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Case Report  |   June 2017
Therapeutic Hypothermia to Treat a Newborn With Perinatal Hypoxic-Ischemic Encephalopathy
Author Notes
  • From the Departments of Family Medicine (Dr Fredricks) and Radiology (Dr Benseler) at the Ohio University Heritage College of Osteopathic Medicine (Student Doctors Gibson and Essien) in Athens, Ohio. 
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to Todd R. Fredricks, DO, Grosvenor Hall 251, Department of Family Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701-2979. E-mail: fredrick@ohio.edu
     
Article Information
Neuromusculoskeletal Disorders / Obstetrics and Gynecology / Pediatrics
Case Report   |   June 2017
Therapeutic Hypothermia to Treat a Newborn With Perinatal Hypoxic-Ischemic Encephalopathy
The Journal of the American Osteopathic Association, June 2017, Vol. 117, 393-398. doi:10.7556/jaoa.2017.078
The Journal of the American Osteopathic Association, June 2017, Vol. 117, 393-398. doi:10.7556/jaoa.2017.078
Abstract

Hypoxic-ischemic encephalopathy is caused by neonatal asphyxia and can lead to mortality or long-term neurodevelopmental morbidity in neonates. Therapeutic hypothermia (TH) is one of the few effective ways to manage mitigating neurologic sequelae. The authors describe the case of a neonate who had a perinatal hypoxic insult and sustained no long-term sequelae after being treated with TH. It is important that osteopathic physicians who provide obstetric and gynecologic, perinatal, and emergency medical care are able to recognize a perinatal hypoxic event, understand the stratification of hypoxic-ischemic encephalopathy risk factors, and implement early TH protocols.

Hypoxic-ischemic encephalopathy (HIE) is a complication resulting from neonatal asphyxia. The incidence of HIE in full-term infants is 6 per 1000 births.1 If not treated, 62% of infants with perinatal hypoxic brain injury will die or have moderate to severe disabilities by the age of 18 to 22 months; treatment reduces this rate to 41%.2,3 The incidence of long-term neurologic disabilities are as follows: 45% have cognitive and developmental delay or learning difficulties; 29%, some degree of cerebral palsy; 26%, blindness or vision defects; 17%, gross motor and coordination problems; 12, epilepsy; 9%, hearing loss or deafness; and 1%, behavioral issues.4 Over the past 2 decades, several studies5-8 have attempted to elucidate the pathophysiologic and cellular mechanisms underlying HIE with the aim of expanding treatment options and reducing neonate mortality. We discuss the case of a patient with HIE whose symptoms were successfully managed with therapeutic hypothermia (TH). 
Report of Case
A 28-year-old woman (gravida 3 para 2) at 39 weeks gestational age presented to the obstetrics and genecology department in active labor. On initial examination, the woman's cervix was dilated 8 cm. Two minutes later her placental membranes ruptured, and the fetal heart rate dropped to 60 beats/min. Her obstetrician discovered an umbilical cord prolapse and unsuccessfully attempted to lift the fetus's head to decompress the umbilical cord. Because the anesthesiologist on call was 20 minutes away and delay of delivery was not an option, the obstetrician obtained consent for an emergency cesarean delivery without anesthesia. 
Upon delivery, the neonate was flaccid, unresponsive, and apneic. His birth weight was 8 lb, 3 oz. A neurologic examination revealed nonreacting pupils, generalized hypotonia, and absent neonatal reflexes. Positive-pressure ventilation was initiated with a bag-valve mask. His heart rate increased to 100 beats/min within 15 seconds, but he remained apneic and was intubated. Apgar scores were 1, 4, 4, and 7 at 1, 5, 10, and 20 minutes, respectively. Laboratory tests conducted 25 minutes after birth yielded the following results: arterial blood pH, 7.09; base excess, 18 mmol/L; lactate, 10.9 mmol/L; lactate dehydrogenase, 741 U/L; creatine kinase, 1594 U/L; glucose, 126 mg/dL; and troponin I, 0.06 ng/mL. 
Neonatal neurointensivist consultation was requested, and the neonate was given the diagnosis of stage II HIE. Whole-body therapeutic hypothermia (TH), also referred to as targeted temperature management, was recommended. Two hours after birth, TH was initiated, and the neonate's core body temperature was maintained at 33.5°C for 72 hours. Sedation was achieved using a weight-based (0.05-0.2 mg/kg) bolus dose of morphine sulfate over 5 minutes followed by a continuous intravenous infusion of 10 to 20 µg/kg per hour. Remote monitoring with amplitude-integrated electroencephalography was conducted during the initial 72 hours of TH. After 72 hours, the neonate's core body temperature was increased by 0.5°C every hour until it reached a core temperature of 37°C. No aberrations were noted during the cooling or rewarming period. Transient renal dysfunction, which responded to fluid boluses and bumetanide, was noted during the first 24 hours of TH. 
A cranial sonograph of the neonate was taken the day after birth and no hemorrhage due to perinatal stress was identified (Figure 1). A magnetic resonance image of the brain was taken 10 days after birth (Figure 2). Periventricular white matter signal characteristics were unremarkable, with no focal parenchymal cystic changes or cystic encephalomalacia identified. 
Figure 1.
Sagittal cranial ultrasound image demonstrating normal, slitlike lateral ventricles in a neonate 1 day after birth while undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 1.
Sagittal cranial ultrasound image demonstrating normal, slitlike lateral ventricles in a neonate 1 day after birth while undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 2.
Diffusion magnetic resonance image showing no evidence of anoxic injury in a neonate 10 days after undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 2.
Diffusion magnetic resonance image showing no evidence of anoxic injury in a neonate 10 days after undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Because the sucking reflex was absent at birth, parenteral feeding was initiated the day after birth and was complemented by the initiation of breast milk nasogastric tube feedings once cooling stabilized at the end of the day. Mild truncal hypotonia persisted until 7 days after birth. Tube feeding ceased 8 days after birth, and bottle and breastfeeding were introduced the next day. A speech pathologist was consulted to help the neonate learn the sucking reflex. The newborn was discharged 13 days after birth, after unremarkable neurologic examination findings. The neonate was able to drink 70 mL of breast milk from a bottle for 15 minutes before tiring. By age 14 days, the neonate was exclusively breastfed. Follow-up appointments were scheduled every 2 to 3 months until the patient was 1 year old, at which time the appointments were scheduled for every 6 months until he was 2 years old. Then, the follow-up appointments were annual. At the patient's 3-year appointment, no sequelae from HIE were identified. 
Discussion
In neonates, HIE can cause death or severe disabilities, especially if it is not properly managed. Brain injury in patients with HIE is the result of pathologic events divided into 3 phases: the primary energy failure, secondary energy failure, and tertiary phases. The primary energy failure phase begins with the initial hypoxic insult and lasts approximately 6 hours. Reduced cerebral blood flow results in lowered oxygen and glucose delivery to the brain. This reduction leads to lowered adenosine triphosphate and a switch to anaerobic metabolism and elevated serum lactate levels. The reduced accessibility to adenosine triphosphate leads to failure of the sodium-potassium pumps and the accumulation of intracellular ions such as calcium and sodium, which cause neuron depolarization. Additional membrane depolarization yields the release of excitatory neurotransmitters such as glutamate. This release leads to a cascade of events that include cerebral edema, cellular necrosis, and apoptosis.9 Disruption of cell membranes leads to the release of intracellular inflammatory mediators, which causes further damage to the brain. 
There is a latent period at the end of the primary energy failure phase before the beginning of the secondary energy failure phase. This period is a critical time during which much of the damage created during the PEF phase can be mitigated with proper intervention.10 If prompt restoration of cerebral oxygen and glucose levels does not occur, the secondary energy failure phase will be initiated.5 The exact mechanisms of this phase are not fully understood. The phase begins 6 to 24 hours after the initial insult and is hallmarked by continued apoptosis and overproduction of free radicals, which cause further damage to the neonatal brain.6 The inflammatory cascade generated by neonatal cerebral hypoxia leads to the accumulation of neutrophils that further exacerbate cerebral edema.6 Excitotoxicity of sensory, learning, and memory neuropathways caused by elevated glutamate levels is also thought to have a negative effect on neonates with HIE.7 
The tertiary phase of brain injury includes the events that follow the primary and secondary phases, and this phase can last from weeks to years.8,11 This period is marked by the long-term sensitization to the inflammation found in the first 2 phases. It is during this phase that patients have increased seizure susceptibility, impaired oligodendrocyte function, persistent inflammation, and gliosis. These phenomena pose serious long-term disability implications for patients.8,11 
Although there are no specific diagnostic tests for patients with possible HIE, some general diagnostic criteria include suspected perinatal insult, gestation greater than 36 weeks, a 10-minute Apgar score lower than 5, the need for continued resuscitation, a pH score of less than 7.0 or base deficit greater than 16 mmol/L, signs of neonatal neurologic dysfunction (eg, lethargy, irritability, seizures), and evidence of multisystem organ dysfunction.12 The diagnosis of HIE is primarily clinical in nature. Thus, attending physicians should maintain a high index of suspicion for HIE during any delivery in which there is evidence of potential perinatal hypoxia. 
When HIE is suspected, TH is initiated on the basis of a combination of clinical signs, laboratory test results, gestational age, and the level of severity of the insult. Severity is determined using the Sarnat staging system (Table).13,14 The severity of HIE influences the prognosis for long-term neurologic sequelae. The incidence of neurologic sequelae is 0% in children younger than 3 years with mild HIE, 32% in children with moderate HIE, and nearly 100% in children with severe HIE.15 Hypoxic insults to the brain have been associated with an elevation in brain temperature.16 It is posited that this temperature increase is caused by increased metabolic demands and inflammatory mediators released after acute ischemic injury.16 There is a direct correlation between brain temperature and the size of an ischemic infarct in the presence of hypoxic insult.17 Research has shown that lowering core temperature by 1°C results in a 6% to 10% reduction in whole-body metabolic demands.18 In 1998, Gunn et al19 showed that selective head cooling in neonates with perinatal asphyxia was a safe method to reduce cerebral temperatures and called for a multicenter trial to study head cooling for the management of neonatal encephalopathy. 
Table.
Sarnat Stages of Hypoxic-Ischemic Encephalopathy
Clinical Findings Stage I Stage II Stage III
Alertness Hyperalert Lethargic Coma
Muscle tone Normal or increased Hypotonic Flaccid
Seizures None Frequent Uncommon
Pupils Dilated and reactive Small and reactive Variable and fixed
Respirations Regular Periodic Apneic
Duration of symptoms (days) <1 2-14 >14

Abbreviations: HIE, hypoxic-ischemic encephalopathy.

Table.
Sarnat Stages of Hypoxic-Ischemic Encephalopathy
Clinical Findings Stage I Stage II Stage III
Alertness Hyperalert Lethargic Coma
Muscle tone Normal or increased Hypotonic Flaccid
Seizures None Frequent Uncommon
Pupils Dilated and reactive Small and reactive Variable and fixed
Respirations Regular Periodic Apneic
Duration of symptoms (days) <1 2-14 >14

Abbreviations: HIE, hypoxic-ischemic encephalopathy.

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In 2001, the first outcome-based study of 40 neonates treated with TH after perinatal asphyxia was published,20 and, although long-term outcome data were not included, the study noted the lack of late-term adverse effects of cooling and identified potential benefits, including a trend toward improved neurologic outcomes. Since 2001, the establishment of specific protocols and the collection of data through randomized controlled trials21,22 has demonstrated the benefits of TH in reducing severe neurodevelopmental outcomes and death in infants with HIE when initiated within the first 6 hours of life. Figure 3 shows the integration of clinical criteria with Sarnat staging to guide the implementation of TH.23 
Figure 3.
Criteria for initiation of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy.
Figure 3.
Criteria for initiation of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy.
The interval between birth and initiation of TH is of critical importance. Although it has been recommended to begin cooling within 6 hours of the hypoxic insult,24 Thoreson et al12 found that starting cooling within 3 hours of birth has been associated with significant improvement in motor outcomes in children studied. Studies25,26 have demonstrated that either elective head or whole-body (systemic blanket) cooling are effective in mitigating neurologic sequelae when the patients’ core body temperature was maintained between 33°C and 35°C for 72 hours before gradual rewarming. Azzopardi et al27 found that 52% of full-term newborns with HIE who were treated with TH had measured IQ scores of 85 or greater at age 6 to 7 years, vs 39% of patients in the control group, who did not undergo cooling. 
Although benefits have been documented, TH can be detrimental to neonates in certain circumstances. Deeper cooling is associated with anuria, the need for inhaled nitric oxide therapy, the need for extracorporeal membrane oxygenation, more days of required oxygen therapy, and a greater incidence of arrhythmias, such as bradycardia.28 Therapeutic hypothermia can lead to lowering of neutrophil and lymphocyte counts, which can be beneficial for reduction of cerebral edema but can also lead to complications secondary to immune suppression, such as chorioamnionitis, in cases of infectious inflammation.29 Because of this risk, careful assessment of both the neonate and the mother for infectious causes must be completed when HIE is identified. A thorough analysis of the risks and benefits of TH should be considered in cases associated with infection. Physicians using TH to treat HIE must provide aggressive oversight of the TH protocol and be prepared to quickly intervene when indicators of therapeutic complications appear. 
Attending physicians must also consider the environment of the patient receiving TH and provide appropriate sedation and ventilator management. Neonates receiving TH undergo intensive medical interventions, including ventilation for optimization of oxygenation, needle sticks, and manipulation by nurses and physicians. Proper sedation and management of heart rate can be confounded by hypothermia-induced bradycardia, medications, and sedative toxicity.30 Because TH is a relatively new intervention for managing HIE, the recommendations for optimal supportive therapy in the literature changes frequently. The use of protocols and regular review of the literature are needed as the data supporting TH matures.31Another benefit of this technique is that TH can be implemented using low-technology methods in areas that are far from tertiary care centers with neonatal intensive care units. A 2015 review32 by South African pediatricians demonstrated the efficacy of low-technology TH using nonelectrical devices to achieve improved outcomes in neonates with HIE. The data from this study32 suggest that the development of low-technology TH early intervention protocols in rural US facilities that provide obstetrician and gynecology services warrant further research. 
Conclusion
This case describes a neonate with HIE who was successfully treated with TH. Because many osteopathic physicians practice primary care in rural hospitals that provide obstetric and gynecologic services as well as newborn care, it is important that they understand the benefits of TH. Hospitals that do not have the capacity to implement advanced TH should consider low-technology options after consultation with pediatric receiving facilities to avoid delays in cooling, which could result in further neurologic damage and long-term sequelae. Facilities that provide emergency services but do not have an obstetrics and gynecology department should develop protocols in consultation with supporting pediatric referral centers. These protocols will allow for rapid assessment and transfer of neonates with HIE to skilled facilities with a neonatal intensive care unit that can support TH to optimize positive outcomes.33 
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Figure 1.
Sagittal cranial ultrasound image demonstrating normal, slitlike lateral ventricles in a neonate 1 day after birth while undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 1.
Sagittal cranial ultrasound image demonstrating normal, slitlike lateral ventricles in a neonate 1 day after birth while undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 2.
Diffusion magnetic resonance image showing no evidence of anoxic injury in a neonate 10 days after undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 2.
Diffusion magnetic resonance image showing no evidence of anoxic injury in a neonate 10 days after undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy.
Figure 3.
Criteria for initiation of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy.
Figure 3.
Criteria for initiation of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy.
Table.
Sarnat Stages of Hypoxic-Ischemic Encephalopathy
Clinical Findings Stage I Stage II Stage III
Alertness Hyperalert Lethargic Coma
Muscle tone Normal or increased Hypotonic Flaccid
Seizures None Frequent Uncommon
Pupils Dilated and reactive Small and reactive Variable and fixed
Respirations Regular Periodic Apneic
Duration of symptoms (days) <1 2-14 >14

Abbreviations: HIE, hypoxic-ischemic encephalopathy.

Table.
Sarnat Stages of Hypoxic-Ischemic Encephalopathy
Clinical Findings Stage I Stage II Stage III
Alertness Hyperalert Lethargic Coma
Muscle tone Normal or increased Hypotonic Flaccid
Seizures None Frequent Uncommon
Pupils Dilated and reactive Small and reactive Variable and fixed
Respirations Regular Periodic Apneic
Duration of symptoms (days) <1 2-14 >14

Abbreviations: HIE, hypoxic-ischemic encephalopathy.

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