HIE in full term neonates is not unusual since it occurs among 1–3 newborns for 1000 live births [
The incidence of HIE is significantly higher in developing countries this may present heavy social and economic costs. In Morocco perinatal asphyxia presents a large part of national public health policy; it is among the main causes of perinatal mortality but we do not have a published national epidemiological data. This high incidence is related mainly to socioeconomic factors: the lack of pregnancy follow-up, the lack of adequate infrastructure, the geographical distance of the delivery centers and consequently the persistence of home deliveries, the absence of structures adapted to the reception of the newborn at the delivery, and the lack of newborn transport policy.
TH as whole body or selective head cooling has become a standard therapy for moderate-severe HIE to reduce neurological damage. Most recent meta-analyses documented the efficacy of TH in term infants with moderate to severe encephalopathy [
In Morocco, Mohamed VI University Hospital is the only center until recently (end of 2015), to implement TH for the treatment of asphyxiated neonates with HIE [
This study was performed in the NICU at the Mohamed VI University Hospital of Marrakech, Morocco. This unit also receives children from all the south of Morocco. The hypothermia protocol was implemented in June 2012.
38 neonates out of 72 admitted for neonatal asphyxia in NICU from July 18, 2012, to May 15, 2014, were included in the study. These children were divided into two groups: the first group included 19 infants who were treated by hypothermia (protocol group) and a control group included 19 newborns with HIE but could not receive hypothermia.
This is a prospective study including neonates born in maternity of Mohamed VI Hospital (inborn) and neonates referred from other institutes (outborn). Data were collected from patients files, analyzing demographic parameters (gestational age, birth, and sex), perinatal-neonatal features (the origin of neonates, mode of delivery, acute intrapartum events, Apgar score at 1, 5, and 10 minutes, and the need of neonatal resuscitation), severity of HIE as assessed prior to cooling (Sarnat and Sarnat criteria), evolving information (hemorrhagic, infectious, renal complications, and death), and the result of the neurological examination at 6, 12, and 18 months. For infants in the protocol group we have registered the time of cooling initiation after birth, the rectal temperature monitoring, the adverse effects, and interventions during cooling.
All babies were selected and treated according to the local NICU protocol which was consistent with those recommended by French Society of Neonatology [
The selective cooling of the head was the hypothermia protocol employed in this work by using special apparatus (COOL CAP OLYMPIC). It should be started before the sixth hour of age. The objective of selective hypothermia was to reach a rectal temperature between 34 and 35°C for 72 h from the beginning of the procedure. At the admission, the newborn was installed in an infant warmer that was off unless the newborn had a temperature less than 34°C. Rectal temperature was checked every 15 min until obtaining a temperature of 34°C. Hypothermia was continued for 72 h while the rectal temperature was checked every 2 hours and the skin probe was held in place continuously. After 72 h of hypothermia, the newborn was gradually warmed from 0.2 to 0.4°C per hour (6 to 12 h). The newborn was under continuous monitoring with cardiopulmonary scope, a monitoring of diuresis, glucose monitoring every 6 to 8 hours, and monitoring of blood pressure every 2 hours (every hour during the warming). A close biological screening was carried out: daily chemistry panel, complete blood count, and coagulation profile.
The results were expressed as number and percentage or by the average. Statistical analysis was carried out by SPSS 17. The difference between the two groups was studied either by the nonparametric Mann–Whitney test for quantitative variables or by Chi2 or Fisher test for qualitative variables. Statistical difference was considered significant if
After the implementation of the protocol in this unit, 38 neonates among 72 hospitalized for neonatal asphyxia had the indication of TH and were included in the study. The remaining 34 were excluded from the study because they did not meet the TH inclusion criteria.
The 38 neonates included in the study were divided into two groups; each one included 19 newborns: one group received hypothermia and the other was a control group.
There were various reasons for the 19 infants who were not cooled, mainly logistical: admission beyond 6 hours of life in 41%, the lack of place in the unit and the nonavailability of the cooling machine in 10%, technical problems in the machine in 15.7%, and cooling contraindication in 10% (extensive cephalohematoma, pulmonary arterial hypertension) and 20% because the diagnosis was not made early.
For the control group, we try to maintain hypothermia as long as possible, but it was difficult to maintain the temperature below 34°C for long time, so they were treated in normal temperature.
Maternal and neonatal characteristics (Tables
Maternal characteristics.
Maternal characteristics | Protocol group |
Control group |
|
---|---|---|---|
Maternal age (average) | 26,3 | 27,3 | NS |
Parity (average) | 1,3 | 2,1 | NS |
|
NS | ||
Gestational diabetes | 0 | 1 (5) | |
Gestational hypertension | 1 (5,2) | 0 | |
|
NS | ||
Abnormal fetal heart rate | 13 (68,4) | 11 (57) | |
Meconium or stained amniotic fluid | 9 (47,4) | 14 (73) | |
|
NS | ||
Prolapsed cord | 2 (10,6) | 2 (10,6) | |
Other cordonal pathologies | 0 | 1 (5) | |
Retention of the after-coming head | 2 (10,6) | 0 | |
Shoulder dystocia | 1 (5) | 1 (5) |
NS: not significant.
Neonatal characteristics.
Neonatal characteristics | Protocol group |
Control group |
|
---|---|---|---|
Female gender, |
6 (31,6) | 7 (36) | NS |
Birth weight (g) (average) | 3336 | 3300 | NS |
Apgar score ≤ 5 at 5 min, |
17 (89,5) | 19 (100) | NS |
Apgar score ≤ 5 at 10 min, |
12 (63,1) | 16 (84) | NS |
Intubation in the delivery room | NS | ||
Intubation only | 2 (10,6) | 4 (21) | |
Intubation and chest compression | 3 (15,8) | 2 (10,5) | |
Features of aEEG, |
NS | ||
Type 2 | |||
(i) With seizure | 9 (47,3) | 6 (32) | |
(ii) Without seizure | 1 (5,3) | 2 (10,5) | |
Type 3 | |||
(i) With seizure | 7 (36,8) | 4 (21) | |
(ii) Without seizure | 0 | 2 (10,5) | |
Electric seizure | 2 (10,6%) | 3 (15,8) |
aEEG: amplitude-integrated electroencephalography (according to Al Naqeeb classification).
Parents or caregivers of the asphyxiated neonates were informed about the important benefit of TH in the HIE. However, written consent was not mandatory for treatment initiation in this institution as cooling is considered a standard of care.
Newborns were admitted in the unit at
Neonatal diseases associated with HIE were similar between the two groups except for pulmonary arterial hypertension that was paradoxically more common in the control group (Table
Complications during hospitalization.
Protocol group |
Control group |
|
|
---|---|---|---|
Bradycardia <90/min | 17 (90) | 2 (10) | S |
Thrombocytopenia | 5 (26,3) | 7 (37) | NS |
Hepatic cytolysis | 7 (36,8) | 11 (57) | NS |
Acidosis | 4 (21) | 7 (37) | NS |
Hyperkalemia | 7 (36,8) | 3 (15) | NS |
Renal failure | 8 (42) | 13 (68) | NS |
PAH | 0 | 6 (31) | S |
Head edema | 1 | 0 | — |
Nosocomial infection | 5 (26,3) | 4 (21) | NS |
S: significant.
PAH: pulmonary arterial hypertension.
The mean duration of hospitalization was longer in the protocol group. Seven children died in the control group versus 3 in the protocol group (Table
Evolution during hospitalization.
Protocol group |
Control group | |
---|---|---|
Average of hospital stay | 12,4 | 6,7 |
Death | 3 (15) | 7 (37) |
Normal neurological exam at discharge | 8 (42) | 5(26) |
Data from the neurological assessment at the age of 18 months.
Protocol group |
Control group | |
---|---|---|
Normal neurological exam | 9 (56) | 5 (41) |
Psychomotor delay | 3 (15,7) | 2 (10,5) |
Epilepsy | 1 (5,2) | 1 (5,2) |
Neurosensorial disorders | 1 (5,2) | 3 (25) |
In this study, we present our experience with TH when preformed for the management of asphyxiated neonates with moderate and severe HIE, especially after the results of major randomized controlled studies that have shown a beneficial effect of controlled hypothermia on survival and long-term neurological outcome for newborns who suffered from HIE using either selective hypothermia [
Two principal methods of cooling exist: selective head cooling and the total body cooling. No superiority of either modality is supported by the existing evidence [
The best neuroprotective effect is obtained if the treatment is started before 6 hours of life as shown in animal studies, where there is still a “therapeutic window” where secondary neuronal injury could be prevented or reduced by brain cooling [
The need to start hypothermia before 6 hours of life has been a major limitation in this study since 41% of newborns referred in this center arrived too late, which explains the reason why the majority of cooled newborn neonates included in this study were inborn. This problem has already been discussed in other studies analyzing the feasibility of hypothermia in low- and middle-income countries [
Starting the hypothermia protocol before 6 h of life assumes a rapid assessment of the severity of HIE and therefore early recognition of anoxic-ischemic nature. Close and repetitive clinical assessment (every 1-2 h during the first 6 h) is required for these patients to determine the stage of HIE and if the HIE stage progresses from stage I to stage II therapeutic hypothermia should be started immediately. The recommendations of neonatal societies were made to this effect [
Careful clinical and laboratory test is essential in newborns with HIE regardless of the mode of treatment, but TH requires additional parameters to be monitored throughout treatment such as umbilical arterial and venous catheterization for blood draw and urinary catheterization for urine output measurements. Full monitoring including heart rate, respiratory rate, blood pressure, core temperature, and SaO2 is required. The core temperature is recorded by esophageal or rectal probe. The axillary temperature measurements have been reported to give variable data and, therefore, should not be preferred over core temperature measurement methods [
The head cooling protocol requires specialized equipment; the hypothermia is obtained by using a special cap with circulating cold water placed on the head of the neonate. All the newborns from the protocol group were already hypothermic on admission with an average rectal temperature of
The core temperature monitoring should continue for several hours after normothermia to avoid overshooting the rewarming [
Side effects related to perinatal asphyxia were similar for both groups; we observed a low rate in pulmonary arterial hypertension in the protocol group compared to the control group which is contradicting with the literature data [
Hospital stay was longer in the protocol group which was also found in the randomized study of Shankaran et al. [
Almost all newborns diagnosed with HIE are started on empirical antibiotic treatment if the etiology of asphyxia is not clear. Hence, the hypothermia is known to cause some degree of immunosuppression with decreased leukocyte number and impaired functions [
We had a higher rate of newborn follow-up in the cooling group comparing to a control group, reaching 80%. In the noncooling group, we had a high rate of loss of views; this may be explained by a possible improvement in their status. A significant decrease in death rates and neurological morbidity at the age of 18 months in children who have moderate or severe HIE was found in newborns of protocol group.
The limit of the study is the small number of included neonates. However, data presented here are derived from a single center and, therefore, only a limited number of neonates could have been assessed in a relative short time, particularly with respect to long-term outcome. On the other hand, the analysis of the results permits the detection of important clinical parameters which could allow further improvement in the clinical implementation of this novel therapeutic approach. The further studies with a larger population as well as training medical team are necessary to confirm these results.
Implementation of TH is facing a lot of problems in Morocco. The generalization of this practice needs to be guided by standardized protocols. Local protocols should be developed based on the existing international experience adapted to local context. Developing training programs, improving infrastructure including neonatal transport, and affording human resources are mandatory to guarantee the success of hypothermia in Morocco.
The authors declare that there are no conflicts of interest regarding the publication of this paper.