Seminars in Fetal & Neonatal Medicine xxx (2015) 1e6

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Seminars in Fetal & Neonatal Medicine

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Review

Management of neonatal morbidities during hypothermia treatment

Subrata Sarkar, John Barks*
Department of Pediatrics, Division of NeonatalePerinatal Medicine, The University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, MI, USA

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).

cooling per se, or more commonly both. Morbidities during cooling

in a controlled NICU setting have been addressed in both pilot
safety trials and the randomized controlled clinical trials, and more
comprehensively in some preliminary studies whose primary aim
was to assess the safety of cooling in asphyxiated newborns [3e9].
Sinus bradycardia and thrombocytopenia have been reported to be
the only signicant morbidities related to hypothermia treatment
in all of the current meta-analyses of the cooling trials [10e12].
Although these studies suggest that therapeutic cooling is generally
safe, it is important to appreciate that these reported safety data are
based on administration of cooling within strict protocols and often
at centers with considerable experience with hypothermia. Data
from the UK TOBY Cooling Register provide an overview of the
morbidities more frequently noted in non-trial settings during
cooling treatment on days 1e4 after birth [13]. In 1384 infants with
completed data forms in the registry, the most prevalent morbidities included hypotension with persistent mean blood pressure of
<40 mmHg in 40%, coagulopathy requiring treatment in order to
maintain or recover normal hemostasis in 31%, hypoglycemia with
blood glucose <2.6 mmol/L in 25%, any evidence of infection
requiring antibiotic therapy which is conrmed on culture in 17%,
sinus bradycardia <80 beats/min and other arrhythmias identied
on the electrocardiogram in 9%, and subcutaneous fat necrosis in
~1% of registered infants [13]. Key clinical diagnoses in the same
cohort of infants reported to the Register during hospital admission
included meconium aspiration in 10%, pulmonary hemorrhage in
3%, pulmonary hypertension in 7%, pulmonary air leak in 5%,
pneumonia in 1%, late onset sepsis in 2%, renal failure treated with

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

dialysis in 0.6%, necrotizing enterocolitis in 0.7%, and major cerebral

anomaly on cranial ultrasound in 3% [13]. These data indicate that
there will be some adverse systemic events in many asphyxiated
infants treated with hypothermia in any setting. Many of these
systemic complications are effects of asphyxia, not of hypothermia,
in the current therapeutic range. Hence, it is less clear whether e
due to advances in intensive care, and better understanding of
pathophysiology of hypothermia in asphyxiated newborns e any of
these adverse events previously reported during cooling might be
reduced considerably.

decrease in core temperature, pH increases by 0.015, and pCO2 and

pO2 decrease by 4% and 7% respectively [19]. Excessively low pPCO2
during therapeutic hypothermia might result in altered cerebral
blood ow autoregulation, and reduced cerebral perfusion [20], and
might lower the seizure threshold [21]. Hence, blood gas values
should be corrected for core body temperature, and ventilatory
adjustments should be aimed to keep the corrected blood gas
values within the normal range, as has been the case in two larger
clinical trials [3e5].
3.2. Cardiovascular morbidities

3. Anticipating, monitoring, and management of neonatal

morbidities during hypothermia treatment
3.1. Ventilation and blood gases during hypothermia treatment
Most infants remain intubated, but have minimal fraction of
inspired oxygen (FiO2) and positive pressure requirements while
receiving mechanical ventilation during the period of cooling [14].
Intubation also minimizes the risk of aspiration of secretions in
presence of a poor gag reex. Overventilation and hypocarbia
should be avoided when treating infants with HIE [15,16]. However,
to compensate for metabolic acidosis, often the infant drives his or
her own ventilation so much so that it is difcult to achieve normocapnia. It is not known whether it is better to heavily sedate or
paralyze the infant and take control of the ventilation and maintain
a higher CO2, or to allow the low partial pressure of carbon dioxide
(pCO2) to occur [15]. In a secondary analysis evaluating the association between early hypocarbia at <12 h of age and 18e22-month
outcome among National Institute of Child Health and Human
Development (NICHD) trial participants with HIE, both minimum
pCO2 and cumulative pCO2 (<35 mmHg) were associated with
increased risk of death or disability [16]. The authors and colleagues
extubated while the infants were receiving cooling only if hyperventilation persisted despite use of low ventilator settings, and in
almost 40% of the infants successful extubation was possible while
the infants were being cooled, without any signs of clinically signicant aspiration during the post-extubation period [14].
Secretions are usually thicker during cooling, necessitating
frequent suctioning of the endotracheal tube with instillation of
normal saline solution and chest physiotherapy [15].
Persistent pulmonary hypertension (PPHN) has always been a
concern specically for infants with a need for a high FiO2 during
cooling, since Eicher et al. reported an increase in persistent pulmonary hypertension that required inhaled nitric oxide treatment
in the cooled infants [9]. However, in recent meta-analyses, the risk
of persistent pulmonary hypertension [typical RR: 1.36 (95% CI:
0.94 to 1.97); typical RD: 0.05 (0.01 to 0.10); four studies, 614
infants], need for inhaled nitric oxide [typical RR: 1.18 (95% CI: 0.72
to 1.92); typical RD: 0.02 (0.04 to 0.09); four studies, 426 infants],
or need for extracorporeal membrane oxygenation (ECMO) were
the same in cooled infants compared with infants receiving standard (normothermic) care [10,12], and cooling does not seem to be
contraindicated in infants with persistent pulmonary hypertension
[15]. Persistent pulmonary hypertension during cooling is usually
managed with inhaled nitric oxide using the standard protocol, and
the need for extracorporeal membrane oxygenation is infrequent,
as previously reported [14]. Use of therapeutic hypothermia is not a
contraindication to rescue therapy with ECMO in infants with refractory cardiorespiratory failure. Maintenance of core temperature
in the desired therapeutic cooling range is feasible via the heat
exchanger of the ECMO circuit, as has been described in a small case
series [17].
Decreasing body temperature lowers metabolic rate by ~5e8%/
 C and leads to a decrease in CO production [18]. With each 1 C
2

Current meta-analyses of the neonatal cooling trials document

that the only consistent cardiovascular effect of cooling is clinically
benign physiological sinus bradycardia [10e12]. Data were not
sufcient to report on the outcomes of any arrhythmia or prolonged QT interval [12]. One group reports that arrhythmias have
rarely been experienced despite many occurrences of overcooling
[15]. The bedside nurse is responsible for providing cardiorespiratory monitoring and pulse oximetry. The nurse must be aware that
hypothermia will induce changes in the expected parameters of
vital signs, especially heart rate, and that cardiorespiratory monitor
alarm limits need to be adjusted accordingly [22].
In a recent meta-analysis [12], there was no signicant effect of
hypothermia on the presence of hypotension dened as mean
blood pressure (MBP) <40 mmHg [typical RR: 1.00 (95% CI: 0.92 to
1.09); typical RD: 0.00 (0.05 to 0.05); eight studies, 1221 infants]
or on the need for blood pressure support with inotropic agents
[typical RR: 1.09 (95% CI 0.96 to 1.24); typical RD 0.04 (0.02 to
0.11); six studies, 768 infants]. Although hypotension with persistent mean blood pressure of <40 mmHg was the most common
morbidity reported in the UK TOBY Cooling Register [13], reassuringly it was much less frequent than the reported incidence of
persistent hypotension of 77% and 88% in the cooled and noncooled groups in the original TOBY Trial [3]. Hemodynamic issues
in asphyxiated infants treated with hypothermia typically require
continuous monitoring of blood pressure and management of hypotension with uid boluses and/or inotropes using the same
treatment principles applicable for all asphyxiated infants, whether
being cooled or not. If an infant is hypotensive during cooling, it is
reasonable to rst attempt to correct hypovolemia with uid boluses judiciously, recognizing that the infant is at risk of uid
overload secondary to acute tubular necrosis (ATN) or syndrome of
inappropriate antidiuretic hormone secretion (SIADH). The need
for uid boluses or inotropic support during cooling is best assessed
with echocardiography [15]. If myocardial contractility is poor,
dobutamine may be preferable; and if the infant is not hypovolemic, not having poor contractility, or clinically appears
peripherally vasodilated, use of dopamine or epinephrine may be
preferable. If an infant has signs of PPHN, the systemic blood
pressure may need to be kept higher to minimize right-to-left
shunting. As in other patients, refractory hypotension may
require addition of hydrocortisone to inotropes.
3.3. Hematological morbidities
Asphyxiated newborns often have abnormal clotting studies,
and therapeutic hypothermia per se does not seem to further
derange their clotting function when the core temperature is
maintained within the target range specied in the published
cooling protocols. Although statistically signicantly increased
thrombocytopenia in the hypothermic groups has been consistent
[typical risk ratio (RR): 1.21 (95% CI: 1.05 to 1.40); typical risk difference (RD): 0.06 (95% CI: 0.02 to 0.10); number needed to treat for
harm: 17 (95% CI: 10 to 50); eight studies, 1392 infants] [12], meta-

Please cite this article in press as: Sarkar S, Barks J, Management of neonatal morbidities during hypothermia treatment, Seminars in Fetal &
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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

venous access will be necessary to maintain euglycemia. Total

parenteral nutrition (TPN) is needed during the entire period of
cooling to optimize nutrition and preserve nitrogen balance while
enteral feeding is being withheld.
Disturbances in electrolytes from ATN and/or SIADH, and disturbances in glucose homeostasis are widespread in infants with
HIE, including those receiving therapeutic hypothermia [13]. The
incidence of acute kidney injury (AKI) can be as high as 38%, as
reported in 96 consecutively cooled asphyxiated newborns, using
modied AKIN criteria based on absolute rise in serum creatinine
(SCr) level from a previous trough [23]. However, six trials which
reported the effect of hypothermia on a diagnosis of renal impairment or acute renal failure showed no statistically signicant difference in the rate of renal impairment in cooled infants [typical
RR: 0.87 (95% CI: 0.74 to 1.02); typical RD: 0.06 (95% CI: 0.12 to
0.01); six studies, 667 infants] [12]. In this review, data were
insufcient to report on the outcomes of renal impairment based
on serum creatinine measurements [12]. A trend toward increasing
SCr over the 72 h of hypothermia treatment is expected in infants
with AKI, but only rarely do infants need renal replacement therapy
[23]. In the same cohort of 96 cooled infants, only three patients
underwent renal replacement therapy after therapeutic hypothermia, one of whom was discharged on peritoneal dialysis and
eventually underwent renal transplantation for cortical necrosis
[23]. Anuria or oliguria secondary to ATN may affect the critical
balance of other physiologic systems, primarily pulmonary and
metabolic homeostasis during hypothermia treatment. If an infant
gains weight excessively, compromising pulmonary function during hypothermia treatment, occasional doses of loop diuretics may
be helpful in an attempt to convert oliguric renal failure to nonoliguric renal failure and mitigate uid overload.
Management of metabolic issues during hypothermia treatment
involves close monitoring, and treatment of glucose, calcium, and
magnesium disorders and comprehensive electrolyte issues.
Although Gluckman et al. [4] reported higher mean plasma glucose
concentrations between 4 h and 24 h in cooled versus control infants which resolved spontaneously, a meta-analysis [12] of seven
trials showed no signicant hypoglycemia in the hypothermic
groups [typical RR: 0.80 (95% CI: 0.60 to 1.06); typical RD: 0.03 (95%
CI: 0.08 to 0.01); seven studies, 1030 infants]. It is recommended
that serum electrolytes and plasma glucose should be kept within
the normal range during hypothermia treatment and adjustments
must be made in the intravenous uids based on measurements of
serum electrolytes at regular intervals (usually every 12e24 h),
assessment of renal function, and urine output. Hypothermia causes
an intracellular shift of potassium, and aggressive correction of hypokalemia during hypothermia has been shown to result in overshoot hyperkalemia on rewarming [24]. Reassuringly, metaanalysis [12] of the ve trials that reported the effect of hypothermia on serum potassium showed no statistically signicant difference in the incidence of hypokalemia (serum potassium <3.5 mmol/
L) in cooled infants [typical RR: 0.93 (95% CI: 0.79 to 1.08); typical
RD 0.03 (95% CI: 0.10 to 0.03); ve studies, 738 infants].
Hypocalcemia and hypomagnesemia are also prevalent in
asphyxiated newborn infants, and may lower the seizure threshold.
Larger falls in serum calcium and lower cord blood serum magnesium are more frequently present in infants with severe HIE and
poor outcome [25,26]. However, the incidence of hypocalcemia in
cooled and non-cooled infants was not different in two larger
cooling trials [4,5]. As there is conicting experimental evidence on
the neuroprotective effect of magnesium on its own [27], or in
combination with hypothermia [28], the present authors and their
colleagues correct hypocalcemia and hypomagnesemia, and try to
maintain serum magnesium level within the high normal range, as
has been recommended by others [15].

Please cite this article in press as: Sarkar S, Barks J, Management of neonatal morbidities during hypothermia treatment, Seminars in Fetal &
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3.5. Risk of overcooling during hypothermia treatment

3.9. Use of sedation and pain management during hypothermia

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].

The role of sedation and pain management is unclear during

hypothermia treatment. It is generally preferable that infants
receiving cooling therapy be sedated as necessary. Excess activity or
agitation can result in elevation of body temperature. Infants with
HIE are at risk for seizure activity [34]. The neo.nEURO.network
trial, in which opiate analgesic was routinely administered, reported a lower incidence of death or severe disability compared to
previously published cooling trials [35]. Opioids have neuroprotective properties, and, when used for sedation, they may blunt
the stress and metabolic responses to hypothermia. However,
routine use of analgesia and sedation during hypothermia is still
debated.

3.6. Specic problems during the rewarming phase

Some authors report that the risk of seizures increases during
the rewarming phase [31], and that these seizures are often nonconvulsive (subclinical) in nature [15]. Continuous video EEG or
amplitude EEG monitoring is important specically for detection of
non-convulsive seizures and to monitor the effectiveness of anticonvulsive treatment. Management of seizures during hypothermia
and the rewarming phase are discussed in this issue of Seminars by
A. Gunn.
In addition, rewarming may cause peripheral vasodilatation and
increase in intravascular volume, and hypotension may occur if the
vascular bed is underlled [15]. Additional volume support with
normal saline boluses, and blood pressure support, may be required
if blood pressure is seen trending down during this phase [30].
3.7. Monitoring skin complications during cooling
Sclerema neonatorum is a known complication of either overcooling or of birth asphyxia, and it has been reported rarely in infants
treated with selective head cooling (SHC). Sclerema eventually resolves as the infants recover. Exaggerated scalp swelling sometimes
occurs with SHC, and in some critically ill infants with coagulopathy
or refractory hypertension this may be associated with bruising and
compromised skin integrity [32]. Rare skin complications reported
with whole-body cooling (WBC) include subcutaneous fat necrosis,
skin erythema, and exaggerated acrocyanosis [32]. However, subcutaneous fat necrosis was a known complication in asphyxiated
infants, prior to the cooling era. Performing scalp checks during SHC,
and evaluation of dependent skin integrity during WBC at regular
intervals (at least every 12 h) seem prudent [32]. Uncomplicated
skin lesions including subcutaneous fat necrosis resolve spontaneously; however, infants who develop subcutaneous fat necrosis
remain at risk for hypercalcemia later on [33].
3.8. Management of sepsis during hypothermia
Early onset sepsis may present as birth depression and thus be
associated with neonatal encephalopathy that meets typical
criteria for HIE. In the UK TOBY Cooling Register, 17% of the 1384
infants with completed data forms had some evidence of infection
requiring antibiotic therapy that was conrmed on culture on days
1e4 after birth [13]. Eight trials reported the effect of hypothermia
on sepsis [12]. There were 1222 infants, of whom 99 had cultureconrmed sepsis. Although meta-analysis [12] of the eight trials
showed no signicant effect of hypothermia on sepsis [typical RR:
0.87 (95% CI: 0.60 to 1.26); typical RD: 0.01 (95% CI: 0.04 to
0.02); eight studies, 1222 infants], broad-spectrum antibiotics
usually are started empirically in infants treated with hypothermia.
A lumbar puncture is not always performed as part of the initial
evaluation for sepsis because infants are sometimes coagulopathic,
thrombocytopenic, or clinically too unstable, requiring signicant
inotropic or ventilator support. Antibiotics are discontinued if
cultures are negative after 36e48 h of incubation and the clinical
course of the infant is not suggestive of sepsis.

3.10. Drug metabolism and therapy during hypothermia

Several groups of drugs including anticonvulsants, sedatives,
neuromuscular paralyzing agents, antibiotics, and inotropic agents
are widely used in asphyxiated infants while receiving therapeutic
cooling. Metabolism and excretion of these drugs and their metabolites might be modied by hypothermia therapy, as well as by
the frequent presence of hypoxiceischemic hepatocellular and
renal injury complicating HIE. The effects of hypothermia on
pharmacokinetics and pharmacodynamics of different medications
have been reviewed recently [36].
Drugs that are excreted unchanged through the kidneys appear
to be less affected by hypothermia treatment. Gentamicin combined with penicillin or ampicillin are often the initial antibiotics of
choice for treatment of suspected sepsis in infants with HIE. As
gentamicin levels are not affected during cooling [37], typical
adjustment of gentamicin dosing for impaired renal function based
on trough serum concentrations is recommended when treating
actual or suspected infection during therapeutic hypothermia.
Inotropic agents to treat hypotension are also widely used in ill
infants with HIE. To date, no difference in response to inotropic
support has been experienced among cooled and non-cooled infants with HIE [15].
The metabolism of drugs such as phenobarbital, morphine,
topiramate, and vecuronium in the liver is reportedly slowed during hypothermia, causing an increase in morphine concentrations,
and accumulation of phenobarbital, topiramate, and neuromuscular paralyzing agents such as vecuronium during hypothermia
treatment [38e40]. In a study in which morphine infusion rates
were determined by clinical state, therapeutic hypothermia was
associated with reduced morphine clearance and elevated serum
morphine concentrations, sometimes to potentially toxic levels
[38]. Close monitoring of anticonvulsant levels during treatment of
seizures, and of clinical level of sedation and paralysis while
morphine and paralyzing agents are being used, is merited during
treatment with hypothermia.
4. Conclusion
The many organ system effects of perinatal hypoxiaeischemia
were well known before the present era of routine use of therapeutic hypothermia for moderate-to-severe HIE. Meta-analyses
suggest that apart from the few exceptions noted above, therapeutic hypothermia neither increases nor decreases the incidence
or severity of multi-organ system complications in infants recovering from perinatal asphyxia. Thus, for any NICU, a commitment
to routine use of therapeutic hypothermia requires the commitment and resources to manage these many complications, which
often continue long after the end of the cooling treatment period.

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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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

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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