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Perinatal asphyxia in term and late preterm infants

Perinatal asphyxia in term and late preterm infants
Authors:
Floris Groenendaal, MD, PhD
Frank van Bel, MD, PhD
Section Editor:
Richard Martin, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Jun 2022. | This topic last updated: Oct 25, 2021.

INTRODUCTION — Perinatal asphyxia is caused by a lack of oxygen to organ systems due to a hypoxic or ischemic insult that occurs within close temporal proximity to labor (peripartum) and delivery (intrapartum). In the neonate, the lack of oxygen may lead to multi-organ failure with brain involvement as the major organ of concern (hypoxic-ischemic encephalopathy [HIE]). In most cases of HIE, injury to other major organ systems occurs, including the heart, kidney, lung, and liver.

An overview of the clinical manifestations and management of neonates with perinatal asphyxia will be reviewed here. The clinical features, evaluation, and management of HIE are discussed in greater detail separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

TERMINOLOGY — Terms that are used in this topic include:

Perinatal asphyxia – Condition of impaired gas exchange or inadequate blood flow that leads to persistent hypoxemia and hypercarbia that occurs in temporal proximity to labor (peripartum) and delivery (intrapartum)

Hypoxemia – Abnormally low blood oxygen levels in the blood

Hypoxia – Abnormally low blood oxygen levels in the body tissue

Ischemia – Reduction or complete cessation of blood flow to an organ, which compromises both oxygen delivery (hypoxia) and substrate delivery to an organ

DEFINITION OF PERINATAL HYPOXIC-ISCHEMIC EVENT — The American College of Obstetricians and Gynecologists published an executive summary that outlines neonatal signs and contributing factors used to establish acute hypoxic-ischemic events in term and late preterm infants (gestational age [GA] ≥35 weeks) that would likely result in hypoxic-ischemic encephalopathy (HIE) (table 1)[1].

Neonatal signs consistent with an acute perinatal hypoxic-ischemic event include:

Apgar score of <5 at 5 minutes and 10 minutes

Fetal umbilical artery pH <7.0, or base deficit ≥12 mmol/L, or both

Brain injury seen on brain magnetic resonance imaging (MRI) or MR spectroscopy consistent with acute hypoxia-ischemia

Presence of multisystem organ failure consistent with hypoxic-ischemic encephalopathy (HIE)

In this summary, contributing factors (type and timing) consistent with an acute perinatal event include:

A sentinel hypoxic or ischemic event occurring immediately before or during labor and delivery, such as ruptured uterus or severe abruptio placentae. (See "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences" and "Placental pathology: Findings potentially associated with neurologic impairment in children", section on 'Acute disorders that may be associated with perinatal asphyxia'.)

Fetal heart rate monitor patterns consistent with an acute peripartum or intrapartum event (eg, conversion of category I fetal heart rate [normal pattern] to a category III pattern [absent variability with recurrent late or variable decelerations or bradycardia or sinusoidal pattern]). (See "Intrapartum fetal heart rate monitoring: Overview", section on 'Category III FHR pattern'.)

The timing and type of brain injury patterns based on imaging studies that are typical of hypoxic-ischemic injury in the term and late preterm newborn. This includes MRI demonstrating deep nuclear gray matter (basal ganglia or thalamus), watershed (borderzone) cortical and white matter injury, or both ("near-total" pattern of injury). (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Brain MRI'.)

No evidence of other proximal or distal factors that could be contributing to encephalopathy.

EPIDEMIOLOGY — The incidence of perinatal asphyxia depends on the definition used, the ability to accurately make the diagnosis, and the quality of obstetrical care [2]. In a Swiss study that recoded 622 clinically diagnosed cases of intrauterine or birth asphyxia based on ICD-10 codes (mean gestational age [GA] 37 5/7 weeks), the incidence of perinatal asphyxia (defined as fulfilling three of the following criteria: five-minute Apgar score ≤5, pH ≤7, base deficit ≥16 mmol/L, or lactate ≥12 mmol/L) ranged from 5 to 8 per 1000 live births over the study period of time from 2004 to 2014 [2]. The incidence of hypoxic-ischemic encephalopathy (HIE) was approximately 1 per 1000 live births.

The risk of perinatal asphyxia is higher in resource-limited countries and is one of the main causes of infant mortality and morbidity [3,4].

CLINICAL MANIFESTATIONS OF INITIAL PERINATAL ASPHYXIA INSULT — Data regarding the direct effects on perinatal asphyxia on major organ systems are limited and based on observations of infants with hypoxic-ischemic encephalopathy (HIE)prior to the routine use of therapeutic hypothermia. The initial physiologic response to perinatal asphyxia is redistribution of blood flow from the nonvital organs (eg, skin and splanchnic area) to the vital organs (brain, heart) [5]. In most infants with moderate to severe HIE, there is evidence of dysfunction in at least one other organ system. However, systemic effects of perinatal asphyxia may be present even in the absence of encephalopathy. Therefore, all major organ functions are evaluated after a well-documented perinatal event, including cases in which there is an absence of findings associated with encephalopathy. (See 'Initial steps' below.)

Brain — The brain is the major organ of concern following a perinatal hypoxic-ischemic event. The risk factors; pathophysiology, including mechanisms of neuronal injury; clinical presentation; evaluation; and management (therapeutic hypothermia) of HIE are discussed in detail separately. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Respiratory findings — Although severe respiratory insufficiency is frequently seen in infants with severe perinatal asphyxia, it is commonly the result of an underlying or concomitant disorder such as sepsis, pneumonia, or meconium aspiration syndrome (MAS) [6]. However, perinatal asphyxia is associated with persistent pulmonary hypertension of the newborn (PPHN), which occurs when pulmonary vascular resistance (PVR) remains elevated after birth, resulting in right-to-left (R to L) shunting of blood through the fetal circulatory pathways that leads to hypoxia (figure 1) [5,7,8].

Following perinatal asphyxia, apnea or hypoventilation may occur due to HIE and seizures. In severe cases, death may occur with terminal apnea if the infant is not successfully resuscitated.

A chest radiograph, pulse oximetry, and capillary blood gases are generally sufficient to assess the pulmonary status of the infant with perinatal asphyxia and to determine underlying etiologies for respiratory distress (eg, pneumonia, MAS, pulmonary congestion, and PPHN). However, echocardiography may be helpful in making the diagnosis of PPHN. (See "Neonatal pneumonia", section on 'Clinical presentation' and "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis", section on 'Pulmonary disease' and "Persistent pulmonary hypertension of the newborn", section on 'Chest radiograph' and "Overview of neonatal respiratory distress and disorders of transition", section on 'Diagnostic approach' and "Persistent pulmonary hypertension of the newborn", section on 'Diagnosis'.)

Infants with respiratory failure require intubation and mechanical ventilation during the first hours of life. Infants who are treated with hypothermia also are typically intubated and mechanically ventilated. (See 'Respiratory support' below and "Overview of mechanical ventilation in neonates".)

Cardiovascular manifestations — After a significant hypoxic-ischemic insult, reduced cardiac output and hypotension are commonly observed due to impaired myocardial contractility secondary to myocardial ischemia [9,10]. In an observational study of 144 term infants born between 1985 and 1995, approximately two-thirds of infants (62 percent) had cardiovascular compromise (defined as hypotension requiring an inotropic agent for blood pressure management for 24 hours or electrocardiographic [ECG] evidence of myocardial ischemia) [5].

The ischemic effects on the cardiovascular system are detected by blood pressure measurement (hypotension) and assessment of myocardial function:

Functional cardiac echocardiography is useful in demonstrating ventricular dysfunction due to myocardial ischemia [11]. Echocardiography can also identify infants with PPHN, which is associated with perinatal asphyxia, and can also assess volume status to guide volume therapy to restore blood pressure and avoid fluid overload. (See "Persistent pulmonary hypertension of the newborn".)

ECG changes demonstrating myocardial ischemia may include ST depression and T-wave inversion. (See "ECG tutorial: Myocardial ischemia and infarction" and "Persistent pulmonary hypertension of the newborn", section on 'Diagnosis'.)

Cardiac markers are used to assess myocardial damage, but they are not specific to injury caused by perinatal asphyxia.

Cardiac troponins as a marker of myocardial injury appear in the blood two to four hours after perinatal asphyxia [12]. They remain detectable for up to 21 days [13]. The association between elevated troponins and long-lasting cardiac depression is uncertain.

Creatine kinase-MB (CK-MB) levels are elevated in newborns after perinatal asphyxia, but this elevation is not specific for only cardiac injury due to perinatal asphyxia [14].

Serum B-type natriuretic peptide (BNP) is used as a biomarker in the diagnosis and management of pulmonary hypertension (PH), and changes in BNP levels have been used to monitor treatment of PPHN.

Renal manifestations — Oliguria as a manifestation of kidney dysfunction is common after perinatal asphyxia [5]. It is due to either reduced cardiac output or acute kidney injury secondary to tubular necrosis. Impaired kidney function is detected by an elevation in serum creatinine (SCr).

In the previously mentioned observational study of 144 term infants with HIE, 70 percent had evidence of kidney impairment (defined as urine output <1 mL/kg per hour [oliguria] for 24 hours and an SCr level > 1.13 mg/dL [100 micromol/L] or oliguria for >36 hours or SCr 1.41 mg/dL [125 micromol/L] or any SCr level that increased postnatally) [5]. (See "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis".)

Serial measurements of SCr and electrolytes and ongoing accurate monitoring of urine output are required to assess and follow the effect of asphyxia on renal function.

Depending on the degree of kidney impairment further management, including adjusting fluid and electrolyte management and drug dosing for medications that are renally excreted and in very severe cases kidney replacement therapy, may be warranted. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Management' and 'Drug monitoring and dosing' below.)

Hepatic findings — Elevation of liver enzymes defined as serum alanine transaminase level >100 units/L is common in infants with perinatal asphyxia [5,15]. Decreased liver function may contribute to hyperbilirubinemia, hypoalbuminemia, reduced production of coagulation factors, and affect pharmacokinetics of drugs that rely on hepatic metabolism or biliary excretion. Long-term effects of neonatal liver hypoxia-ischemia are unknown. (See 'Drug monitoring and dosing' below.)

Gastrointestinal tract effects — A reduced tolerance of enteral feedings in infants with perinatal asphyxia is common due to the redistribution of blood flow away from the splanchnic circulation to vital organs such as the brain. Therefore, either no or only minimal enteral feeding is provided to infants with perinatal asphyxia, particularly during therapeutic hypothermia [16]. (See 'Nutrition' below.)

In addition, perinatal asphyxia carries an increased risk of necrotizing enterocolitis in the term and near-term infants [17,18]. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis", section on 'Term infants'.)

Hematologic manifestations

Impaired coagulation and thrombocytopenia — Impaired coagulation and thrombocytopenia are common after a severe asphyxial event due to several factors:

Disseminated intravascular coagulation occurs after perinatal asphyxia resulting in ongoing consumption of clotting factors and platelets [19-22]. (See "Disseminated intravascular coagulation in infants and children", section on 'Other etiologies in neonates'.)

Bone marrow suppression contributing to thrombocytopenia.

Impaired hepatic production of clotting factors due to hepatic injury.

Perinatal asphyxia has also been reported to be associated with increases in bleeding time and endothelial dysfunction [23].

Acute blood loss — Severe antenatal or peripartum/intrapartum blood loss due to hemolysis, massive feto-maternal transfusion, or blood loss during placental abruption may be the cause of perinatal asphyxia. Severe anemia at birth needs immediate treatment. (See "Red blood cell transfusions in the newborn", section on 'Acute blood loss'.)

Glucose metabolism — In neonates with perinatal asphyxia, there is an initial stress-induced hyperglycemia that is followed by a sharp drop in blood glucose levels due to increased glucose consumption. Hypoglycemia is also more common in infants with severe liver damage due to inadequate glycolysis. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Increased glucose utilization'.)

INITIAL STEPS

Clinical stabilization — at delivery — At birth, an initial assessment is made for cardiorespiratory stability. The management in the delivery room for infants who fail to meet criteria for routine care (absence of good tone, crying or breathing without difficulty) and who require further resuscitative measures is discussed separately. (See "Neonatal resuscitation in the delivery room", section on 'Infants requiring delivery room resuscitation'.)

Evaluation

Goal — The goal of a concurrent initial evaluation during stabilization is to determine the presence and extent of end-organ damage, identify a possible etiology or concomitant condition that require specific therapy, the need for therapeutic hypothermia, and to obtain a baseline to compare changes in organ function over time. The general assessment is based on physical findings, laboratory testing, imaging, and monitoring of brain function (which is discussed separately). (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Evaluation'.)

General assessment — General assessment consists of an evaluation of the neonate's respiratory status (evidence of respiratory distress [labored breathing/tachypnea] and need for respiratory support), cardiac status (eg, hypotension or need for inotropic blood pressure support), neurologic status (hypotonia and the presence of seizures), and basic laboratory evaluation. Urinary output is also monitored.

Basic laboratory tests — Routine laboratory testing includes:

Blood gas analysis – Arterial or venous blood gases are obtained to assess gas exchange (oxygenation and ventilation) and acid-base disturbances. Indication for therapeutic hypothermia is based on a sample of umbilical cord blood or any blood obtained within the first hour after birth and after resuscitation with a pH of ≤7.0 or a base deficit of ≥16 mmol/L along with evidence of hypoxic-ischemic encephalopathy. (See 'Therapeutic hypothermia' below.)

Complete blood count (CBC) – CBC are obtained to identify patients with anemia, which may have contributed to asphyxia, thrombocytopenia (increased risk of bleeding), and/or elevated white count (suggestive of infection). It has been suggested that elevated nucleated red blood cell (NRBC) counts in cord blood is a marker of fetal hypoxia and perinatal brain injury [24-26]. (See 'Hematologic manifestations' above.)

Glucose – Infants with perinatal asphyxia are at-risk for abnormal glucose levels (hypoglycemia and hyperglycemia), which may require interventions to normalize blood glucose levels. (See 'Glucose metabolism' above and "Management and outcome of neonatal hypoglycemia" and 'Nutrition' below.)

Kidney function studies – Initial testing for kidney function includes serum creatinine (SCr), BUN, and electrolytes to identify infants with acute kidney injury (decrease in glomerular filtration rate), which may result in electrolyte abnormalities due to renal dysfunction and fluid overload. (See 'Renal manifestations' above and "Neonatal acute kidney injury: Evaluation, management, and prognosis".)

Liver function studies – Initial hepatic testing includes measuring total and conjugated bilirubin, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Perinatal asphyxia is associated with hepatic damage confirmed by an elevated ALT and AST, which may increase the risk of hyperbilirubinemia. (See 'Hepatic findings' above.)

Cardiac evaluation – Electrocardiography is performed to detect myocardial ischemia. (See "Suspected heart disease in infants and children: Criteria for referral", section on 'Electrocardiography' and "ECG tutorial: Myocardial ischemia and infarction".)

Infectious disease evaluation:

Blood and surface cultures are performed in all infants with perinatal asphyxia because serious infections (eg, sepsis) is a major complication [27].

C-reactive protein (CRP) is obtained, as an elevated level is a nonspecific marker for bacterial infection.

Although cerebral spinal fluid samples may yield important information including meningitis, infants are often too sick to undergo lumbar puncture.

Cranial ultrasound – Cranial ultrasound is performed to exclude subdural or intraventricular hemorrhage. Daily imaging with cranial ultrasound is performed after birth to detect ischemic lesions in particular to the deep grey matter, which may not be seen earlier than 24 hours after the insult [28,29].

Additional testing — Based on the clinical status of the infants and initial evaluation, additional testing may be performed:

Chest radiography – For infants with respiratory distress, chest radiography is performed to identify other concomitant conditions (eg, pneumonia, meconium aspiration syndrome, pulmonary congestion, or persistent pulmonary hypertension of the newborn). (See 'Respiratory findings' above.)

Abdominal ultrasound – For patients with severe anemia, abdominal ultrasound is performed to detect any evidence of hepatic injury or adrenal hemorrhage. In addition, for neonates with persistent thrombocytopenia, ultrasound evaluation of major vessels may be helpful in detecting an underlying thrombosis.

Cardiac evaluation – For infants with evidence of cardiac injury (hypotension, administration of inotropic drugs, or respiratory distress), functional cardiac echocardiography is performed, and cardiac troponins and serum B-type natriuretic peptide (BNP) are obtained. (See 'Cardiovascular manifestations' above.)

Coagulation studies - For infants with evidence of multiorgan dysfunction with liver involvement or with massive bleeding, coagulation tests including PT (prothrombin time) and aPTT (activated partial thromboplastin time) are obtained.

Inborn errors of metabolism – In infants with neonatal encephalopathy due to moderate perinatal asphyxia, or in infants without an obvious sentinel event, testing for inborn errors of metabolism include blood ammonia levels to identify an underlying urea cycle deficiencies and qualitative urine organic acid to identify elevated levels of sulfite seen in neonatal encephalopathy due to sulfite oxidase deficiency and molybdenum cofactor deficiency. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hyperammonemia' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Seizures' and "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies'.)

MANAGEMENT

Therapeutic hypothermia — Therapeutic hypothermia is the only proven neuroprotection intervention for hypoxic-ischemic encephalopathy (HIE) and perinatal asphyxia in term and late preterm infants (ie, gestational age [GA] ≥35 weeks in our center, although some centers use a cutoff of ≥34 weeks) [30]. It is initiated for infants with pH of ≤7 or a base deficit of ≥16 mmol/L, moderate to severe encephalopathy, and need for ongoing resuscitative efforts. Care for these infants should be in centers with expertise in managing neonatal therapeutic hypothermia. If hypothermia is not available at the birth center, it is imperative that infants who meet the criteria for hypothermia are transferred immediately, as hypothermia needs to be initiated within the first six hours after delivery. The indications, support, and implementation of therapeutic hypothermia are discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia'.)

Because cooling needs to be started within the first six hours after delivery to be neuroprotective, it has clinical effects on all the other major organ systems affected by perinatal asphyxia (eg, kidney, heart, gastrointestinal tract including the liver, and lungs). Reducing the body temperature to the therapeutic hypothermic range of 33 to 34°C from the optimal temperature of 37°C alters all organ function. Thus, it is imperative for the clinical team to understand the impact of cooling on the function of the major organ systems that have already undergone injury from perinatal asphyxia [23,31]:

Brain – Cooling reduces the rate of brain metabolism, which has been shown to be neuroprotective and is discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Effectiveness'.)

Respiratory effects – Partial pressure of carbon dioxide (pCO2) decreases by 3 to 4 percent for every 1°C drop in temperature below 37°C. This is due to reduced CO2 production as metabolism declines and increasing of CO2 in blood as body temperature is lowered [32]. In blood gas samples, there is a concomitant increase in pH with the lower pCO2. It remains uncertain what the optimal target ranges should be for pCO2 and pH during therapeutic hypothermia. In our center, pCO2 levels are set for 50 mmHg (6.7 kPa) to avoid hypocapnia.

Blood gas analysis is performed at 37°C. The actual pCO2 at 33.5°C is obtained by multiplying the pCO2 value measured at 37°C by a correction factor of 0.8. As an example, a blood gas measurement of pCO2 at 37°C of 50 mmHg represents an in-vivo value of 40 mmHg.

A single center study reported lower pulse oximetry during hypothermia compared with normal body temperatures [33]. These results suggested that therapeutic hypothermia shifts the oxygen-hemoglobin dissociation curve to the left, resulting in lower partial pressure of oxygen (PaO2), which could lead to underestimation of hypoxemia. Further studies are needed to confirm these findings.

Cardiovascular effects – Cardiac output falls due to a reduction in heart rate (sinus bradycardia) and stroke volume. However, there appears to be no significant change in the risk of hypotension due to the initial perinatal asphyxia. This is most likely due to peripheral vasoconstriction that occurs with cooling. A systematic review suggested that therapeutic hypothermia provides a cardioprotective effect [34].

Metabolism and glucose metabolism – The metabolic rate declines linearly with decreasing temperature. As the metabolic rate declines, glucose utilization, insulin release, and insulin sensitivity may decrease. This can result in an increase in glucose levels. In a prospective cohort of term infants with neonatal encephalopathy in which 44 of 45 neonates received therapeutic hypothermia, 16 episodes of hypoglycemia and 18 episodes of hyperglycemia were detected by continuous interstitial glucose monitoring [35]. In this observational study, after adjusting for hypoxia–ischemia severity, hyperglycemia was associated with worse global brain function (monitored by amplitude-integrated electroencephalography) and seizures. However, because of the observational nature of the study, no causal relationship between episodes of hyperglycemia and abnormal brain function could be established, as it is possible that hyperglycemia is a marker for multi-organ injury, including the brain.

Coagulopathy and thrombocytopenia – Limited data suggest that there is no additional effect of hypothermia on the increased risk of coagulopathy induced by perinatal asphyxia, but cooling is associated with an increased risk of thrombocytopenia [30]. However, coagulopathy requiring intervention remains a common occurrence during therapeutic hypothermia so that ongoing monitoring of clotting factors (eg, plasma fibrinogen) and liver function is needed.

Hepatic and renal function – Based on animal data, therapeutic hypothermia does not appear to increase the risk of hepatic and renal injury [36]. Limited clinical data have suggested that cooling may improve hepatic and renal outcome, but these results need to be confirmed with additional trials and follow-up of larger number of patients [10,34]. Hypothermia decreases hepatic metabolism and thereby function, which impacts drug dosing for medications that are dependent on hepatic metabolism and excretion. (See 'Drug monitoring and dosing' below.)

Intestinal function – Hypothermia does not appear to increase the risk of necrotizing enterocolitis and may provide potential benefit for preventing additional ischemic intestinal injury. However, the mandatory administration of morphine for sedation/analgesia during therapeutic hypothermia may further reduce intestinal motility. As a result, full enteric feeding is avoided during therapeutic hypothermia, but "minimal enteral feeding" is provided. (See 'Nutrition' below.)

Monitoring

Clinical monitoring — In experienced neonatal intensive care units (NICUs) equipped to care for infants with perinatal asphyxia, including therapeutic hypothermia, routine monitoring at the bedside consists of (amplitude-integrated, continuous) electroencephalography (EEG or aEEG) and ongoing measurements of heart rate, blood pressure, respiratory rate, and oxygen saturation using pulse oximetry. In dedicated level III NICUs, near-infrared spectroscopy is also used to assess cerebral oxygenation.

Laboratory and imaging ongoing assessment include the following:

Blood gas analysis, glucose, and CBCs are obtained several times during the first three days after resuscitation and daily until therapeutic hypothermia is discontinued. For infants who do not qualify for therapeutic hypothermia, most abnormalities will have normalized by the third day. However, we continue to monitor these laboratory studies until values have returned to normal ranges, especially in infants who receive parenteral nutrition and/or have multiorgan failure.

Daily testing includes SCr, total and conjugated bilirubin, liver enzyme studies (ALT and AST), and CRP. In addition, coagulation testing is monitored for infants who have multiorgan failure with liver involvement and massive bleeding.

Daily cranial ultrasound is performed to assess the presence of hemorrhage or hypoxic-ischemia alterations.

Drug monitoring and dosing — Levels of many drugs will be elevated by perinatal asphyxia because the pharmacokinetics for these drugs are altered due to reduced renal excretion and hepatic metabolism/excretion [37]. This effect may be aggravated or enhanced by therapeutic hypothermia. Drug levels testing may be needed when drugs with potentially harmful side effects such as aminoglycosides or anticonvulsants are administered because their metabolism is affected by the changes in renal and hepatic function [38-41]. Decisions on initial dosing are made based on the available pharmacokinetics of a specific drug during hypothermic therapy. The most commonly used medications include antibiotics, morphine, and anticonvulsants (table 2).

Supportive care based on organ system — Supportive care measures are provided for all infants with perinatal asphyxia both before, during, and after therapeutic hypothermia, and for those infants in whom cooling is not performed.

Respiratory support — Respiratory support is needed for most infants with perinatal asphyxia and for all infants treated with therapeutic hypothermia [7]. The goal of supportive care is to maintain adequate oxygenation and ventilation, especially during sedation needed for hypothermia, and avoid episodes of hyperoxia, hypoxia, hypercapnia, and hypocapnia. In our center, temperature-corrected target ranges of arterial partial pressure of oxygen (pO2) are 60 to 80 mmHg (8 to 10.7 kPa) and for partial pressure of carbon dioxide (pCO2) 35 to 45 mmHg (4.7 to 6 kPa).

Most infants receiving therapeutic hypothermia will need intubation and mechanical ventilation for optimal respiratory support [7] as the mandatory need for sedation (eg, with morphine) during cooling impairs the respiratory drive of the neonate. However, some patients may only require nasal continuous positive airway pressure (nCPAP).

As previously discussed, blood gas values need to be interpreted differently during therapeutic hypothermia as the pCO2 decreases by 3 to 4 percent for every 1°C drop in temperature [7,32]. Although it remains uncertain what the optimal values for pCO2 and pH are during therapeutic hypothermia, we target pCO2 levels of 50 mmHg (6.7 kPa) to avoid hypocapnia. Generally, a correction factor of 0.8 is used to calculate the in vivo pCO2 at 33.5°C, as the test is performed at 37°C. (See 'Therapeutic hypothermia' above.)

Persistent pulmonary hypertension of the newborn (PPHN) is a known complication associated with perinatal asphyxia. In these patients, administration of inhaled nitric oxide (iNO) may be needed, which can also be administered during therapeutic hypothermia.

Cardiovascular support — For infants with evidence of myocardial failure, inotropic agents may be used to support cardiac function. Sympathomimetic stimulation by catecholamine agents such as dobutamine and dopamine improves myocardial contractility and may have an additional beneficial effect on peripheral vascular beds.

Dopamine is the most commonly used agent, including in our center. Dobutamine is an excellent alternative. In some cases, milrinone, a selective phosphodiesterase type III inhibitor, may be useful as it increases contractility and reduces afterload without a significant increase in myocardial oxygen consumption. However, hypotension may be a side effect of milrinone, and additional vasoconstrictive agents may be needed. (See "Heart failure in children: Management", section on 'Inotropes'.)

For infants with severe hypotension not responding to high doses of inotropes, hydrocortisone (1.25 mg/kg per dose, 4 doses per 24 hours) is typically used, especially if there is evidence or concern for adrenal insufficiency [42]. A clinical trial in 35 infants has reported low-dose hydrocortisone (0.5 mg/kg per dose given every six hours) was more effective than placebo in raising blood pressure and decreasing inotrope dosing, suggesting that lower doses of hydrocortisone might also be effective in increasing blood pressure [43]. Nevertheless, we continue to use the standard higher dose until there is confirmation that the lower dose of hydrocortisone is equally as effective.

Fluid and electrolyte management — Infants with perinatal asphyxia are at-risk for fluid and electrolyte abnormalities due to acute kidney injury and the syndrome of inappropriate antidiuretic hormone (SIADH), which is frequently associated with brain injury [44]. Adjustments of fluid and electrolyte management are made in response to the changes in the clinical status of the patient with ongoing monitoring of fluid balance, including monitoring net fluid intake, weight, and respiratory status and frequent assessment of blood electrolytes. Electrolyte levels should be maintained in the normal range during cooling by adjusting fluid therapy. (See "Fluid and electrolyte therapy in newborns".)

In the first day of life, infants generally are maintained on intravenous fluids of 10 percent dextrose without additional sodium and potassium at a rate of 30 to 60 cc/kg per day. This degree of fluid restriction is to avoid the risk of water retention associated with SIADH, which commonly occurs in neonatal perinatal asphyxia. Infants with severe kidney failure also are prone to develop fluid overload and may require fluid restriction.

If there is evidence of fluid overload resulting in a decline/compromise in pulmonary function, we administer a trial dose of loop diuretic (eg, furosemide 1 mg/kg per dose) to correct hypervolemia [31]. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Fluid management'.)

Nutrition — Nutritional management is highly variable as there is little evidence to guide optimal nutritional support during hypothermia [45]. In our center, full enteral feeding is withheld during the period of therapeutic hypothermia, and "minimal enteral feeding" is only provided due to concern of reduced intestinal function and metabolism. Total parenteral nutrition (TPN) is used to provide adequate nutrition. The amount and composition of intravenous fluids may need to be adjusted based on changes in the monitored levels of electrolytes, triglycerides, and glucose. Clearance of intravenous lipids from TPN may be reduced due to hepatic impairment. In contrast, other centers provide enteral feeds. Research efforts are underway to help inform practice regarding the optimal nutritional approach. (See 'Gastrointestinal tract effects' above and 'Therapeutic hypothermia' above and "Parenteral nutrition in infants and children".)

As noted above, perinatal asphyxia is associated with hypoglycemia, whereas hypothermia tends to result in higher glucose levels. Variable glucose levels, particularly hyperglycemia, may negatively impact on neurologic function. As a result, glucose levels are monitored several times daily and glucose infusion rates are adjusted to maintain glucose levels between 72 to 145 mg/dL (4 to 8 mmol/L). (See 'Glucose metabolism' above.)

Hemostatic management

Coagulation deficiency – For infants with significant coagulation disorders (eg, severely prolonged aPTT and PT times) or overt bleeding, we provide fresh frozen plasma to replace clotting factors that may be either be consumed (disseminated intravascular coagulation) or be low due to impaired hepatic function. (See "Disseminated intravascular coagulation in infants and children", section on 'Replacement therapy'.)

Thrombocytopenia – In our center, platelets are transfused when the platelet count falls below 50,000/microL. However, new evidence suggest that a lower threshold of 20,000/microL may be used. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)

Acute blood loss – Neonates with significant acute blood loss require immediate fluid resuscitation, but may not require a red blood cell (RBC) transfusion. Indications after volume resuscitation include >20 percent blood loss, 10 to 20 percent blood loss with evidence of inadequate oxygen delivery (eg, persistent acidosis), and/or ongoing hemorrhage. (See "Red blood cell transfusions in the newborn", section on 'Acute blood loss'.)

Neurologic management — The management of neurologic complications (eg, seizure control) are discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia' and "Treatment of neonatal seizures", section on 'Antiseizure medication therapy'.)

Additional supportive measures

Hyperbilirubinemia – The risk of hyperbilirubinemia and bilirubin-induced neurologic dysfunction is increased in infants with perinatal asphyxia because of the impact on hepatic function with reduced ability to conjugate bilirubin for biliary excretion and compromise of the protective blood-brain barrier (calculator 1).

Infectious disease management – Because patients are at-risk for serious infection [46], we administer empirical antibiotics until culture results are known. Antibiotic dosing should be adjusted to account for changes due to hepatic and renal function due to the initial asphyxial insult and if applicable, therapeutic hypothermia [38,47,48]. (See "Management and outcome of sepsis in term and late preterm infants", section on 'Initial empiric therapy'.)

Renal management – No interventions are proven effective in restoring or preserving kidney function. Small trials have reported that the administration of theophylline reduced or prevented acute kidney injury, but further studies are needed to test the safety and efficacy of this intervention especially during therapeutic hypothermia as renal clearance is significantly reduced [49]. In rare cases with major kidney function impairment, kidney replacement therapy may be needed [50]. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Theophylline and perinatal asphyxia' and "Pediatric acute kidney injury (AKI): Indications, timing, and choice of modality for kidney replacement therapy (KRT)".)

OUTCOME — The outcome of perinatal asphyxia is primarily based on the likelihood and extent of brain damage. Mortality and long-term development outcome for infants with perinatal asphyxia have improved with the advent of therapeutic hypothermia. It remains uncertain whether therapeutic hypothermia has similar benefit for other organ systems (eg, heart, kidney, and liver). (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Prognosis'.)

SUMMARY AND RECOMMENDATIONS

Introduction and terminology – Perinatal asphyxia is caused by a lack of oxygen to organ systems due to a hypoxic or ischemic insult that occurs within close temporal proximity to labor (peripartum) and delivery (intrapartum). In the neonate, the lack of oxygen leads to multi-organ failure. The brain is the major organ of concern (hypoxic-ischemic encephalopathy [HIE]). (See 'Terminology' above.)

Definition – The American College of Obstetricians and Gynecologists published a summary of specified neonatal signs and contributing factors used to establish the presence of an acute perinatal hypoxic-ischemic event (table 1). (See 'Definition of perinatal hypoxic-ischemic event' above.)

Epidemiology – The incidence of perinatal asphyxia varies and is dependent on the quality of obstetrical care and the ability to make an accurate diagnosis. The risk of perinatal asphyxia is higher in resource-limited countries and is one of the main causes of infant mortality and morbidity. (See 'Epidemiology' above.)

Clinical manifestations – In most infants with moderate to severe HIE, there will be evidence of dysfunction in at least one other organ system. However, systemic effects of perinatal asphyxia may be present even in the absence of encephalopathy. The major organ systems affected include:

Respiratory – Although severe respiratory insufficiency is frequently seen in infants with severe perinatal asphyxia, it is most commonly the result of an underlying or concomitant disorder (eg, sepsis, pneumonia, meconium aspiration syndrome, persistent pulmonary hypertension of the newborn [PPHN]). (See 'Respiratory findings' above.)

Heart – Myocardial ischemia results in impaired myocardial contractility leading to reduced cardiac output and hypotension.

-Echocardiography is used to detect ventricular dysfunction, identify patients with PPHN, and assess volume status.

-Electrocardiographic changes may include ST depression and T-wave inversion as evidence of myocardial ischemia. (See 'Cardiovascular manifestations' above.)

Kidney – Renal findings include oliguria (due to reduced cardiac output or acute tubular necrosis) and elevation in serum creatinine. (See 'Renal manifestations' above.)

Liver – Hepatic injury is manifested by increase in serum alanine transaminase level (ALT) and aspartate aminotransferase (AST), and risk of hyperbilirubinemia, hypoalbuminemia, and reduced production of coagulation factors. (See 'Hepatic findings' above.)

Hematologic – Hematologic manifestations include impaired coagulation and thrombocytopenia. Acute blood loss may be a contributor of perinatal asphyxia. (See 'Hematologic manifestations' above.)

Clinical stabilization and evaluation – Initial management of an infant following a perinatal asphyxia event includes cardiorespiratory stabilization in the delivery room and evaluation of the extent of end-organ involvement and whether therapeutic hypothermia should be initiated. Assessment is based on clinical parameters (cardiorespiratory status [need for ongoing intervention] and neurologic status [evidence of HIE (eg, seizures)]) and laboratory testing (eg, severe metabolic acidosis). (See 'Clinical stabilization' above and 'Evaluation' above.)

Therapeutic hypothermia – Therapeutic hypothermia is the only proven neuroprotection intervention for HIE in term and late preterm infants. Hypothermia reduces brain metabolism, which is neuroprotective, decreases in cardiac output due to fall in both heart rate and stroke volume, increases the partial pressure of carbon dioxide (pCO2), decreases glucose utilization, and decreases hepatic metabolism, which impacts on drug half-life and dosing. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia' and 'Therapeutic hypothermia' above.)

Therapeutic hypothermia is initiated for infants with a gestational age (GA) of ≥35 weeks, a pH of ≤7.0, or a base deficit of ≥16 mmol/L, moderate to severe encephalopathy, and need for ongoing resuscitative efforts. Care for these infants should be in centers with expertise in neonatal therapeutic hypothermia. If hypothermia is not available at the birth center, it is imperative that infants who meet the criteria for hypothermia are transferred immediately, as hypothermia needs to be initiated within the first six hours after delivery in order for it to be neuroprotective. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Therapeutic hypothermia' and 'Therapeutic hypothermia' above.)

Supportive care measures are provided for all infants with perinatal asphyxia both before, during, and after therapeutic hypothermia, and for those infants in whom cooling is not performed. This includes:

Respiratory – Maintenance of adequate ventilation (avoidance of hypoxemia or hyperoxia, hypercapnia, and hypocapnia). In our center, temperature-corrected target ranges of arterial partial pressure of oxygen (pO2) are 60 to 80 mmHg (8 to 10.7 kPa) and for pCO2 35 to 45 mmHg (4.7 to 6 kPa). Most infants receiving therapeutic hypothermia will need intubation and mechanical ventilation for optimal respiratory support because of the need for sedation during cooling impairs the respiratory drive of the neonate. (See 'Respiratory support' above.)

Cardiovascular – Maintenance of cardiovascular stability including the use of inotropic agents and, in refractory cases, hydrocortisone. (See 'Cardiovascular support' above.)

Fluid and electrolyte – Avoidance of fluid overload by restricting fluid intake especially in patients with syndrome of inappropriate antidiuretic hormone (SIADH) or severe renal impairment. Adjustments of fluid and electrolyte management are made in response to the changes in the clinical status of the patient with ongoing monitoring of fluid balance, including monitoring net fluid intake, weight, and respiratory status and frequent assessment of blood electrolytes. (See 'Fluid and electrolyte management' above.)

Nutrition – During the period of therapeutic hypothermia, enteral feedings are withheld (due to reduced intestinal function and metabolism) and total parenteral nutrition (TPN) is used to provide adequate nutrition. (See 'Nutrition' above.)

Glucose levels are monitored, and glucose infusion rates are adjusted to maintain glucose levels between 72 to 145 mg/dL (4 to 8 mmol/L). (See 'Nutrition' above.)

Antibiotics – Empirical antibiotics are administered until culture results are known. (See 'Additional supportive measures' above.)

Drug dosing – For infants with reduced renal excretion or decreased liver metabolism, drug dosing is altered as needed. (See 'Drug monitoring and dosing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ann R Stark, MD, who contributed to an earlier version of this topic review.

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