Management of Neonatal Morbidities During Hypothermia Treatment 2015
Management of Neonatal Morbidities During Hypothermia Treatment 2015
Management of Neonatal Morbidities During Hypothermia Treatment 2015
Review
s u m m a r y
Keywords:
Benchmarking
Hypoxiceischemic injury
Therapeutic hypothermia
Although the primary goal of therapeutic hypothermia is to improve the neurodevelopmental outcome
in asphyxiated infants, optimal management of the full range of multi-organ system complications
typically presented by such infants during cooling treatment is necessary for improvement of the overall
outcome. For this reason, adequate knowledge of how cooling affects all organ systems of asphyxiated
infants with multi-organ hypoxiceischemic injury is essential. Adequate diagnostic resources, readily
available subspecialty consultant services and trained multidisciplinary staff to monitor and manage
multi-organ system complications in asphyxiated infants during therapeutic cooling must be ensured
during implementation of a cooling program. As therapeutic hypothermia is being used more widely,
centers should consider participation in national or international benchmarking of outcomes and shortterm adverse events during cooling to facilitate continuous quality improvement efforts.
2015 Elsevier Ltd. All rights reserved.
1. Introduction
Hypothermia is currently the standard of care for term or nearterm infants with moderate-to-severe hypoxiceischemic encephalopathy (HIE) [1,2]. In addition to the many sites that participated
in the original randomized trials [3e5], a growing number of
neonatal intensive care units (NICUs) that did not participate in the
original trials and that may be less experienced with cooling protocols are now offering cooling of neonates with HIE as a part of
routine clinical care. This article reviews the potential neonatal
morbidities during hypothermia treatment only and emphasizes
the need to understand what to expect, in order to best handle the
full range of multi-organ system complications typically presented
by asphyxiated infants during cooling treatment. Management of
problems during passive cooling of the asphyxiated infant in the
delivery room, or of problems related to cooling and monitoring
during transport, is to be reviewed elsewhere in this issue.
2. Common neonatal co-morbidities, and adverse events
associated with hypothermia treatment
Morbidities during cooling may be related to multi-organ system complications typically present in asphyxiated infants or
* Corresponding author. Address: Department of Pediatrics, Division of NeonatalePerinatal Medicine, The University of Michigan, C.S. Mott Children's Hospital,
1540 East Hospital Drive, Ann Arbor, MI 48108, USA. Tel.: 1 734 763 4109; fax: 1
734 763 7728.
E-mail address: jbarks@med.umich.edu (J. Barks).
http://dx.doi.org/10.1016/j.siny.2015.01.007
1744-165X/ 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sarkar S, Barks J, Management of neonatal morbidities during hypothermia treatment, Seminars in Fetal &
Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.01.007
S. Sarkar, J. Barks / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
Please cite this article in press as: Sarkar S, Barks J, Management of neonatal morbidities during hypothermia treatment, Seminars in Fetal &
Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.01.007
S. Sarkar, J. Barks / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
analysis of the published trials showed no signicant effect of hypothermia on coagulopathy [typical RR: 1.10 (95% CI: 0.93 to 1.29);
typical RD: 0.03 (95% CI 0.02 to 0.08); seven studies, 1188 infants],
or on coagulopathy resulting in major thrombosis or hemorrhage in
cooled infants [typical RR: 1.68 (95% CI: 0.58 to 4.83); typical RD:
0.01 (95% CI: 0.01 to 0.03); four studies, 689 infants] [12]. Metaanalysis of six trials also showed no signicant effect of hypothermia on the presence of hepatic dysfunction dened as elevated liver
enzymes of aspartate aminotransferase >200 U/L or alanine
aminotransferase >100 U/L [typical RR: 0.88 (95% CI: 0.74 to 1.05);
typical RD: 0.04 (0.10 to 0.02); six studies, 975 infants] [12].
However, coagulopathy requiring treatment in order to maintain or
recover normal hemostasis during cooling was the second most
prevalent morbidity reported in the UK TOBY Cooling Register [13],
highlighting the importance of monitoring the infants for abnormal
clotting parameters, and also for the physical signs of coagulopathy,
such as petechiae; oozing from heelsticks or venepuncture sites; or
bloody gastric or endotracheal secretions during cooling. Poor
microcirculation and hyperviscosity have been reported in the
hypothermic infant, which poses a potentially increased risk for
microembolism, but there is no evidence that hypothermic infants
suffer more emboli than normothermic infants [15].
Management of hematological issues during hypothermia
treatment requires monitoring of liver function tests as well as
other clotting studies including plasma brinogen level at regular
intervals (usually every 24 h, or more frequently as clinically indicated), and treatment with blood products, using the same treatment principles applicable for all asphyxiated infants.
Coagulopathy is usually manageable with transfusions of fresh
frozen plasma, packed red blood cells, platelets, and cryoprecipitate, as indicated. The authors and colleagues usually try to
maintain plasma brinogen within normal range, international
normalized ratio <2, and platelets >50,000/ mL in infants with
coagulopathy. However, in oliguric, uid-overloaded infants,
treatment goals may need to be more modest, focused on control of
bleeding, to minimize further uid overload. The most concerning
infants are those who had a traumatic delivery and have ongoing
bleeding, especially subgaleal hemorrhages, as these infants may
need aggressive management of the bleeding with administration
of back-to-back fresh frozen plasma, cryoprecipitate, blood, and/or
platelets [15].
3.4. Nutritional support, renal adverse effects, and management
uid and electrolytes during hypothermia treatment
Initial uid and electrolyte support in asphyxiated newborns
during cooling is aimed at establishment of appropriate hydration
and euglycemia. The authors and their colleagues withhold enteral
feeding during the entire hypothermia period, as was done in the
larger trials [4,5] due to concerns surrounding hypoxiceischemic
insult to the bowel. The incidence of necrotizing enterocolitis was
low (1e2%) and similar between the cooled and non-cooled groups
in the trials [15]. Some clinicians allow non-nutritive trophic feeds
with breast milk during the cooling period and report no adverse
consequences [15].
Infants undergoing therapeutic hypothermia are initially started
on 10% dextrose/water without any added sodium or potassium, at
a restricted volume of 60e80 mL/kg/day, and it is usually necessary
to continue with restricted uid intake to reduce the risk of syndrome of inappropriate anti-diuretic hormone (SIADH) in the
presence of cerebral injury and to anticipate the high likelihood of
ATN. Occasionally some infants develop a signicant decline in
serum sodium to around 125 mmol/L requiring further uid restriction to 40 mL/kg/day; however, in such situations, higher
concentration of dextrose infusion through established central
Please cite this article in press as: Sarkar S, Barks J, Management of neonatal morbidities during hypothermia treatment, Seminars in Fetal &
Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.01.007
S. Sarkar, J. Barks / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
The risk of overcooling (core temperature <32.0 C) during hypothermia treatment was reported in the NICHD trial among cooled
infants who were of lower birth weight and those with a greater need
for blood pressure support [29]. Therefore, smaller, sicker neonates
may require very close monitoring of temperature during hypothermia therapy to avoid temperature decreases below the target range,
and may require additional therapy for blood pressure support [30].
Please cite this article in press as: Sarkar S, Barks J, Management of neonatal morbidities during hypothermia treatment, Seminars in Fetal &
Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.01.007
S. Sarkar, J. Barks / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6
Practice points
Therapeutic hypothermia does not increase or decrease
the incidence or severity of most multi-organ system
complications typically presented by asphyxiated infants
during hypothermia treatment.
Management of multi-organ system problems during
hypothermia treatment usually requires close monitoring
and intensive supportive care using the same treatment
principles applicable for all asphyxiated infants whether
being cooled or not.
Hypothermia treatment affects blood gas values, and can
alter the metabolism and excretion of various drugs that
are commonly used in asphyxiated infants.
Research directions
Potential complications during therapeutic hypothermia
for HIE in late preterm infants require further study in the
context of clinical trials of the safety and efficacy of therapeutic hypothermia in such infants.
Determination is needed of the depth of systemic cooling
that provides optimal neuroprotection without significantly increasing adverse systemic effects of cooling.
Further studies are necessary regarding medical management and systemic side-effects in asphyxiated infants during clinical trials of hypothermia plus adjuvant therapies.
Conict of interest statement
None declared.
Funding sources
None.
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