Journal of Perinatology (2012) 32, 981–984
r 2012 Nature America, Inc. All rights reserved. 0743-8346/12
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PERINATAL/NEONATAL CASE PRESENTATION
Congenital diaphragmatic hernia repair during whole body
hypothermia for neonatal hypoxic ischemic encephalopathy
S Buratti, E Lampugnani, P Tuo and A Moscatelli
1
Department of Neonatal and Pediatric Anesthesia and Intensive Care, Istituto G. Gaslini, Genova, Italy
Major malformations, surgery and persistent pulmonary hypertension
(PHT) have been considered contraindications to therapeutic hypothermia
(TH) in newborns with hypoxic-ischemic encephalopathy (HIE). We report
two patients with undiagnosed congenital diaphragmatic hernia (CDH) who
developed HIE after birth. Diagnosis of moderate HIE was formulated based
on clinical, laboratory and electroencephalographic criteria. The patients
were treated with whole body hypothermia (33.5 1C) for 72 h. During
hypothermia the patients underwent surgical repair with regular
perioperative course. Ventilatory support with high-frequency oscillatory
ventilation, oxygen requirements and inotropic support remained stable
during hypothermia. Serial echocardiographic evaluations did not
demonstrate any change in pulmonary pressure values. In our experience
TH did not increase the risk of hemodynamic instability, PHT or bleeding.
Hypothermia may be considered in patients with HIE and CDH or other
surgical conditions with favorable prognosis.
Journal of Perinatology (2012) 32, 981–984; doi:10.1038/jp.2012.29
Keywords: HIE; CDH; hypothermia; bleeding; pulmonary vascular
resistance
Introduction
Several randomized controlled trials have demonstrated that
therapeutic hypothermia (TH) is beneficial to term newborns
with moderate to severe hypoxic-ischemic encephalopathy (HIE).
Cooling significantly reduces mortality and neurodevelopmental
disability to 18 months of age.1–6 Hypothermia is induced within
6 h of life either by selective head cooling or by whole-body cooling
to a target core temperature of 33 to 34 1C for 72 h. Major
congenital abnormalities and surgery have been considered
contraindications to TH.1–4 Moreover, hypothermia is recognized
as a risk factor for precipitating pulmonary hypertension (PHT),
thus, it might be relatively contraindicated in patients with
congenital diaphragmatic hernia (CDH).
Correspondence: Dr S Buratti, Department of Neonatal and Pediatric Anesthesia and
Intensive Care, U.O.C. Anestesia e Rianimazione Neonatale e Pediatrica, Istituto G. Gaslini,
L.go G. Gaslini 5, 16147 Genova, Italy.
E-mail: [email protected]
Received 15 September 2011; revised 10 January 2012; accepted 22 February 2012
CDH occurs in 1/2500 to 1/5000 live births and half of the cases
are not detected by prenatal ultrasound leading to the birth of
babies with a life threatening condition in peripheral hospitals
or in unprepared delivery rooms.7 We describe two cases of CDH
without prenatal diagnosis who developed HIE and underwent
surgical repair during systemic hypothermia.
Case 1
Patient 1 was born at 38 weeks gestational age by repeat cesarean
section in a first level hospital. At birth the patient was apneic,
with heart rate <60 b.p.m. After cardiopulmonary resuscitation
the patient was transferred to the tertiary care neonatal center.
On admission, at 2 h of life, diagnosis of CDH and right
pneumothorax was done based on clinical findings and chest X-ray
(CXR) (Figure 1a). SatO2 was 70% with FiO2 0.7. Chest tube was
placed and inotropic and ventilatory support initiated with
epinephrine and high-frequency oscillatory ventilation (HFOV).
Inhaled nitric oxide (iNO) was used for initial stabilization at
20 p.p.m. and rapidly discontinued at 18 h of life. Diagnosis
of moderate HIE was formulated based on clinical (modified
Sarnat stage II, need for resuscitation at birth), laboratory
(at 15 min: pH 6.59, base deficit 10), and amplitude integrated
electroencephalographic (aEEG) criteria (Olympic 6000 CFM,
Olympic Medical, Seattle, WA, USA). The patient was treated
with whole body mild hypothermia (33.5 1C) for 72 h. On day
of life (DOL) 2 surgical repair of a large left latero-posterior
diaphragmatic defect was performed. Oxygen requirement (FiO2)
was 0.40 to 0.50 and pCO2 45 to 55 mm Hg before cooling and
remained in these ranges during hypothermia. On admission,
cardiac ultrasound showed moderate tricuspid valve regurgitation,
mild PHT and bidirectional ductal shunt. Pulmonary vascular
resistances and cardiac performance were assessed with serial
echocardiographic evaluations with no significant changes during
and after hypothermia. Inotropic and ventilatory support were
weaned and discontinued on DOL 6. Platelet count dropped
from 330 000 mm 3 on DOL 2 to 110 000 mm 3 on DOL 3,
whereas coagulation parameters remained stable. No bleeding
complications were observed. Sedation with morphine was required
to prevent shivering and related increase in metabolic rate and
CDH and therapeutic hypothermia
S Buratti et al
982
SURGERY
100
90
80
70
60
50
40
30
iNO 20 ppm
Epinephrine 0.04-0.06 mcg/kg/min
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84
hours from admission
SURGERY
100
Figure 1 CXR of patient 1 (a) and patient 2 (b) on the day of presentation:
stomach and loops of bowel above the diaphragm, mediastinal shift, right
pneumothorax.
90
80
70
60
oxygen consumption and suppress the hypothermia-induced stress
responses.
50
40
30
iNO 20 ppm
Case 2
Patient 2 was born at 38 weeks gestational age by instrumental
delivery in a first level hospital. APGAR score was 5 at 1 min and
9 at 10 min. At 30 min of life she developed severe respiratory
distress, bradycardia, hypotension and hypotonia. After several
attempts endotracheal intubation was obtained. Blood gases were
significant for severe low cardiac output state with pH 6.98 and
base deficit 16.9. The CXR was suggestive for CDH (Figure 1b).
After stabilization the patient was transferred to the tertiary care
center. Clinical, neurological (modified Sarnat stage II) and aEEG
criteria were consistent with moderate HIE and cooling was started
at 4 h of life. Ventilatory (HFOV, iNO 20 p.p.m.) and inotropic
support (epinephrine) was effective in achieving and maintaining
respiratory and hemodynamic stability during TH. Oxygen
requirement was 0.30 to 0.40 and pCO2 48 to 55 mm Hg during
hypothermia. Diaphragmatic surgical repair was performed on
DOL 3 without complications. Inhaled NO and ventilatory support
were weaned and discontinued on DOL 2 and 9, respectively.
Echocardiographic evaluations showed mild PHT on admission,
but did not demonstrate any change in pulmonary pressure values
during hypothermia. At 1 month of life persistent signs of PHT
were present at echocardiography, but resolved in the following
weeks. Platelets and coagulation parameters remained in the
normal range.
Patients’ respiratory and hemodynamic parameters from
admission to re warming are shown in Figure 2.
Brain MR performed at 1 month of age in both patients did
not show any abnormal finding and, at 18 months of age, Bayley
Scales of Infant Development III composite scores were as follows:
cognitive 102 and 95, language 95 and 89, and motor 103 and
100, for patient 1 and 2, respectively.
Journal of Perinatology
Epinephrine 0.04-0.06 mcg/kg/min
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
hours from admission
Figure 2 Patient 1 (a) and patient 2 (b): respiratory and hemodynamic
parameters from admission to rewarming (punctual or average values every 6 h):
core temperature, 1C (gray line), mean arterial pressure, mm Hg (dashed line),
PaCO2, mm Hg (dotted line), SatO2, % (black line).
Discussion
The pathophysiology of CDH is characterized by lung hypoplasia
and structural vascular alterations leading to refractory respiratory
failure, PHT and high mortality rate at birth.8 Patients with CDH
have to be centralized to tertiary newborn care centers in order to
guarantee the highest level of care starting from the first minutes
of life. Undiagnosed CDH complicated by HIE is not a remote event,
especially in outborn infants.
Guidelines on neonatal resuscitation recommend that infants
born at X36 weeks gestation with moderate to severe HIE should
be offered TH.9,10 The neuroprotective effect of hypothermia is
thought to be related to the inhibition of the neuroexcitotoxic
cascade and the apoptotic pathways activated during ischemia
reperfusion. Diagnosis of HIE is formulated based on clinical,
laboratory (pH, base deficit) and aEEG criteria. In patients
with CDH, diagnosis of HIE may not be straightforward: initial
blood gas findings may be the result of acute hypoxic-ischemic
injury, respiratory failure and PHT. Moreover, in our experience
clinical evaluation is less sensitive than the other criteria and
may be difficult for the effects of early pharmacological
interventions. These observations confirm the diagnostic role of
aEEG tracing on admission as the best single outcome predictor in
CDH and therapeutic hypothermia
S Buratti et al
983
term infants with perinatal asphyxia at normothermia with an
overall sensitivity of 91%.11
CDH may be considered a contraindication to TH as major
malformation and for the increased risk of PHT, hemodynamic
instability and bleeding during surgical repair associated with
cooling. The physiological and pathophysiological effects of cooling
have been extensively described.12–14 Hypothermia decreases the
metabolic rate by 8% per 1 1C drop in core temperature.15 The
decrease in oxygen consumption and production of carbon dioxide
may determine the need to adjust the ventilatory settings
in order to avoid hyperventilation, hypocapnia and cerebral
vasoconstriction. Thoresen and Whitelaw12 observed a worsening
oxygenation in two patients during hypothermia and attributed the
effect to induced pulmonary vasoconstriction. Such an effect has
been previously documented in animal models, but at temperatures
below 32 1C.16 In the reported cases oxygen requirement, blood
gases and ventilatory settings did not change significantly during
hypothermia.
Systemic cooling increases the release of catecholamines and
induces peripheral vasoconstriction. Reduction of heart rate and
cardiac output, mild increase in arterial blood pressure, intact
physiological cardiovascular regulation and normal blood lactate
levels have been reported in cooled newborns.12,13 Arrhythmias
and bradycardia are expected only at temperatures below 33 1C.13
The tight hemodynamic balance needed for patients with CDH
was not altered by hypothermic conditions in our cases;
inotropic support remained stable and was rapidly weaned after
rewarming.
Temperatures of 33 to 35 1C can cause platelet dysfunction and
a mild decrease in platelet count; the synthesis and kinetics of
clotting enzymes and plasminogen activator inhibitors may be
affected only at temperatures below 33 1C.14 We observed a drop
in platelet count in one patient during TH, but after the surgical
procedure. No bleeding occurred during or after the surgical repair
in our patients.
Recent published trials suggest that there may be some minor
cardiovascular and respiratory events, but not an increased
incidence of PHT, coagulopathy or serious adverse effects associated
with mild hypothermia in newborns.2–5 These findings are
confirmed in our experience in two newborns with HIE
secondary to CDH.
The spectrum of severity of CDH is wide and the clinical course
of our patients suggest that parenchymal abnormalities were
moderate, although one of the patients showed persistent PHT
beyond the neonatal age. Severe cases may be associated with a
more difficult management of respiratory failure and PHT.
The optimal timing for surgery in CDH patients is widely
debated and the literature reports controversial results.17
Stabilization of hemodynamic and respiratory parameters before
surgery is essential to improve outcome18 and, once achieved,
this condition is often labile in the complex physiology of CDH. For
this reason a decision was made to perform the surgical correction
as soon as the patients were stable, despite the ongoing TH.
Neurodevelopmental disability is the most concerning long-term
morbidity associated with CDH19 and the pathogenesis is likely
multifactorial. Although the role of hypothermia in this particular
setting is unknown, we considered HIE a possible independent
risk factor for adverse neurological outcome and, therefore,
TH was applied. Evaluation of specific management protocols
for CDH complicated by HIE and multidisciplinary long-term
follow-up programs are critical to ensure optimal care for these
patients.
Conclusion
Hypothermia is a highly promising treatment and major
malformations associated with surgery in the neonatal period may
not be considered a contraindication if the prognosis is favorable.
A careful risk assessment of the single case is warranted. Infants
with hemodynamic instability or significant oxygen requirement
before cooling should be carefully monitored to determine whether
a worsening clinical status with cooling is an indication for
discontinuation of TH. Physicians should be aware of all potential
side effects of TH for adequate prevention and management. More
cases are needed to confirm these observations and prompt further
discussion regarding exclusion criteria for hypothermia.
Conflict of interest
The authors declare no conflict of interest.
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