H-FABP, heart-type fatty acid-binding protein.
blood products, medications and nutrition should occur using maxi­
mally concentrated fluids, with an understanding of the potential dele­
terious effects of fluid overload. A trial of diuretics should be instituted
in patients with fluid overload in whom medical management has been
optimized and a reduction of fluid intake has been instituted. However,
if the diuretic response is limited, the clinician should avoid repeated
dosing hoping the kidney “wakes up” [36]. In this framework, KST is
indicated in patients with impending harm to vital organ systems due to
the inability of the kidneys to maintain fluid balance despite optimal
medical management. In the pediatric critical care arena, 10–15% fluid
overload has been argued to be a reasonable time for nephrology
consultation and consideration of KST [37]. Further delay can make KST
more difficult because as fluid overload progresses, vascular access/­
peritoneal dialysis catheter placement becomes more difficult, and the
secondary effects of fluid overload (i.e. pulmonary edema) can make the
patient more clinically unstable.
Uremia is another indication for KST. In patients who have adequate
urine output, and can maintain electrolyte balance, KST is not urgent,
even in context of an elevated serum urea/creatinine. Instead, the in­
dications for KST due to uremia are when organs dysfunction from
accumulation of waste products are evident, often manifested by cardiac
dysfunction, encephalopathy, or bleeding from platelet dysfunction.
If a patient meets criteria for KST, two factors need to be considered.
The first is whether the KST can accomplish the necessary goals better
via the peritoneal membrane or extracorporeal blood-based (vascular)
therapy. The second factor to consider is the duration of time the patient
will likely require KST. Traditionally, timing has been divided into
intermittent therapies (3–4 h per day) and continuous (24 h a day),
although we and other have found a role for prolonged intermittent
(6–18 h) therapies [38]. Continuous therapies (both peritoneal or
vascular) allow for a more sustained approach to achieving and main­
taining homeostasis. Ultimately, the type and duration of therapy will
depend on several factors, including goals of therapy, patient
5
Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx
characteristics and center experience.
A full description of peritoneal dialysis, intermittent hemodialysis
and continuous KST procedures are beyond the scope of this review and
have been published elsewhere [39]. However, a brief discussion of the
novel machines that have been developed to overcome limitations in
providing KST in neonates is appropriate. One of the biggest risk­
s/challenges to performing KST in neonates is the volume of fluid
needed to prime the filter/tubing. Until recently, the smallest circuits
available in the United States and other countries required about 100 ml.
If one considers the blood volume of a neonate is around 80 ml/kg, the
percent extra-corporeal volume would be 100/160 (62.5%), 100/240
(41.7%) and 100/320 (31.2%) for a 2, 3 and 4 kg neonate, respectively.
For these reasons, KST in neonates using ‘adult’ machines is technically
difficult and commonly leads to hemodynamic instability during the
initiation. A recent study reported hypotension at onset in 55% of
continuous renal replacement therapy (CRRT) sessions in neonates with
25% showing recovery within 60 min [40]. Besides the challenges
during circuit initiation with traditional machines, a larger vascular
access is needed to maintain the obligate blood flow necessary for the
machines to function.
In 2016, Askenazi et al. published their initial experience with
continuous veno-venous hemofiltration using an Aquadex Flexflow
machine (33 ml filter/tubing set) that can be used for up to 72 h, though
its use is ‘off-label’ in children < 20 kg [41]. Continuous veno-venous
hemofiltration (CVVH) was accomplished using an independent fluid
delivery system Y’d in to one of the pigtails of the filter set. This
approach allowed for removal of waste products and fluids, and ach­
ieved electrolyte homeostasis. Moreover, hemodynamic stability was
maintained during circuit initiation. Menon et al. recently published a
3-center experience with this device and showed that <3% of neonates
required any medications for hemodynamic support during the initia­
tion [38].
In 2014, the first reported neonatal patient on the Cardio-Renal
J.L. Segar et al.
Pediatric Dialysis Emergency Machine (CARPEDIEM) device in Italy was
published [42]. This device was designed specifically for neonates and
young infants (2.5–10.0 kg), can run with low blood flows, has inte­
grated pumps that can titrate blood flow and fluid removal with high
precision. In 2020, after review of data from Europe, the FDA approved
the use of the CARPEDIEM kidney support therapy device for children in
the United States. The device can be used for up to 24 h and can deliver
fluid for either convective or diffusive clearance. Also in 2014, the first
reported neonatal patients on the Newcastle infant dialysis and ultra­
filtration system (NIDUS) machine in England was published [43]. This
device uses a mechanical syringe system with an extracorporeal volume
of <10 ml, a single lumen catheter (as small as 4 Fr) and has exquisite
precision of fluid delivery. As of 2020, a multi-center study in England of
the device is ongoing. With the advent of these new systems, neonatal
KST has dramatically changed. Given that the risk of KST with these
devices appears to be similar to that in other populations, neonates with
kidney dysfunction can now receive safe and effective KST to optimize
short and long-term outcomes.
6. Role of kidney injury biomarkers in neonates with NE treated
with hypothermia
Ideal measures of kidney function in this population would allow
early diagnosis of kidney dysfunction, provide guidance for fluid and
medication management, and predict short and long-term kidney out­
comes. There is general agreement that current diagnostic criteria for
AKI are imprecise and lack sensitivity to kidney injury, as increased
serum creatinine and decreased urine output may not appear until 25%–
50% of renal function is lost. While these measures are still commonly
used and easily obtained in clinical practice, each has significant
shortcomings, particularly in neonates with NE.
Serum creatinine has been identified more as a functional biomarker
than an injury biomarker and has significant limitations [44]. In the first
day after birth, SCr is reflective of maternal SCr levels. Neonates with NE
often are born to mothers with multiple risk factors for an elevated
creatinine, e.g. hypertension, preeclampsia, and maternal diabetes,
making estimation of renal function and diagnosis of AKI based on the
neonate’s initial SCr particularly challenging [45]. In term neonates
with normal renal function, SCr values drop over the first week after
birth, reaching a nadir of about 0.4 mg/dl on about day 5 [46]. It has
been suggested that the failure to drop SCr appropriately over this
period, even in the absence of a rise in SCr, represents abnormal kidney
function [47].
The use of urine output to diagnose AKI in neonates presents similar
challenges. As previously discussed, neonates with kidney dysfunction
are not always oliguric. Additionally, measuring urine output in neo­
nates without urinary catheters is challenging especially when urine is
mixed with stool. However, attempts at measurement are important as
there is a growing body of literature identifying patients with AKI,
defined by urine output changes, as having worse outcomes – potentially
secondary to the effect of fluid overload [48]. Knowing the quantity of
urine being produced is extremely important to meticulously provide
fluids while minimizing the effect of fluid overload.
Measurement of novel serum and urinary biomarkers, which are
upregulated shortly after an injury and independent of the level of the
glomerular filtration rate, offer promise for more accurate identification
and effective management of infants at risk for AKI. An increasing
number of studies have evaluated the use of kidney injury biomarkers in
neonates over the past decade (Fig. 1). These studies have established
normal values in healthy and critically ill neonates with and without AKI
[49,50]. Select centers now have the capability to perform these assays
and have incorporated them into their daily testing, with rapid turn­
around times making them clinically useful. Because AKI in the NE
population occurs prior to or immediately at birth, biomarkers that can
determined on cord blood or soon after birth may guide immediate in­
terventions to ameliorate injury.
6
Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx
Neutrophil gelatinase associated lipocalin (NGAL) is the most stud­
ied biomarker outside of SCr and urine output in neonates with NE.
NGAL is a lipocalin protein expressed in many tissues, including the
kidney, and is released following kidney injury into urine and blood
[51]. A comparison of cord blood serum NGAL levels among three
different groups: 8 neonates with NE and AKI (all stage 1), 35 neonates
with NE and no AKI, and 30 healthy neonates found levels were
significantly higher in the AKI group compared to the NE without AKI
group and healthy group (174.3 ng/mL vs. 88.5 ng/mL (p < 0.01) and
28.25 ng/mL (p < 0.001) respectively) [52]. This same pattern of sig­
nificance was also true at 24 h of age. At an optimal cutoff of 140.7
ng/mL, NGAL had an 88.9% sensitivity and 95% specificity to diagnose
AKI. Two studies on urinary NGAL showed similar findings. Esajee et al.
evaluated 108 term asphyxiated neonates and found that urine NGAL
levels were significantly higher in patients with AKI compared to those
without [53]. Tanigasalam et al. evaluated term neonates with asphyxia
(n = 120) and found that those with AKI had a median NGAL of 165
ng/mL compared to 59 ng/mL in those without (p=<0.001) [54]. A
meta-analysis of the 9 NGAL studies published between 2012 and 2016
found that urinary levels provide greater sensitivity (89.7%) but serum
levels are more specific (87%) for identifying AKI [55]. Utilizing these
findings and a Fagan’s nomogram, assuming a pre-test AKI probability of
30% and positive serum NGAL test, the authors found that the posttest
probability of neonatal AKI increased to 71.3% while a negative serum
NGAL reduced post-test probability to 8.4%. Given the volume of data
on NGAL values in this specific population, the biomarker holds the most
promise to be incorporated into standard clinical care of neonates with
NE.
The utility of serum cystatin C as a biomarker of kidney function
rather than tubular injury has been recently reported in several studies
of neonates with NE. Examination of 13 asphyxiated neonates (8 with
AKI and 5 without) compared to 22 controls neonates found that serum
cystatin C had an AUC of 0.731 (p = 0.067) [56] to define AKI using
serum creatinine criteria. A more recent study of 110 full term
asphyxiated neonates (37 with AKI) showed that serum cystatin C was
significantly different between the AKI and no AKI groups (1.96 vs. 1.78
mg/L, p = 0.004) [57]. As a functional marker serum cystatin C may
have similar issues as SCr (need of substantial time for the biomarkers to
accumulate after an injury with initial values similar to maternal
values), thus potentially limiting its utilization to identify AKI. Alter­
natively, urinary cystatin C (a marker of tubular injury) has been shown
to predicted AKI with an AUC of 0.927 (p < 0.001) [56].
As studies move forward and our understanding of biomarkers con­
tinues to evolve, novel proteomic markers that can identify AKI specific
to neonates with NE will surface. Furthermore, it is possible that a
combination of urine proteomic markers (and perhaps metabolomic)
may improve the sensitivity and specificity of the diagnosis of AKI.
Nonetheless, the use of biomarkers alone is unlikely to provide the
advancement in diagnosis of early kidney injury. Rather, adaption of a
dynamic, multidimensional approach to AKI, as proposed by Basu, will
likely be necessary to identify and test novel, targeted therapeutic
strategies [58]. In this paradigm, kidney damage biomarkers are utilized
in a dynamic fashion and coupled with other clinical data to drive
clinical practice. Utilizing such frameworks in neonates with NE may
ultimately identify kidney injury early in the course of illness and pro­
vide opportunities to target specific aspects of injury.
7. Renal oxygen saturation and NIRS monitoring in neonates
with NE treated with hypothermia
NIRS utilizes technology similar to pulse oximetry but with the
important distinction that it provides an estimate of full tissue hemo­
globin oxygenation, derived from pulsatile (artery) as well as non-
pulsatile sources (capillary and venous) rather than pre-capillary (pul­
satile) oxygen values. NIRS values indicate a mixed saturation (venous,
arterial and capillary). As most tissue beds in the human body are
J.L. Segar et al.
Practice points
• Fluid and electrolytes management should be individualized to patients’ needs.
• Initial fluid intake of 60–70 ml/kg/d on the first day of life may be considered for infants with NE.
• Systemic restriction of fluids and sodium should be avoided.
• Individualizing the approach based on daily monitoring of fluid and electrolytes at least through the cooling period should be performed.
70–80% venous blood (capillary 5%, arterial 20%), NIRS is primarily a
reflection of venous oxygen saturation and a surrogate estimate of local
tissue oxygen utilization [59].
Renal tissue oxygenation (RrSO2) monitoring with near infrared
spectroscopy (NIRS) is a promising, non-invasive technology that can be
available in the neonatal intensive care unit (NICU) [60]. Studies of term
neonates after surgical repair of congenital heart disease have shown
that NIRS monitoring of the kidney can predict and detect AKI prior to
changes in serum creatinine and urine output [61]. A recent study of
premature neonates also showed that low renal tissue oxygenation on
the first day of age predicted AKI in the first week [62]. With the ability
to measure tissue oxygenation changes every 5 s, NIRS may be a mo­
dality readily available to clinicians with the potential to be a reliable
and early marker of AKI.
NIRS is an ideal modality to continuously and non-invasively assess
renal tissue oxygenation in the NE population at high risk for AKI.
However, to date clinical application has been limited and normative
data has yet to be established. In the most extensive data reported to
date, 38 neonates with NE at a single tertiary NICU had cerebral and
RrSO2 measured for 72 h during cooling and until 24 h after re-warming
[20]. During cooling, average RrSO2 was 72 ± 9%, significantly lower
than concurrent cerebral saturations (approximately 83 ± 3%) and
RrSO2 during the rewarming period (87 ± 6%),. The lower renal satu­
ration during cooling corresponds with the decreased heart rate, cardiac
output and peripheral vasocontriction associated with hypothermia.
This pattern of renal and cerbral regional saturation during hypothermia
differs from normal saturation patterns in the term infant, in which renal
saturations are typically 10–15% higher than cerebral saturations [63].
Infants who developed AKI based on an abnormal rate of serum creati­
nine decline displayed significantly increased RrSO2 values during
cooling therapy, most notably after 24 h of life. ROC curves showed that
at 24 h of age, RrSO2 >80% predicted AKI with an AUC of 0.68, sensi­
tivity of 66.7% and specificity of 72.7%. A RrSO2 value of >75% be­
tween 24 and 48 h of age produced a positive predictive value for AKI
was 73% and negative predictive value was 86%. While further studies
are needed to establish the feasibility and clinical utility of renal NIRS
monitoring during therapeutic hypothermia, early detection of
increased risk of AKI through the use of NIRSs will allow clinicians to
identify infants most likely to benefit from protective interventions.
8. Potential new therapies
There are currently no FDA approved therapies to prevent or miti­
gate AKI in neonates with NE. While numerous pharmacological agents
have been evaluated for prevention of AKI, methylxanthines, including
aminophylline and theophylline, appear to be the most promising ones
in neonates with NE. A recent systematic review of six studies involving
436 infants designed to determine the efficacy of theophylline or
aminophylline compared with standard therapy for prevention of AKI in
neonates with NE found a single dose of theophylline (either 5 mg/kg or
8 mg/kg) given within the first hour after birth asphyxia resulted in a
60% reduction in the incidence of AKI (RR:0.40; 95% CI 0.3 to 0.54) and
improvement in fluid balance without increasing the risk of death or
seizures [64]. All studies were single center, and none included infants
7
Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx
receiving therapeutic hypothermia. These findings are consistent with
the recommendation from the Kidney Disease: Improving Clinical Out­
comes workgroup that “a single dose of theophylline may be given in
neonates with severe neonatal encephalopathy, who are at high risk of
AKI”, as per level of evidence being 2 B [15].
More recently, Chock et al. reported their experience with using
aminophylline as a renal protective management strategy in neonates
with NE undergoing hypothermia who develop low urine output and/or
rising serum creatinine [65]. These investigators administered a loading
dose of aminophylline (5 mg/kg) starting at 25 ± 14 h of life with
maintenance dosing (1.8 mg/kg) every 6 h. Compared to untreated in­
fants, aminophylline use was associated with increased urine output and
similar rates of decline in serum creatinine. Methylxanthines may thus
improve kidney function in infants with NE. However, adequately
powered, clinical trials that include assessment of short- and long-term
outcomes of infants receiving methylxanthines as an adjunct to thera­
peutic hypothermia are needed before widespread adoption of this
therapy is likely to occur.
9. Risk of chronic kidney disease
Limited data have been published exploring kidney function beyond
the newborn period in the NE population. There is a growing body of
evidence that patients with AKI are at increased risk of chronic kidney
disease (CKD) [66]. Among 8 observational studies in neonates with
AKI, high rates of chronic renal dysfunction (GFR <60 ml/min/1.73 m2)
were found at later follow-up between 1 month and 20 years [67]. In
very low birth weight neonates the risk of chronic renal dysfunction
(eGFR < 90 ml/min/1.73 m2, urine protein/creatinine >0.2, or blood
pressure >95th percentile) at 5 years of age was 4.5 fold higher in those
who had AKI versus those who did not [90]. Neonates treated with
therapeutic hypothermia for NE require long-ter m neurodevelopmental
follow-up at routine intervals in the first year of life and typically qualify
for neurocognitive testing at 18–24 months of age. A similar follow-up
schedule for assessment of renal function by a Pediatric Nephrologist
is recommended in those with a history of AKI and could include blood
pressure, urine protein, and SCr measurements on a minimum yearly
basis. The occurrence of chronic renal dysfunction in this high-risk
population needs close scrutiny to truly delineate the potential
long-term effects of perinatal hypoxic ischemic injury on the developing
kidney.
10. Summary
Infants with NE experience a wide array of fluid, electrolyte and
metabolic disturbances that may contribute to morbidity and mortality.
Careful monitoring of clinical parameters and thoughtful, physiologi­
cally based therapeutic approaches are needed to optimize outcomes.
Although SCr has its limitations as a biomarker of kidney function and
injury, serial measures of SCr are essential over the first week of life to
establish a pattern of renal function. Early involvement of the Pediatric
Nephrology team is critical in a patient with even low-grade AKI to
guide management with a focus on appropriate fluid and electrolyte
balance and reducing further nephrotoxic exposures. We remain
J.L. Segar et al. Seminars in Fetal and Neonatal Medicine xxx (xxxx) xxx

Research directions
• Identifying biomarker combinations that lead to direct improvement in care of neonates with AKI and the development of novel therapies.
• Establishing the feasibility and clinical utility of renal NIRS monitoring during therapeutic hypothermia may allow the early detection of
kidney injury and ultimately optimize renal outcomes.
• Adequately planned clinical trials are needed to determine whether methylxanthines as an adjunct to therapeutic hypothermia may decrease
kidney injury in neonates with NE.

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