CASE REPORT

Therapeutic Hypothermia to Treat a Newborn With Perinatal Hypoxic-Ischemic

Todd R. Fredricks, DO; Christopher Gibson, OMS III; Francis Essien, OMS III; Jeffrey S. Benseler, DO

From the Departments of Hypoxic-ischemic encephalopathy is caused by neonatal asphyxia and can lead Family Medicine to mortality or long-term neurodevelopmental morbidity in neonates. (Dr Fredricks) and Radiology (Dr Benseler) at the Ohio Therapeutic hypothermia (TH) is one of the few effective ways to manage miti- University Heritage College of gating neurologic sequelae. The authors describe the case of a neonate who had Osteopathic Medicine a perinatal hypoxic insult and sustained no long-term sequelae after being (Student Doctors Gibson and treated with TH. It is important that osteopathic physicians who provide obstet- Essien) in Athens, Ohio. ric and gynecologic, perinatal, and emergency medical care are able to recog- Financial Disclosures: nize a perinatal hypoxic event, understand the stratification of hypoxic- None reported. ischemic encephalopathy risk factors, and implement early TH protocols. Support: None reported. J Am Osteopath Assoc. 2017;117(6):393-398 Address correspondence to doi:10.7556/jaoa.2017.078 Todd R. Fredricks, DO, Keywords: hypoxic-ischemic encephalopathy, neonate, obstetrics and gynecology, therapeutic hypothermia Grosvenor Hall 251, Department of Family Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701-2979. ypoxic-ischemic encephalopathy (HIE) is a complication resulting from neonatal asphyxia. The incidence of HIE in full-term infants is 6 per 1000 E-mail: [email protected] births.1 If not treated, 62% of infants with perinatal hypoxic brain injury will Submitted H die or have moderate to severe disabilities by the age of 18 to 22 months; treatment July 22, 2016; 2,3 revision received reduces this rate to 41%. The incidence of long-term neurologic disabilities are as November 21, 2016; follows: 45% have cognitive and developmental delay or learning difficulties; 29%, accepted some degree of cerebral palsy; 26%, blindness or vision defects; 17%, gross motor and January 12, 2017. coordination problems; 12, ; 9%, hearing loss or deafness; and 1%, behavioral issues.4 Over the past 2 decades, several studies5-8 have attempted to elucidate the patho- physiologic and cellular mechanisms underlying HIE with the aim of expanding treat- ment 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 obste- trics 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,

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and absent neonatal reflexes. Positive-pressure ventila- initial 72 hours of TH. After 72 hours, the neonate’s tion was initiated with a bag-valve mask. His heart rate core body temperature was increased by 0.5°C every increased to 100 beats/min within 15 seconds, but he hour until it reached a core temperature of 37°C. No remained apneic and was intubated. Apgar scores were aberrations were noted during the cooling or rewarming 1, 4, 4, and 7 at 1, 5, 10, and 20 minutes, respectively. period. Transient renal dysfunction, which responded to Laboratory tests conducted 25 minutes after birth fluid boluses and bumetanide, was noted during the first yielded the following results: arterial blood pH, 7.09; 24 hours of TH. base excess, 18 mmol/L; lactate, 10.9 mmol/L; lactate A cranial sonograph of the neonate was taken the day dehydrogenase, 741 U/L; creatine kinase, 1594 U/L; after birth and no hemorrhage due to perinatal stress glucose, 126 mg/dL; and troponin I, 0.06 ng/mL. was identified (Figure 1). A magnetic resonance image Neonatal neurointensivist consultation was of the brain was taken 10 days after birth (Figure 2). requested, and the neonate was given the diagnosis of Periventricular white matter signal characteristics were stage II HIE. Whole-body therapeutic hypothermia unremarkable, with no focal parenchymal cystic (TH), also referred to as targeted temperature manage- changes or cystic encephalomalacia identified. ment, was recommended. Two hours after birth, TH Because the sucking reflex was absent at birth, paren- was initiated, and the neonate’s core body temperature teral feeding was initiated the day after birth and was was maintained at 33.5°C for 72 hours. Sedation was complemented by the initiation of breast milk nasogas- achieved using a weight-based (0.05-0.2 mg/kg) bolus tric tube feedings once cooling stabilized at the end of dose of morphine sulfate over 5 minutes followed by a continuous intravenous infusion of 10 to 20 mg/kg per hour. Remote monitoring with amplitude-integrated was conducted during the

Figure 1. Figure 2. Sagittal cranial ultrasound image demonstrating normal, Diffusion magnetic resonance image showing no evidence slitlike lateral ventricles in a neonate 1 day after birth while of anoxic injury in a neonate 10 days after undergoing undergoing therapeutic hypothermia for hypoxic-ischemic therapeutic hypothermia for hypoxic-ischemic encephalopathy. encephalopathy.

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the day. Mild truncal hypotonia persisted until 7 days secondary energy failure phase. This period is a critical after birth. Tube feeding ceased 8 days after birth, and time during which much of the damage created during bottle and breastfeeding were introduced the next day. the PEF phase can be mitigated with proper interven- A speech pathologist was consulted to help the tion.10 If prompt restoration of cerebral oxygen and neonate learn the sucking reflex. The newborn was dis- glucose levels does not occur, the secondary energy charged 13 days after birth, after unremarkable neuro- failure phase will be initiated.5 The exact mechanisms logic examination findings. The neonate was able to of this phase are not fully understood. The phase drink 70 mL of breast milk from a bottle for 15 begins 6 to 24 hours after the initial insult and is hall- minutes before tiring. By age 14 days, the neonate was marked by continued apoptosis and overproduction of exclusively breastfed. Follow-up appointments were free radicals, which cause further damage to the scheduled every 2 to 3 months until the patient was 1 neonatal brain.6 The inflammatory cascade generated year old, at which time the appointments were sched- by neonatal leads to the accumulation uled for every 6 months until he was 2 years old. of neutrophils that further exacerbate .6 Then, the follow-up appointments were annual. At the Excitotoxicity of sensory, learning, and memory neuro- patient’s 3-year appointment, no sequelae from HIE pathways caused by elevated glutamate levels is also were identified. 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 Discussion phase can last from weeks to years.8,11 This period is In neonates, HIE can cause death or severe disabilities, marked by the long-term sensitization to the inflamma- especially if it is not properly managed. Brain injury in tion found in the first 2 phases. It is during this phase patients with HIE is the result of pathologic events that patients have increased susceptibility, divided into 3 phases: the primary energy failure, impaired oligodendrocyte function, persistent inflam- secondary energy failure, and tertiary phases. The mation, and gliosis. These phenomena pose serious primary energy failure phase begins with the initial long-term disability implications for patients.8,11 hypoxic insult and lasts approximately 6 hours. Although there are no specific diagnostic tests for Reduced cerebral blood flow results in lowered oxygen patients with possible HIE, some general diagnostic and glucose delivery to the brain. This reduction leads criteria include suspected perinatal insult, gestation to lowered adenosine triphosphate and a switch to anaer- greater than 36 weeks, a 10-minute Apgar score lower obic metabolism and elevated serum lactate levels. The than 5, the need for continued resuscitation, a pH score reduced accessibility to adenosine triphosphate leads to of less than 7.0 or base deficit greater than 16 mmol/L, failure of the sodium-potassium pumps and the accumu- signs of neonatal neurologic dysfunction (eg, lethargy, lation of intracellular ions such as calcium and sodium, irritability, ), and evidence of multisystem organ which cause neuron depolarization. Additional mem- dysfunction.12 The diagnosis of HIE is primarily clinical brane depolarization yields the release of excitatory neu- in nature. Thus, attending physicians should maintain a rotransmitters such as glutamate. This release leads to a high index of suspicion for HIE during any delivery in cascade of events that include cerebral edema, cellular which there is evidence of potential perinatal hypoxia. necrosis, and apoptosis.9 Disruption of cell membranes When HIE is suspected, TH is initiated on the basis leads to the release of intracellular inflammatory media- of a combination of clinical signs, laboratory test tors, which causes further damage to the brain. results, gestational age, and the level of severity of the There is a latent period at the end of the primary insult. Severity is determined using the Sarnat staging energy failure phase before the beginning of the system (Table).13,14 The severity of HIE influences the

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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.

prognosis for long-term neurologic sequelae. The inci- TH in reducing severe neurodevelopmental outcomes dence of neurologic sequelae is 0% in children and death in infants with HIE when initiated within younger than 3 years with mild HIE, 32% in children the first 6 hours of life. Figure 3 shows the integration with moderate HIE, and nearly 100% in children with of clinical criteria with Sarnat staging to guide the severe HIE.15 Hypoxic insults to the brain have been implementation of TH.23 associated with an elevation in brain temperature.16 It The interval between birth and initiation of TH is of is posited that this temperature increase is caused by critical importance. Although it has been recommended increased metabolic demands and inflammatory media- to begin cooling within 6 hours of the hypoxic insult,24 tors 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. In 2001, the first outcome-based study of 40 neo- nates treated with TH after perinatal asphyxia was pub- lished,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 bene- fits, including a trend toward improved neurologic outcomes. Since 2001, the establishment of specific Figure 3. protocols and the collection of data through randomized Criteria for initiation of therapeutic hypothermia in neonates 21,22 controlled trials has demonstrated the benefits of with hypoxic-ischemic encephalopathy.

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Thoreson et al12 found that starting cooling within 3 the literature changes frequently. The use of protocols hours of birth has been associated with significant and regular review of the literature are needed as the improvement in motor outcomes in children studied. data supporting TH matures.31Another benefitofthis Studies25,26 have demonstrated that either elective head technique is that TH can be implemented using low- or whole-body (systemic blanket) cooling are effective technology methods in areas that are far from tertiary in mitigating neurologic sequelae when the patients’ core care centers with neonatal intensive care units. A 2015 body temperature was maintained between 33°C and 35° review32 by South African pediatricians demonstrated C for 72 hours before gradual rewarming. Azzopardi the efficacy of low-technology TH using nonelectrical et al27 found that 52% of full-term newborns with HIE devices to achieve improved outcomes in neonates who were treated with TH had measured IQ scores of 85 with HIE. The data from this study32 suggest that the or greater at age 6 to 7 years, vs 39% of patients in the development of low-technology TH early intervention control group, who did not undergo cooling. protocols in rural US facilities that provide obstetrician Although benefits have been documented, TH can be and gynecology services warrant further research. detrimental to neonates in certain circumstances. Deeper cooling is associated with anuria, the need for inhaled nitric oxide therapy, the need for extracorporeal mem- Conclusion brane oxygenation, more days of required oxygen This case describes a neonate with HIE who was therapy, and a greater incidence of arrhythmias, such as successfully treated with TH. Because many osteopathic bradycardia.28 Therapeutic hypothermia can lead to low- physicians practice primary care in rural hospitals that ering of neutrophil and lymphocyte counts, which can be provide obstetric and gynecologic services as well as beneficial for reduction of cerebral edema but can also newborn care, it is important that they understand the lead to complications secondary to immune suppression, benefits of TH. Hospitals that do not have the capacity such as chorioamnionitis, in cases of infectious inflam- to implement advanced TH should consider low- mation.29 Because of this risk, careful assessment of technology options after consultation with pediatric both the neonate and the mother for infectious causes receiving facilities to avoid delays in cooling, which must be completed when HIE is identified. A thorough could result in further neurologic damage and long-term analysis of the risks and benefits of TH should be sequelae. Facilities that provide emergency services but considered in cases associated with infection. Physicians do not have an obstetrics and gynecology department using TH to treat HIE must provide aggressive oversight should develop protocols in consultation with supporting of the TH protocol and be prepared to quickly intervene pediatric referral centers. These protocols will allow for when indicators of therapeutic complications appear. rapid assessment and transfer of neonates with HIE to Attending physicians must also consider the environ- skilled facilities with a neonatal intensive care unit that ment of the patient receiving TH and provide appropri- can support TH to optimize positive outcomes.33 ate sedation and ventilator management. Neonates receiving TH undergo intensive medical interventions, References including ventilation for optimization of oxygenation, 1. Levene ML, Kornberg J, Williams TH. The incidence and severity of needle sticks, and manipulation by nurses and physi- post-asphyxial encephalopathy in full-term infants. Early Hum Develop. 1985:11(1):21-26. cians. Proper sedation and management of heart rate 2. Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes can be confounded by hypothermia-induced brady- after hypothermia for neonatal encephalopathy. N Engl J Med. cardia, medications, and sedative toxicity.30 Because 2012;366(22):2085-2092. doi:10.1056/NEJMoa1112066 TH is a relatively new intervention for managing HIE, 3. Finer NN, Robertson CM, Richards RT, Pinnell LE, Peters KL. Hypoxic-ischemic encephalopathy in term neonates: perinatal factors the recommendations for optimal supportive therapy in and outcome. J Pediatr. 1981;98(1):112-117.

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4. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term 20. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. neurodevelopmental outcomes after intrauterine and neonatal Neurodevelopmental outcome of infants treated with head cooling and insults: a systematic review. Lancet. 2012;379(9814):445-452. mild hypothermia after perinatal asphyxia. Pediatrics. 2001;107 doi:10.1016/S0140-6736(11)61577-8 (7):480-484.

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