Neonatal hypoxic-ischemic encephalopathy due to birth asphyxia: clinical guidelines

List of Abbreviations

BE – base excess / base deficit

P CO2 – partial pressure of carbon dioxide

P O2 – partial pressure of oxygen

pH – hydrogen ion exponent

S100 – neurospecific protein

SpO 2 – blood oxygen hemoglobin saturation

BP – blood pressure

ATC – Anatomical Therapeutic Chemical classification

aEEG - amplitude-integrated electroencephalography

GA – gestational age

HIE – hypoxic-ischemic encephalopathy

IMV – invasive mechanical ventilation

ABDS – acid-base balance status

CT – computed tomography of the brain

ICD – International Statistical Classification of Diseases

MO – medical organization

MRI – magnetic resonance imaging of the brain

NI – neutrophil index

NSG – neurosonography

ICU – intensive care unit

ICU – intensive care unit

RDS – respiratory distress syndrome

RCTs – Randomized Controlled Trials

CRP – C-reactive protein

TTN – transient tachypnea of the newborn

US – ultrasound examination

CNS – central nervous system

RR – respiratory rate

HR – heart rate

ECG – electrocardiography (recording of electrocardiogram)

EchoCG – echocardiography

Terms and Definitions

Birth asphyxia is a syndrome characterized by the lack of effective gas exchange in the lungs immediately after birth, the inability to breathe spontaneously in the presence of a heartbeat and (or) other signs of live birth (spontaneous muscle movement, umbilical cord pulsation).

Severe birth asphyxia is a condition characterized by a low Apgar score and a complex of clinical and laboratory signs of impaired infant status.

Hypoxic-ischemic encephalopathy (HIE) is a brain injury that develops in the first hours of life and is characterized by a complex of neurological disorders of varying severity resulting from birth asphyxia.

Cerebral ischemia (brain ischemia) is a condition that arises from a wide range of causes leading to brain ischemia, such as sepsis, shock, HIE, respiratory distress syndrome, etc.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Birth asphyxia is a syndrome characterized by the lack of effective gas exchange in the lungs immediately after birth, the inability to breathe spontaneously in the presence of a heartbeat and (or) other signs of live birth (spontaneous muscle movement, umbilical cord pulsation).

Severe birth asphyxia is a condition characterized by a low Apgar score and a complex of clinical and laboratory signs of impaired infant status [1,2].

Hypoxic-ischemic encephalopathy (HIE) is a brain injury that develops in the first hours of life and is characterized by a complex of neurological disorders of varying severity resulting from birth asphyxia [1,3].

Cerebral ischemia (CI) (brain ischemia) is a condition that arises from a wide range of causes leading to brain ischemia, such as sepsis, shock, HIE, respiratory distress syndrome, etc.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Hypoxic-ischemic encephalopathy (HIE) develops in the first hours of life and is characterized by a complex of neurological disorders of varying severity resulting from birth asphyxia [1].

A low Apgar score (Appendix G1) alone may be a consequence of fetal drug depression or other factors leading to respiratory depression and is not always an independent criterion determining the presence of hypoxic central nervous system (CNS) injury in a newborn.

Risk factors for neonatal asphyxia [1]:

• ­ premature birth;

• ­ maternal diabetes mellitus;

• ­ maternal obesity;

• ­ preeclampsia; eclampsia;

• ­ chronic hypertension (maternal hypertension);

• ­ maternal rhesus immunization;

• ­ ultrasound signs of fetal anemia or hydrops;

• ­ stillbirth or previous children born in a state of severe asphyxia;

• ­ clinical signs of maternal infectious disease immediately before or during labor (chorioamnionitis, elevated temperature before or directly during labor);

• ­ suspected congenital fetal infection;

• ­ bleeding in the second or third trimesters of pregnancy;

• ­ polyhydramnios;

• ­ oligohydramnios;

• ­ multiple pregnancy;

• ­ discrepancy between estimated fetal weight and gestational age;

• ­ maternal drug or alcohol addiction;

• ­ maternal use of medications capable of depressing newborn respiration and cardiac activity;

• ­ presence of fetal malformations detected during antenatal diagnostics;

• ­ abnormal fetal cardiotocography or ultrasound Doppler of uteroplacental blood flow before or during labor;

• ­ suppression of fetal motor activity before labor;

• ­ lack of prenatal care data;

• ­ prolonged rupture of membranes (more than 18 hours).

Intrapartum risk factors:

­ premature birth (gestational age less than 37 weeks);

• ­ post-term birth (gestational age more than 42 weeks);

• ­ acute fetal hypoxia during labor;

• ­ uterine rupture;

• ­ amniotic fluid embolism;

• ­ maternal collapse/shock (of any etiology) during delivery;

• ­ placental abruption;

• ­ placenta previa;

• ­ placenta accreta;

• ­ umbilical cord prolapse;

• ­ abnormal fetal presentation;

• ­ use of general anesthesia during delivery;

• ­ labor abnormalities;

• ­ presence of meconium in amniotic fluid;

• ­ fetal heart rate abnormalities;

• ­ shoulder dystocia;

• ­ instrumental delivery (obstetric forceps, vacuum extraction).

Four main causes of neonatal asphyxia are distinguished:

1. Impairment of maternal blood oxygenation (anemia, shock, cardiovascular and (or) respiratory failure).

2. Inadequate hemoperfusion of the maternal placenta (maternal arterial hypotension or hypertension, impaired uterine contractility).

3. Impairment of placental gas exchange (infarctions, calcifications, edema and inflammatory changes of the placenta, premature placental abruption and placenta previa).

4. Impairment of umbilical cord blood flow (true knots of the cord, its compression, tight nuchal cord or around other parts of the child's body, umbilical cord prolapse).

The pathogenesis of HIE includes phases of primary and secondary neuronal injury. Primary injury develops at the moment of asphyxia exposure and is characterized by irreversible brain cell death, the volume of which depends on the depth and duration of hypoxia. Secondary injury is activated in the reoxygenation-reperfusion phase 2–12 hours after the primary injury. Secondary injury is triggered by the activation of a number of pathogenetic mechanisms: glutamate and calcium stress, free radical damage, aseptic inflammatory process, and apoptosis activation, leading to an increased volume of neuronal injury and a worsened prognosis for life and health [4,5].

[1] Resuscitation and stabilization of newborns in the delivery room. Methodological Letter No. 15-4/I/2-2570 dated 04.03.2020.

1.3 Epidemiology of the Disease or Condition

According to global statistics, the incidence of severe HIE in the newborn population ranges from 0.37 to 3 per 1,000 live births [6,7]. The incidence of intrauterine hypoxia and birth asphyxia in newborns in the Russian Federation in 2020 was 13.3% [1], and globally it is 5–9 cases per 1,000 live births [8].

[1] Russian Ministry of Health data "Federal Statistical Observation" form No. 32, 2020

1.4 Features of Coding the Disease or Condition

P21.0 Severe birth asphyxia

P21.1 Mild and moderate birth asphyxia

P91.0 Cerebral ischemia

P91.6 Hypoxic-ischemic encephalopathy of newborn

1.5 Classification of the disease or condition

Acute asphyxia – neonatal asphyxia caused by intranatal factors.

Asphyxia developing against the background of chronic intrauterine hypoxia – neonatal asphyxia developing antenatally under conditions of prolonged placental insufficiency and/or intranatal hypoxia.

The severity of HIE is determined using the modified scale by Sarnat H., Sarnat M. (1976), modified by Stoll B., Kliegman R. (2004) [9,10]. (Appendix G2)

The severity of cerebral ischemia is determined in accordance with the "Classification of Perinatal Nervous System Disorders in Newborns" (severity of neurological disorders, as well as the nature and prevalence of structural and morphological changes in the brain tissue) [10,11]. (Appendix G3)

1.6 Clinical presentation of the disease or condition

The clinical presentation depends on the severity of asphyxia.

In moderate or mild birth asphyxia, the newborn's condition after birth is moderate or severe. In the first minutes of life, the infant is lethargic, motor activity and response to examination are reduced or absent. The cry, if present, is low-emotional. Neonatal reflexes are depressed, suppressed, or absent. Cardiac auscultation reveals a normal rhythm or tachycardia, heart sounds are enhanced or muffled. Breathing is arrhythmic or periodic, often involving accessory muscles, and scattered conductive rales may be present. Diffuse cyanosis is noted, though the skin rapidly pinks up as oxygenation is restored; however, acrocyanosis often persists. During the first two to three days of life, these newborns typically exhibit a transition from depression syndrome to hyperexcitability syndrome, manifested by fine-amplitude tremor of the extremities, hyperesthesia, regurgitation, sleep disturbance, spontaneous Moro reflex (phase I), reduction or suppression of support, stepping, and crawling reflexes, muscular hypotonia, and adynamia. However, changes in physiological neonatal reflexes and muscle tone are individual and may depend on other concurrent diseases and conditions.

In severe birth asphyxia, the newborn's condition at birth is severe or extremely severe. Response to examination is mostly absent or very sluggish. Neonatal reflexes are suppressed or sharply reduced. Muscle tone is absent or sharply reduced, and spontaneous movements are absent. Neurological status shows signs of coma or stupor (absence of response to examination and painful stimuli, adynamia, areflexia, atonia, pupillary response to light is sluggish or absent, local ocular signs may be present). The skin is cyanotic, pale with a "marbled" pattern (microcirculatory disturbance). Spontaneous breathing is arrhythmic, shallow, or absent. Auscultation reveals decreased breath sounds. Palpation of the abdomen reveals moderate hepatomegaly. Pronounced signs of peripheral (capillary refill time > 3 s) and central hemodynamic disturbances (arterial hypotension) may be noted. Signs of multiple organ dysfunction are present.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic Criteria

The diagnosis of "Severe birth asphyxia" can be established if the following clinical and laboratory signs are detected: intrauterine fetal compromise, Apgar score of 3 or less at 1 minute of life, pH < 7.0 or BE greater than –16 mmol/L in the first 60 minutes of life, multiple organ dysfunction, neurological disorders.

The diagnosis of "Moderate and mild birth asphyxia" can be established if the Apgar score is 4–6 at 1 minute of life.

Only a combination of both clinical and laboratory markers, including a low Apgar score, can indicate birth asphyxia, which in turn leads to HIE of varying severity [1,2,12,13].

The diagnosis of "Cerebral ischemia" is made after the early neonatal period following the clarification of the nature and severity of structural brain injury using neuroimaging methods.

2.1 Complaints and Anamnesis

2.2 Physical Examination

See Section 1.6 "Clinical Presentation"

• It is recommended to perform a physical examination of the newborn to detect HIE and determine further therapeutic tactics [15].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Physical examination of a newborn with HIE includes:

• response to examination (depression, excitation, stupor, coma);

• examination of the skin and visible mucous membranes assessing pallor, degree of hydration, presence of rashes, hemorrhagic manifestations, and microcirculatory disturbances;

• assessment of the central nervous system status (reflexes, muscle tone, tremor, seizures, pupillary response);

• auscultation and percussion of the lungs and heart, pulse examination;

• abdominal palpation;

• visual inspection of external genitalia;

• identification of visible malformations and dysmorphic stigmata.

Assessment of the central nervous system status is included in group "B" criteria for determining indications for therapeutic hypothermia.

• It is recommended that a newborn with HIE due to prior asphyxia undergo determination of daily and hourly urine output to identify urination disorders [16].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.3 Laboratory Diagnostics

• It is recommended that a newborn with severe or moderate/mild birth asphyxia undergo an assessment of acid-base balance (ABB), blood gases, and blood lactate levels in the first 60 minutes of life to evaluate gas exchange disorders, signs of tissue hypoxia, and metabolic disturbances in order to determine indications for therapeutic hypothermia [17–23].

LoE CGoE 3Level of Evidence C (Grade of Recommendation - 3).

Comments: The study of ABB, blood gases, and blood lactate levels is performed using umbilical cord, capillary, or venous blood and is included in group "A" criteria for determining indications for therapeutic hypothermia. The blood lactate test depends on the laboratory capabilities of the medical organization (MO).

• To determine the further management of concomitant therapy in a newborn infant with HIE due to perinatal asphyxia, it is recommended to perform a complete blood count (CBC) with differential white blood cell count [24–26].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: A newborn following asphyxia may exhibit changes in the complete blood count that require correction (anemia, thrombocytopenia).

• It is recommended to perform a coagulogram (screening hemostasis test) — measuring blood fibrinogen levels, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time (APTT), and international normalized ratio (INR) — for a newborn with HIE due to prior asphyxia to assess hemostatic disorders [27,28].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: The coagulogram panel and the range of analyzed parameters depend on the laboratory capabilities of the medical organization (MO). Hypothermia can adversely affect hemostasis; a 3.5°C drop in body temperature reduces coagulation by an average of 30%. Coagulogram monitoring is necessary in the presence of hemorrhagic syndrome.

• It is recommended that a newborn with HIE undergo serial assessment of acid-base balance (ABB) and blood gases for timely correction of homeostasis disorders and reduction of mortality [29].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: Target values for ABB parameters depend on the type of blood sample collected for testing (arterial, venous, or capillary).

• It is recommended that newborns with grade 2 and 3 HIE due to birth asphyxia undergo blood sodium, potassium, total calcium, glucose, and creatinine testing to reduce mortality and long-term neurological complications [30–33].

LoE CGoE 3Level of Evidence C (Grade of Recommendation - 3).

2.4 Instrumental Diagnostics

• It is recommended to perform 24-hour bedside monitoring of vital signs and parameters (heart rate, respiratory rate, peripheral blood pressure, pulse oximetry, body temperature [general thermometry and basal temperature measurement], and urine output determination) for a newborn with HIE due to birth asphyxia to monitor vital signs [34].

GGR BLEL 2 Grade of Recommendation B (Level of Evidence - 2).

Comments: During therapeutic hypothermia, it is necessary to place neonatal electrocardiographic electrodes to monitor cardiac arrhythmias.

• To exclude intracranial hemorrhage and internal organ damage, and to assess central hemodynamics in a newborn with HIE due to birth asphyxia, in order to determine further etiotropic and symptomatic therapy tactics, it is recommended to perform ultrasound examinations: neurosonography (NSG), echocardiography (Echo-CG), comprehensive ultrasound examination of the abdominal organs, kidneys, and adrenal glands [35,36].

LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2)

Comments: The performance of these imaging methods depends on the capabilities of the specific medical organization.

• If subdural hemorrhage is suspected in a newborn with HIE due to birth asphyxia, in order to rule out subdural hematomas, it is recommended to perform computed tomography or magnetic resonance imaging of the brain [37,38].

GGR CLEL 4 Grade of Recommendation C (Level of Evidence - 4)

Comments: The performance of these neuroimaging methods depends on the capabilities of the specific medical organization.

• For a newborn infant with HIE due to birth asphyxia, to assess the bioelectrical activity of the brain and detect seizures, it is recommended to perform amplitude-integrated electroencephalography (aEEG) no later than 6 hours after birth and during the rewarming period after general therapeutic hypothermia [39–42].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: aEEG is included in the criteria of group "C". The indication for aEEG is the presence of criteria from groups A and B.

Electroencephalography should be performed before starting anticonvulsant therapy, as anticonvulsant therapy affects the aEEG results. The recording is performed for 20-30 minutes, using at least 1 recording channel with a biparietal electrode placement, and a sweep speed of 6 cm/hour.

Registration of one of the pathological patterns listed below is a definitive predictor of the need for therapeutic hypothermia:

• normal amplitude pattern (upper border of the trend - maximum amplitude, > 10 µV, lower border of the trend - minimum amplitude, > 5 µV), combined with recurrent seizures (Appendix G4, Figure 2b; 2c);

• discontinuous pattern with a maximum amplitude of > 10 µV and a minimum amplitude of < 5 µV. Cyclic variability is absent (Appendix G4, Figure 1b);

• continuous low-voltage pattern with a maximum amplitude of < 10 µV and a minimum amplitude of < 5 µV. Cyclic variability is absent (Appendix G4, Figure 1c);

• status epilepticus (continuous seizure activity for 20 minutes or more) against the background of any of the listed patterns (Appendix G4, Figure 1d; 2b; 2c) [34,39,43].

aEEG evaluation must be performed upon admission of the child to a medical organization capable of performing this diagnostic method.

Assessment of the brain's electrical activity is carried out during therapeutic hypothermia, rewarming, and for 24 hours after the end of the procedure.

• For a newborn infant with HIE due to birth asphyxia in the presence of cardiac abnormalities: arrhythmia, pronounced bradycardia or tachycardia, in order to determine the nature of cardiac rhythm disorders, it is recommended to perform an electrocardiogram (ECG) [44–46].

GGR CLEL 4 Grade of Recommendation C (Level of Evidence - 4).

• To detect brain lesions in a newborn with HIE due to birth asphyxia after therapeutic hypothermia, it is recommended to perform neurosonography and magnetic resonance imaging of the brain [47–49].

GGR CLEL 4 Grade of Recommendation C (Level of Evidence - 4).

Comments: Neurosonography is performed dynamically on days 3, 7–10, and subsequently as clinically indicated. Brain magnetic resonance imaging (MRI) depends on the capabilities of the specific medical organization.

2.5 Other Procedures

• A newborn infant with HIE due to birth asphyxia is recommended an initial inpatient consultation (examination) by a neurologist for the diagnosis of neurological disorders [50].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The main focus of treatment for grade 2 and 3 HIE due to birth asphyxia is neuroprotective therapy.

3.1 Conservative Treatment

3.1.1 Neuroprotective therapy

One of the promising techniques that can reduce the adverse effects of CNS injury is therapeutic hypothermia, which is recognized as the most effective and safe neuroprotective method in infants who have suffered severe birth asphyxia. Numerous experimental studies have shown that hypothermia helps reduce the body's metabolic demands, decrease secondary cellular energy depletion, block glutamate release, inhibit free radical synthesis, and suppress inflammation and apoptosis [4,42,51–57].

General selection criteria for therapeutic hypothermia in newborns who required resuscitation in the delivery room:

• gestational age of 36 weeks or more;

• birth weight greater than 1800 grams [35,58–63].

The decision to perform hypothermia in newborns with a GA of 35⁰–35⁶ weeks, in case of indications, is made solely by a medical board (consilium).

Further selection criteria are divided into three groups: A, B, and C. The newborn must be evaluated sequentially against these groups. If a criterion from a group is met, proceed to evaluate the criteria from the next group. The presence of at least one criterion in each of the three groups is an indication for therapeutic hypothermia [35,58–64].

Group "A" criteria:

- Apgar score ≤ 5 at 10 minutes, or

- continued need for mechanical ventilation at 10 minutes of life, or

- the first acid-base balance and blood gas analysis (umbilical cord, capillary, or venous), taken within the first 60 minutes of life, showing pH < 7.0, or

- the first acid-base balance and blood gas analysis (umbilical cord, capillary, or venous), taken within 60 minutes of life, showing a base deficit (BE) ≥ 16 mmol/L.

Group "B" criteria:

- clinically pronounced seizures (tonic, clonic, mixed), or

- muscular hypotonia and hyporeflexia, or

- pronounced hypertonia and hyperreflexia, or

- pupillary reflex abnormalities (narrowed and unreactive to dimming, dilated and unreactive to light, sluggish pupillary reaction to changes in lighting).

Group "C" criteria:

- based on amplitude-integrated electroencephalography (aEEG) results;

- indications for performing aEEG are the presence of criteria from groups A and B.

• For a newborn with moderate to severe HIE due to birth asphyxia, provided there is at least one criterion from groups A, B, and C, whole-body therapeutic hypothermia is recommended for 72 hours for neuroprotective purposes. Initiation of whole-body therapeutic hypothermia should be no later than 6 hours of life [65,66].

GGR ALEL 1Grade of Recommendation A (Level of Evidence 1).

Comments: if it is not possible to evaluate Group C criteria, the therapeutic hypothermia procedure should be initiated based on the evaluation of criteria from the first two groups (A and B). The leading indications in this case are documented metabolic acidosis and multiorgan failure. The infant should be evaluated against the above criteria as quickly as possible. The optimal time to initiate therapeutic hypothermia is within the first two hours after birth. Cooling initiated later than 6 hours reduces therapy efficacy [1,35,58–64,67].

Contraindications for the procedure [1,35,58–64,68,69].

- birth weight less than 1800 grams, gestational age less than 36 weeks;

- infant's age at the time of the decision on hypothermia greater than six hours;

- congenital malformations requiring emergency or urgent (within 72 hours) surgical intervention;

-       multiple congenital malformations incompatible with life;

-       refusal of the procedure by the child's legal representatives.

Method of device-based hypothermia:

-       operating procedure of the hypothermia device must strictly comply with its instructions for use;

-       duration of therapeutic hypothermia with the established target temperature should be 72 hours;

-       the core temperature range should be maintained between 33.5º±0.5ºС, the optimal core temperature is 33.5 ºС.

Rewarming.

-       upon completion of therapeutic hypothermia, rewarming is performed by increasing the core temperature by no more than 0.3º - 0.5°(C) / hour to a core temperature of 37°(C); provided the child's condition is stable, the rewarming phase duration is 7-9 hours;

-       in case of emergency cessation of therapeutic hypothermia, rewarming is performed at the same rate;

-       it is important to prevent overheating of the child after the rewarming procedure; the core temperature must be maintained in the range of 36.5º – 37.0°С;

-       measurement of core temperature is carried out for 24 hours after normothermia is achieved;

-       if seizures occur during rewarming, further rewarming should be stopped for several hours and anticonvulsant therapy initiated; rewarming at the same rate can be resumed only if seizures have not recurred for at least 2 hours [70–72];

-       rewarming causes peripheral vasodilation, which may lead to systemic hypotension. Correction of circulating blood volume can be performed by intravenous administration of electrolyte solutions (ATX code B05XA) - sodium chloride** - 0.9% solution. If the child receives inotropic support, an increase in the doses of cardiotonic agents, except cardiac glycosides (ATX code C01C), is possible. If in doubt, it is advisable to evaluate echocardiography data to choose further tactics for correcting hemodynamic disorders [70,71].

Side effects of therapeutic hypothermia

As a rule, therapeutic hypothermia is well tolerated by patients. In isolated cases, the following adverse reactions occur, which typically resolve after the hypothermia session is discontinued:

-       sinus bradycardia;

-       QT interval prolongation;

-       thrombocytopenia;

-       hypocoagulation;

-       glycemia level disorders [73];

-       subcutaneous fat necrosis [74,75];

-       arterial hypotension;

-       increased oxygen consumption;

-       decreased surfactant production;

-       increased pulmonary vascular resistance;

-       hyperbilirubinemia;

-       decreased immunity [76].

Indications for emergency cessation of therapeutic hypothermia.

The therapeutic hypothermia procedure should be stopped in the following situations:

-       available respiratory support methods fail to relieve hypoxemia (SpO2 less than 90%);

-       there are signs of life-threatening coagulopathy that cannot be managed with standard therapy;

-       detection of an intracranial hemorrhage upon examination requiring neurosurgical intervention;

-       severe cardiac rhythm disturbances unresponsive to pharmacological agents;

-       persistent severe hemodynamic disorders that cannot be managed with fluid resuscitation and cardiotonic agents, except cardiac glycosides (ATX code C01C) [77,78].

• For a newborn presenting with signs of groups A and B in the delivery room, total passive therapeutic hypothermia is recommended for neuroprotective purposes [79].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Initial measures in the delivery room in the presence of signs of groups A and B:

-       turn off the radiant warmer;

-       turn off the heating in the incubator (neonatal transport incubator / neonatal transport incubator / neonatal intensive care transport incubator / mobile resuscitation complex);

-       monitor acid-base balance and blood gases if this examination is available at the facility;

-       within 20 minutes after birth, start measuring core temperature with temperature recording every 15 minutes. The depth of probe insertion into the rectum is 5 cm;

-       prevent hyperthermia.

Further actions at the neonatal ward / neonatal intensive care unit stage:

-       do not turn on heating;

-       if technically feasible, perform neurosonography (NSG), start aEEG recording;

-       measure core temperature and general thermometry every 15 minutes;

-       maintain the target core temperature at 33.5º±0.5 ºС;

-       avoid core temperature dropping below 33.0ºС;

-       do not rewarm the child until criteria for the need for or contraindications to therapeutic hypothermia are fully assessed;

-       if there are no indications for therapeutic hypothermia or contraindications are identified, total passive therapeutic hypothermia is discontinued. Rewarming of the child is carried out by increasing the core temperature by 0.2º - 0.5°C per hour, followed by standard therapy depending on the clinical situation;

-       if indications for therapeutic hypothermia are present, cooling is carried out for 72 hours.

• For a newborn with HIE due to birth asphyxia requiring total therapeutic hypothermia when a therapeutic hypothermia device is not available, transportation to a medical organization with appropriate equipment is recommended [80].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Transportation of the child to a higher-level medical organization for device-based hypothermia.

The administration of therapeutic hypothermia is not a contraindication for transporting a newborn infant. Contraindications for transportation are determined by generally accepted criteria or criteria established by local protocols.

It is optimal to use total device-based therapeutic hypothermia during transportation (if the transport team has the appropriate equipment).

If this is not possible, total passive therapeutic hypothermia should be continued during transportation according to the following algorithm:

-       installation and fixation of the core sensor before transportation;

-       vehicle temperature 18º-24º(C);

-       incubator temperature (neonatal transport incubator / neonatal transport incubator / neonatal intensive care transport incubator / mobile resuscitation complex) 25º(C);

-       target core temperature 33.5º±0.5º (C);

-       measurement of core temperature before transportation and every 15 minutes thereafter;

-       if the core temperature drops to 33.0 °C, increase the temperature of the incubator (neonatal transport incubator / neonatal transport intensive care incubator / mobile resuscitation complex) by 0.5 °C;

-       if the core temperature rises above 34 °C, decrease the temperature of the incubator (neonatal transport incubator / neonatal transport intensive care incubator / mobile resuscitation complex) by 0.5 °C;

-       if the temperature remains above 34 °C and it is impossible to decrease the incubator temperature (neonatal transport incubator / neonatal transport intensive care incubator / mobile resuscitation complex), therapeutic hypothermia using hypothermic packs or cold water containers may be performed;

-       if apparatus-based therapeutic hypothermia can be performed during transport, the core temperature range should be maintained strictly between 33°–34 °C; the optimal core temperature is 33.5 °C

• In a newborn with HIE due to perinatal asphyxia requiring whole-body therapeutic hypothermia, during planned transportation of the infant prior to the arrival of the neonatal transport team, it is recommended to perform passive whole-body therapeutic hypothermia [80].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: prior to the arrival of the transport resuscitation team from a level 3 medical organization, passive whole-body therapeutic hypothermia should be continued according to the following algorithm:

-       the infant should be placed in a turned-off neonatal resuscitation system / open neonatal intensive care resuscitation system / open resuscitation system / open resuscitation complex / newborn resuscitation table / neonatal table / resuscitation station or in a turned-off neonatal incubator / neonatal intensive care incubator / infant incubator with open ports;

-       the ambient temperature should be 18°–24 °C;

-       core temperature measurement and general thermometry are performed every 15 minutes;

-       precise recording of the initial temperature and the time when the target temperature is reached;

-       the target core temperature is 33.5°±0.5 °C; 

-       the time to reach the target core temperature is 60 minutes after the initiation of passive hypothermia;

-       if the temperature decreases or increases, check the position of the core temperature probe;

-       if the temperature remains above 34.0 °C during one hour of passive cooling, therapeutic hypothermia using hypothermic packs or cold water containers may be performed;

-       do not use ice packs due to the high risk of severe hypothermia and skin damage;

-       if the temperature drops to 33.0 °C, additional warming may be required to prevent overcooling and to maintain the target body temperature of the infant;

-       if core temperature measurement is not possible, ensure general thermometry and maintenance of temperature in the range of 34°–35 °C;

-       if the target temperature cannot be reached, consult a level 3 medical organization and/or specialists from the neonatal resuscitation and consultation center (NRCC).

• In a newborn with HIE due to perinatal asphyxia requiring whole-body therapeutic hypothermia, in the absence of a therapeutic hypothermia device or if transportation of the infant is not possible, it is recommended to perform passive whole-body therapeutic hypothermia or whole-body therapeutic hypothermia using hypothermic packs for 72 hours [80–82].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: contraindications and indications for emergency discontinuation of passive therapeutic hypothermia and therapeutic hypothermia using hypothermic packs are the same as for apparatus-based therapeutic hypothermia.

Method of performing passive therapeutic hypothermia and therapeutic hypothermia using hypothermic packs:

-       the infant should be placed in a turned-off neonatal resuscitation system / open neonatal intensive care resuscitation system / open resuscitation system / open resuscitation complex / newborn resuscitation table / neonatal table / resuscitation station or in a turned-off neonatal incubator / neonatal intensive care incubator / infant incubator. The infant's skin remains exposed; a diaper is placed underneath but not fastened;

-       ambient temperature 18°–24 °C. It is optimal to provide conditions for keeping the patient in a single room;

-       precise recording of the initial temperature and the time when the target temperature is reached;

-       target core temperature 33.5°±0.5 °C.

-       if the temperature decreases or increases, checking the position of the core temperature probe is required;

-       if the temperature drops to 33.0 °C, additional warming may be required to prevent overcooling and to maintain the target body temperature of the infant;

-       for core temperature monitoring, it is optimal to use a multi-functional patient monitoring system module. Insertion depth is 5 cm.

In addition to apparatus-based therapeutic hypothermia and passive whole-body therapeutic hypothermia, there is a cooling method using hypothermic packs and cold water containers placed along the flanks of the infant without touching the infant's skin – therapeutic hypothermia using hypothermic packs.

In the absence of a hypothermia device / medical thermoregulatory system / thermoregulatory device / hypo/hyperthermic device for cooling and warming newborns, hypothermic packs may be used to achieve the target temperature level. Hypothermic packs are placed in a thermostat at 34 °C and sequentially changed around the patient. Warmed hypothermic packs are returned to the thermostat [83].

If a hypothermia machine / medical temperature-control system / temperature-control device / hypo/hyperthermia device for cooling and warming newborns is unavailable to maintain the target temperature level, it is also possible to use containers with cold water [84] wrapped in a swaddle blanket and placed near the patient at a distance of 5–15 cm.

The placement of hypothermic packs, their arrangement around the infant's body, and the duration of use may vary depending on the clinical situation.

All methods of therapeutic hypothermia (apparatus-based, passive, using hypothermic packs) are equally effective in achieving the target temperature level [85].

The methods of passive hypothermia and body hypothermia using hypothermic packs, compared to apparatus-based hypothermia, are associated with a high risk of unintended deviations from the target temperature. To prevent this, a mandatory requirement for performing passive therapeutic hypothermia and therapeutic hypothermia using hypothermic packs is continuous core temperature measurement. The target core temperature is 33.5 °C. 

If conditions for continuous core temperature measurement are lacking during care in a medical organization or during transportation of the newborn by a transport team, it is advisable to ensure general thermometry with maintenance of the temperature in the range of 34°–35 °C.

• In a newborn with HIE due to perinatal asphyxia at birth, requiring whole-body therapeutic hypothermia, it is recommended to prescribe other antianemic drugs (ATX code B03XA) [86–89].

GSR ALE 2Recommendation Strength – A (Level of Evidence – 2)

Comments: the group of "other antianemic drugs" (ATX code B03XA) includes the following drugs used in newborns: #epoetin alfa** (ATX code B03XA01) and #epoetin beta** (ATX code B03XA01). Treatment regimen: dose of 1000 IU/kg IV on days 1, 2, 3, 5, and 7 of life [88]. Therapy is prescribed by a medical panel decision.

3.1.2 Concomitant Symptomatic Therapy

Concomitant intensive care during therapeutic hypothermia should be performed according to generally accepted rules and indications [64].

-       Respiratory support: mechanical ventilation is not a mandatory prerequisite for therapeutic hypothermia; indications for transition to spontaneous breathing do not differ from standard approaches.

-       Vascular access: ideally, one central and one peripheral venous access should be established.

- Hemodynamic support: performed according to general guidelines to maintain blood pressure within target ranges [90].

- Infusion therapy: the calculation of daily fluid requirement is carried out according to the following principles: starting volume 40–60 ml/kg/day, sodium supplementation 0–3 mmol/kg/day, potassium supplementation 0–3 mmol/kg/day, calcium supplementation 2–3 mmol/kg/day [91]; considering the possible fluid retention associated with prior asphyxia, it is necessary to monitor the fluid balance and determine urine output.

- Parenteral nutrition is prescribed in the absence of contraindications: starting protein provision of 1.5 g/kg/day, increasing up to 2.5 g/kg/day via intravenous administration of parenteral amino acid solutions** [92,93]; starting lipid provision of 1.0 g/kg/day, increasing up to 3.0–3.5 g/kg/day via intravenous administration of lipid emulsion medicinal products for parenteral nutrition** (ATX code B05BA02) [94]; starting carbohydrate provision of 2.5–5 mg/kg/min (3.6–7.2 g/kg/day), increasing up to 12 mg/kg/min (17.3 g/kg/day) via intravenous administration of medicinal products – dextrose** (ATX code B05BA03) [95].

- Antibacterial therapy. The procedure of therapeutic whole-body hypothermia is not an indication for prescribing systemic antibacterial medicinal products (ATX code J01). If a congenital infectious disease is suspected, empirical combination therapy with broad-spectrum penicillins (ATX code J01CA) combined with aminoglycosides (ATX code J01GB) is prescribed [96].

- Enteral nutrition. The procedure of therapeutic whole-body hypothermia is not a contraindication to starting enteral nutrition. Early initiation of enteral nutrition during therapeutic whole-body hypothermia does not increase the incidence of NEC, but decreases the incidence of late-onset neonatal sepsis. Enteral nutrition is provided either with breast milk or with a standard infant formula adapted for newborns from birth, with maternal milk being the optimal nutritional substrate. Enteral nutrition is prescribed in the absence of contraindications on the first day of life at 10–20 ml/kg/day with a daily volume increase of 10–30 ml/kg/day [97–99].

- Therapy of metabolic lactic acidosis [100–104]. At a pH below 7.1, intravenous administration of sodium bicarbonate** medicinal product may be prescribed.

The following formula is used to calculate the requirement:

M (mmol) = 0.3 × BW × BE

where BE is base excess (mmol/L); BW is body weight (kg)

1 ml of 5% sodium bicarbonate** solution contains 0.6 mmol of bicarbonate ions).

The dose of other medicinal products for the treatment of nervous system diseases (ATX code N07XX) — inosine + nicotinamide + riboflavin + succinic acid** for newborns is 2 ml/kg per day as a component of complex therapy for cerebral ischemia in newborns.

• For a newborn with HIE due to birth asphyxia when seizure syndrome is detected, it is recommended to prescribe anticonvulsant therapy [105,106].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: indications for anticonvulsant therapy are clinical seizures or signs of seizure activity detected during amplitude-integrated EEG (aEEG).

The list of drugs used for anticonvulsant therapy may be modified in accordance with local protocols and formularies.

• For a newborn with HIE due to birth asphyxia undergoing therapeutic hypothermia in the presence of shivering, it is recommended to prescribe opioids (ATX code N02A) [107].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: indications for prescribing opioids (ATX code N02A) may be modified in accordance with local protocols and formularies.

3.2 Surgical Treatment

Not applicable.

3.3 Other Treatment

3.3.1 Newborn care

• it is preferable to place the infant in a neonatal resuscitation system / open-care neonatal intensive care system / open resuscitation system / open resuscitation unit / newborn resuscitation table / neonatal table / resuscitation station with built-in scales;

• changing body position every 6 hours with examination of the infant's skin;

• when using a suit, do not tighten it tightly around the infant's body;

• attachment of disposable scalp analytical electrodes for monitoring electrical brain activity, and monitoring of skin condition at the electrode placement sites must be carried out in accordance with the requirements described in the guidelines for performing aEEG in newborns [1].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• For newborns with HIE due to birth asphyxia who are at high risk of developing cerebral palsy, it is recommended to carry out a set of physical rehabilitation/habilitation methods depending on the leading pathological symptom at the age from 0 months to 2 years. The principle of a comprehensive approach implies the use of physical, psychological, medicinal, and other methods. General medical, trophic, point massage, positioning treatment, therapeutic gymnastics for central nervous system diseases and injuries in children [108–111].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

• For a newborn with HIE due to birth asphyxia, for the prevention and correction of persistent movement disorders, it is recommended to establish an early global movement stereotype starting from 3–4 weeks of life using medical rehabilitation services for children with neurological diseases via applied kinesiotherapy methods (Vojta therapy) [112,113].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• For newborns with HIE due to birth asphyxia, for the prevention and correction of neuropsychological function disorders, it is recommended to build sensory integration. Methods: development of sensory perception (emotional, visual, tactile, facial), conducting therapeutic and preventive speech therapy sessions (articulation gymnastics and massage, development of oral and articulatory praxis) [111,114].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

5. Prevention and Dispensary Observation

• For a newborn with HIE due to birth asphyxia, for assessing the dynamics of neurological disorders and timely correction of therapy, it is recommended to have a repeat appointment (examination, consultation) with a neurologist and follow-up dispensary appointment (examination, consultation) with a neurologist [50].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: subsequent follow-up of the child after discharge is mandatory at the follow-up care stage for at least 18 months of life. The duration of follow-up care may be extended according to regional protocols.

• For a newborn with HIE due to birth asphyxia, to assess visual impairment, it is recommended to have an initial appointment (examination, consultation) with an ophthalmologist and a dispensary appointment (examination, consultation) with an ophthalmologist [115,116].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• For a newborn with HIE due to birth asphyxia, during dispensary follow-up to assess hearing function, it is recommended to test hearing using otoacoustic emission [117,118].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

6. Organization of Medical Care

For medical organizations (obstetric inpatient facilities) of groups 1 and 2 — in the event of the birth of a child meeting the criteria for therapeutic hypothermia, urgent notification of the birth to a group 3 medical organization / resuscitation and consultation center is mandatory no later than 30–60 minutes after birth, along with joint determination of further patient management tactics.

Regardless of the group to which the medical organization belongs — in the event of the birth of a child meeting the criteria for therapeutic hypothermia and the absence of facilities for device-based hypothermia in that medical organization, the optimal solution is to arrange urgent transfer of the patient to a medical organization with conditions for device-based hypothermia.

Transfer routing tactics must be regulated by a regional protocol.

If there is a medical organization in the region of the Russian Federation capable of performing device-based therapeutic hypothermia, the regional protocol must establish clear routing to ensure maximum availability of device-based therapeutic hypothermia for newborns in need of this treatment method.

7. Additional Information

The outcome of HIE is determined by the degree, localization, and extent of structural post-ischemic brain damage.

Mortality: Overall, the mortality rate of HIE is 9.1–9.9%, reaching 70–80% in infants with stage III HIE [119].

Cerebral palsy: Epidemiological studies on HIE demonstrate the development of persistent motor disorders, represented mainly by spastic and dyskinetic forms of cerebral palsy, as an outcome of the disease in 20–50% of children. The risk of cerebral palsy increases 3-fold in the presence of seizures and neonatal status epilepticus in the neonatal period [119,120].

Epilepsy: more than 30% of children develop a structural form of epilepsy in the postneonatal period. The maximum risk of developing epilepsy occurs with diffuse hypoxic-ischemic injury, combined damage to the basal ganglia and the deep white matter of the cerebral hemispheres [120].

Behavioral and cognitive impairments: Cognitive impairments and behavioral problems (IQ ≤ 70) occur in 50–80% of cases. Long-term follow-up shows that cognitive and memory problems can occur even in children without motor deficits. Even in the absence of neurological disorders in early childhood, 15–20% of children experience difficulties with the school curriculum, which are more pronounced due to memory and attention impairments [120–123]. The existing pathognomonic HIE patterns on neuroimaging in the form of combined damage to the white matter of the hemispheres, basal ganglia and/or internal capsule have a strong direct correlation with a decrease in IQ (IQ < 70) and the intelligence level at 6–7 years of age [124–127].

Medical documentation management.

1. Informed voluntary consent of the child's legal representative must be obtained for therapeutic hypothermia.

2. In the event of re-hospitalization of the child to another hospital for therapeutic hypothermia, it is necessary to obtain the informed voluntary consent of the child's legal representative for the procedure in the maternity hospital, during transportation, in another medical organization, as well as consent to transportation.

3. If it is impossible to obtain the informed voluntary consent of the child's legal representative, the decision to perform therapeutic hypothermia is made by a medical board (consilium).

4. The legal representatives of the child must be provided with a Parent Information Leaflet that details the main aspects of therapeutic hypothermia.

5. Upon re-hospitalization of a child undergoing therapeutic hypothermia, information regarding the procedure must be recorded in the transportation chart.

6. The implementation of therapeutic hypothermia is documented in the newborn developmental history / inpatient medical record / intensive care charts and does not require separate medical documentation.

7. In regions where centers concentrating patients for therapeutic hypothermia are organized, a territorial protocol must be developed defining the tactics for interaction between obstetric facility physicians and physicians of therapeutic hypothermia centers, as well as the provision of care to newborns at the maternity hospital stage prior to transportation.

8. Formulation and coding of the clinical diagnosis:

• upon transfer of the child from the delivery room into the insert chart for resuscitation and stabilization of the newborn in the delivery room, regulated by Methodological Letter No. 15-4/I/2-2570 dated 04.03.2020 "Resuscitation and stabilization of newborns in the delivery room". ICD-10 code - P21.0, P21.1;

• at the time of the decision to perform therapeutic hypothermia, the clinical diagnosis is established and substantiated: "Hypoxic-ischemic encephalopathy" indicating the severity grade and leading neurological syndromes according to the classification of Sarnat H., Sarnat M. (1976) as modified by Stoll B., Kliegman R. (2004) [9, 128]; ICD-10 code - P91.6 [129];

• in addition, based on regulatory acts in force in the Russian Federation regulating, inter alia, the procedure for paying for neonatal medical care[1], the clinical diagnosis may also include the diagnosis of "Cerebral ischemia" as part of the primary pathology, indicating the severity grade. ICD-10 code - P91.0.

Example of clinical diagnosis formulation:

Severe asphyxia at birth P21.0. Newborn hypoxic-ischemic encephalopathy grade II (III) P91.6. Brain ischemia (Cerebral ischemia) grade 2 (3) P91.0.

[1] Methodological recommendations on methods for paying for specialized medical care in inpatient settings and day hospitals based on disease groups, including clinical-statistical groups and clinical-profile groups at the expense of compulsory medical insurance funds

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ekaterina N. Balashova – PhD in Medical Sciences, Leading Researcher at the Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Council of the Russian Society of Neonatologists

2. Artem A. Burov - PhD in Medical Sciences, Head of the Department of Anesthesiology, Resuscitation and Neonatal Intensive Care, Department of Neonatal and Pediatric Surgery, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Member of the Council of the Russian Society of Neonatologists

3. Valery V. Gorev - PhD in Medical Sciences, Chief Medical Officer of the Morozov City Children's Clinical Hospital of the Moscow Healthcare Department, Chief freelance Neonatologist of the Moscow Healthcare Department, Member of the Council of the Russian Society of Neonatologists

4. Konstantin D. Gorelik – Head of the Neonatal Intensive Care Unit, Children's City Hospital No. 1, Saint Petersburg

5. Maria G. Degtyareva - Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Professor at the Department of Neonatology, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation

6. Oleg V. Ionov – Doctor of Medical Sciences, Head of the Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chairman of the Russian Society of Neonatologists

7. Anna L. Karpova - PhD in Medical Sciences, Head of the Neonatal Inpatient Unit, City Clinical Hospital No. 67 named after L.A. Vorohobov of the Moscow Healthcare Department, Associate Professor at the Professor V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Assistant Professor at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Yaroslavl State Medical University of the Russian Ministry of Health, Member of the Council of the Russian Society of Neonatologists.

8. Anna R. Kirtbaya - Doctor of Medical Sciences, Head of Clinical Work at the Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Russian Society of Neonatologists

9. Lyudmila V. Malyutina - PhD in Medical Sciences, Deputy Chief Medical Officer for Pediatric Care, Shchelkovo Perinatal Center, Head of the Department of Neonatology, Faculty for Advanced Medical Training, Moscow Regional Research Clinical Institute (MONIKI), Leading Researcher at the Department of Neonatal Medicine and Cognitive Development, Research Institute of Childhood of the Ministry of Health of the Moscow Region

10. Inessa I. Mebelova – Deputy Chief Medical Officer for Neonatology, Republican Perinatal Center named after K.A. Gutkin, Chief freelance Specialist in Neonatology of the Ministry of Health of the Republic of Karelia, Member of the Council of the Russian Society of Neonatologists

11. Alexey V. Mostovoy - PhD in Medical Sciences, Head of the Resuscitation and Intensive Care Service, City Clinical Hospital No. 67 named after L.A. Vorohobov of the Moscow Healthcare Department, Associate Professor at the Professor V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Assistant Professor at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Yaroslavl State Medical University of the Russian Ministry of Health, Chief freelance Neonatologist of the Russian Ministry of Health in the North Caucasian Federal District, Member of the Council of the Russian Society of Neonatologists

12. Diana M. Mustafina-Bredikhina – PhD in Law, Associate Professor at the Department of Administrative Law, Patrice Lumumba Peoples' Friendship University of Russia, Legal Counsel of the Russian Society of Neonatologists

13. Rustam F. Mukhametshin - PhD in Medical Sciences, Head of the Department of Anesthesiology, Reanimation, Intensive Care for Newborns and Infants No. 2, Regional Children's Clinical Hospital, Yekaterinburg, Associate Professor at the Department of Anesthesiology, Resuscitation, Toxicology and Transfusiology, Ural State Medical University of the Russian Ministry of Health, Roszdravnadzor Expert in Neonatology

14. Mark E. Prutkin – Head of the Neonatal Department, Regional Children's Clinical Hospital, Yekaterinburg, Member of the Council of the Russian Society of Neonatologists

15. Konstantin V. Romanenko - PhD in Medical Sciences, Head of the Neonatal Intensive Care Unit, Regional Perinatal Center, Chelyabinsk, Chief Neonatologist of the Ministry of Health of the Chelyabinsk Region, Member of the Council of the Russian Society of Neonatologists

16. Olga I. Sapun – Head of Neonatal Intensive Care Unit No. 2, Children's Regional Clinical Hospital, Krasnodar, Chief freelance Neonatologist of the Ministry of Health of the Krasnodar Krai, Assistant Professor at the Department of Pediatrics with a Course in Neonatology, Faculty of Advanced Training and Retraining, Kuban State Medical University, Member of the Council of the Russian Society of Neonatologists

17. Lyubov V. Ushakova – PhD in Medical Sciences, Head of the Department of Neonatal and Pediatric Neurology, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health

18. Mikhail V. Fomichev - Head of the Pediatric Service, Perinatal Center, Tyumen

19. Diyana R. Sharafutdinova – PhD in Medical Sciences, Anesthesiologist-Intensivist at the Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Russian Society of Neonatologists

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the recommendations included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, e-library, clinicaltrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and The European Society for Neonatology. The search depth was 66 years.

Methods used for assessing the quality and strength of evidence:

· expert consensus;

· significance assessment according to a rating scheme.

Scales for assessing levels of evidence (LoE) (Table P1) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, and rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GoR) (Table P2) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions).

Methods used for analyzing evidence:

· reviews of published meta-analyses;

· systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not evaluated.

Method of guidelines validation:

· external peer review;

· internal peer review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

Recent changes in these guidelines are presented for discussion in a draft version. The updated version for broad discussion was posted on the websites of the Russian Society of Neonatologists (RSN) and the Russian Association of Perinatal Medicine (RAPM) www.neonatology.pro and www.raspm.ru so that all interested parties could take part in discussing and improving the guidelines.

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience of these clinical guidelines:

1. Neonatologists

2. Anesthesiologists-intensivists

3. Pediatricians

4. Obstetricians-gynecologists

Table 1.Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Levels of evidence (LoE) rating scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Rating scale for grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

2. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On approval of criteria for assessing the quality of medical care".

3. "International Statistical Classification of Diseases and Related Health Problems (10th Revision) (ICD-10)"

4. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On approval of the nomenclature of medical services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808)

5. Methodological Letter "Resuscitation and Stabilization of Newborn Infants in the Delivery Room" No. 15-4/i/2-2570 dated March 4, 2020. Edited by E.N. Baybarina. Moscow: Ministry of Health of the Russian Federation; 2020.

6. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on April 16, 2024) "On Approval of the List of Vital and Essential Drugs, as Well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care"

7. Procedure for the Provision of Medical Care in the Profile "Neonatology" (Order of the Ministry of Health of the Russian Federation No. 921n dated November 15, 2012).

8. State Register of Medicines: https://grls.rosminzdrav.ru

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Hypoxic-ischemic encephalopathy is brain damage that occurs due to oxygen deprivation during childbirth. Therapeutic hypothermia (hypothermia; Greek hypo- + thermos heat) is the artificial cooling of the body to reduce the intensity of metabolic processes in the body and increase the child's resistance to the oxygen deprivation experienced during childbirth. The term therapeutic comes from the Latin language and translates as curative.

Therapeutic hypothermia is performed by cooling the child. The child's body temperature is artificially lowered from a normal 36.7°C to 33.5°C.

The medical name for this procedure is: "therapeutic hypothermia with intracorporeal temperature monitoring for the treatment of perinatal hypoxic brain injury."

There are several causes of such injuries, the main ones being:

• interruption of blood flow through the umbilical cord (true knots of the cord, compression, tight nuchal entanglement, etc.);

• disruption of gas exchange through the placenta (premature placental abruption, placenta previa, etc.);

• circulatory disorders in the maternal part of the placenta (excessively active contractions, very low or very high maternal blood pressure, etc.);

• reduction in the amount of oxygen in the mother's blood (anemia, cardiovascular diseases, respiratory failure).

Numerous scientific studies conducted in leading clinics in Europe and the US have proven the efficacy of therapeutic hypothermia, and the results of the practical application of this method have shown that, in addition to the standard treatment regimen, therapeutic hypothermia improves the neurodevelopmental outcomes of children and reduces the risk of disability. Furthermore, therapeutic hypothermia has no negative impact on the child's future development.

As with any treatment, whole-body cooling can lead to various side effects: edema, decreased blood platelet count, heart rhythm disturbances, skin damage, impaired blood clotting, etc. Some of these effects are transient, but may require additional treatment. If any adverse reaction of your child's body to therapeutic hypothermia occurs, the procedure will be stopped immediately and rewarming will begin.

During therapeutic hypothermia, the child can be fed breast milk (in addition to intravenous nutrition), which will be very beneficial for your baby.

In order to help your child in a timely manner, therapeutic hypothermia must be initiated no later than the first 6 hours of life, so the decision must be made by you in the near future; otherwise, therapeutic hypothermia becomes ineffective.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Neonatal assessment using the Apgar score 1

Russian title: Neonatal assessment using the Apgar score

Original title: The Apgar Score

Source (official developer website, validation publication):

 Apgar V, Holaday DA, James LS, Weisbrot IM, Berrien C. Evaluation of the newborn infant-second report. JAMA. 1958; 168 (15): 1985–1988 [130].

Type: rating scale

Purpose:

Content (template)

Key (interpretation) and notes: A score of 4–7 at 1 minute after birth corresponds to mild to moderate birth asphyxia (P21.1), and 0–3 points at 1 minute after birth corresponds to severe asphyxia (P21.0). Although according to ICD-10 a total of 7 points at 1 minute after birth corresponds to moderate to severe asphyxia, it is inappropriate to assign this diagnosis, since an Apgar score of 7 at the end of the 1st minute is not clinically and/or prognostically significant.

Appendix G2. Grades of hypoxic-ischemic encephalopathy in newborns (Sarnat H., Sarnat M., 1976 as modified by Stoll B., Kliegman R., 2004)

Russian title: Grades of hypoxic-ischemic encephalopathy in newborns

Original title: Hypoxic-Ischemic Encephalopathy in term infants

Source: Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976 Oct;33(10):696-705 [9].

B.J. Stoll R.M.K. Nervous System Discorders // Nelson Text book of Pediatrics. 17th ed. Philadelphia: SAUNDERS, 2004. P. 561–569 [10].

Type: rating scale

Purpose: assessment of HIE grade

Content (template), key (interpretation), explanations:

Appendix G3. Classification of perinatal nervous system disorders in newborns (RAVSP, 2000).

Russian title: Classification of perinatal nervous system disorders in newborns

Original title: Classification of perinatal nervous system disorders in newborns

Source: Classification of perinatal nervous system disorders in newborns / ed. RASPM. Moscow, 2000. 40 p. [128].

Type: classification

Purpose: determination of the cause and leading pathogenetic mechanism of CNS injury

Content (template):

I. Hypoxic lesions of the nervous system

II. Traumatic injuries of the nervous system

III. Dysmetabolic and toxic-metabolic nervous system disorders

IV. CNS involvement in infectious diseases of the perinatal period

Key (interpretation), explanations:

Hypoxic CNS disorders

I. A) P91.0 Cerebral ischemia (hypoxic-ischemic encephalopathy, perinatal hypoxic brain damage)

Grade I cerebral ischemia (mild)

a) Intrapartum hypoxia, mild birth asphyxia;

b) CNS excitation, more frequently in term infants, or depression in preterm infants, lasting no more than 5-7 days;

c) Moderate hypoxemia, hypercarbia, acidosis;

Neurosonography (NSG), brain computed tomography, brain magnetic resonance imaging: unremarkable/normal;

Transcranial duplex scanning of arteries and veins: compensatory increase in flow velocity in major cerebral arteries;

Diagnosis example:

P91.0 "Grade I cerebral ischemia" or "Grade I hypoxic-ischemic encephalopathy"

Grade II cerebral ischemia (moderate)

a) Factors indicating fetal intrauterine hypoxia; moderate birth asphyxia; extracerebral causes of cerebral hypoxia arising postnatally;

b) CNS depression, excitation, or alternation of cerebral activity phases (lasting more than 7 days);

Seizures in preterm infants are more frequently tonic or atypical (apneic seizures, stereotyped spontaneous oral automatisms, eyelid fluttering, eye-ball myoclonus, "rowing" arm movements, "pedaling" leg movements). In term infants: multifocal clonic. Seizures are usually short-lived, single, less frequently recurrent;

Intracranial hypertension (transient, more common in term infants);

Autonomic-visceral disorders;

c) Metabolic disturbances (hypoxemia, hypercarbia, acidosis are more pronounced and persistent).

NSG: localized hyperechoic foci in brain tissue (in preterm infants, most commonly in the periventricular region; in term infants, subcortically).

Brain magnetic resonance imaging: focal parenchymal brain lesions identified as alterations in MRI signal characteristics on T1- and T2-weighted images.

Brain computed tomography: localized hypodense foci in brain tissue (in preterm infants, most commonly in the periventricular region; in term infants, subcortically and/or cortically).

Transcranial duplex scanning of arteries and veins: signs of hypoperfusion in the middle cerebral artery in term infants and the anterior cerebral artery in preterm infants. Increased diastolic blood flow velocity component, decreased resistance index.

Diagnosis example:

P91.0 "Cerebral ischemia, grade II" or "Hypoxic-ischemic CNS injury, grade II".

If specific structural brain changes are diagnosed, an additional code is assigned (e.g., P91.2 Neonatal cerebral leukomalacia).

Cerebral ischemia, grade III (severe)

a) Factors leading to fetal intrauterine hypoxia and/or severe perinatal asphyxia; extracerebral causes of persistent brain hypoxia (congenital heart disease, severe respiratory distress syndrome, hypovolemic shock, etc.);

b) Progressive loss of cerebral activity exceeding 10 days;

(profound depression or coma in the first 12 hours of life; transient increase in the level of wakefulness between 12–24 hours; increasing depression or coma from 24 to 72 hours onwards)

Recurrent seizures; status epilepticus is possible.

Brainstem dysfunction (disorders of respiratory rhythm, pupillary responses, oculomotor disorders).

Decorticate or decerebrate posture (depending on the extent of the lesion).

Pronounced autonomic-visceral disorders.

Progressive intracranial hypertension.

c) Persistent metabolic disorders.

Neurosonography (NSG): diffuse increase in the echogenicity of the brain parenchyma, typical of term infants. Increased echogenicity of periventricular structures, typical of preterm infants. Narrowing of the lateral ventricles. Subsequently, cystic periventricular cavities (PVL) develop in preterm infants, and signs of cerebral hemisphere atrophy appear with passive enlargement of the cerebrospinal fluid spaces.

Brain CT: decreased density of the brain parenchyma, narrowing of the CSF spaces, multifocal cortical and subcortical hypodense lesions, altered density of the basal ganglia and thalamus (predominantly in term infants), periventricular cystic cavities (in preterm infants).

Brain MRI: parenchymal brain lesions are identified as changes in the MRI signal on T1- and T2-weighted images.

Transcranial duplex scanning of arteries and veins: paralysis of major cerebral arteries, progressing to persistent cerebral hypoperfusion. Decreased diastolic blood flow velocity, altered curve waveform (leasing or pendulum-like character). Increased resistance index.

Diagnosis example:

P91.0 "Cerebral ischemia, grade III" or "Hypoxic-ischemic CNS injury, grade III".

If specific structural brain changes are diagnosed, an additional code is assigned.

Appendix G4. Classification of seizure and background bioelectrical brain activity in term newborns

Russian title: Classification of seizure and background bioelectrical brain activity in term newborns.

Original title: The classification of primary aEEG background patterns, as well as the three degrees of sleep-wake cycling (SWC).

Source: Hellström-Westas L. et al. Amplitude-integrated EEG Classification and Interpretation in Preterm and Term Infants // Neoreviews. 2006. Vol. 7, № 2. P. e76–e87 [39].

Type: classification

Purpose: determination of the bioelectrical activity of the brain

Content (template), key (interpretation), explanations:

Background aEEG activity is regarded as activity with normal amplitude, with the upper margin of the pattern ≥ 10 µV and the lower margin ≥ 5 µV. Normal variant (Fig. 1a).

Moderate deviations from the norm are characterized by an upper margin of the pattern ≥ 10 µV and a lower margin ≤ 5 µV. High amplitude variability with the absence of cyclic variability in bioelectrical activity (Fig. 1b).

Severe abnormalities, depression of bioelectrical activity, with an upper margin ≤ 10 µV and a lower margin ≤ 5 µV (Fig. 1c).

Status epilepticus: continuous seizure activity, high-amplitude pattern with low amplitude variability (Fig. 1d).