Perinatal hypoxia in the form of hypoxic-ischaemic encephalopathy (HIE) is a frequent cause of cerebral impairment in neonates. HIE occurs in 3 to 5 of 1000 neonates in developed countries and is significantly higher in developing countries at 25 of 1000 neonates. Despite developments in medicine, increasing understanding of HIE pathophysiology and progress in neonatal intensive care as well as treatment of moderate or severe perinatal asphyxia, HIE continues to be associated with significant mortality and late neurological sequelae.

Episodes of ischaemia-hypoxia in the perinatal period as well as the changes in the redistribution of blood may lead to decreased perfusion and ischaemia of the cardiac muscle. Additionally, there is a negative impact from the reduced contractility of the cardiac muscle secondary to acidosis and hypoxia. Therapeutic hypothermia (TH) improves the late effects in moderate and severe cases of hypoxia-ischaemia encephalopathy (HIE). The direct impact of TH on the cardiovascular system includes moderate bradycardia, increased pulmonary vascular resistance (PVR), inferior filling of the left ventricle (LV) and LV stroke volume. The above-mentioned consequences of TH and episodes of HI in the perinatal period are therefore exacerbation of respiratory and circulatory failure. The impact of the warming phase on the cardiovascular system is not well researched and currently few data has been published on this topic. Physiologically, warming increases heart rate, improves cardiac output and increases systemic pressure. The effect of TH and the warming phase on the cardiovascular values has a decisive impact on the metabolism of drugs, including vasopressors / inotropics, which in turn affects the choice of medication and fluid therapy

Impact of hypoxia on the cardiovascular system Transitory hypoxia of the myocardium (and its resultant dysfunction), which may, but not necessarily, present clinically, occurs in two thirds of neonates born with perinatal asphyxia. There is no doubt that that this is one of the more frequent cause of circulatory insufficiency. Both an episode of ischaemic hypoxia in the perinatal period and the changes in the distribution of blood may lead to diminished perfusion of the cardiac muscle. An additional but no less important impact on cardiac function is the immaturity of the neonatal myocardium and its reduced contractility secondary to acidosis and hypoxia. Ischaemia and acidosis lead to imbalance in favour of production of endothelin 1, which leads to reduced production of nitric oxide and vasoconstriction of pulmonary vessels and therefore greater pulmonary vascular resistance (PVR) which has a detrimental effect on the already impaired right ventricular (RV) function. The weak RV function and increase PVR impair filling and function of the left ventricle (LV) and thus, they can affect systemic and cerebral blood flow.

The impact of therapeutic hypothermia on the cardiovascular system

TH improves the distant results in cases of moderate and severe HIE and is currently the standard of care for neonates born at or near term (> 35 weeks of gestation). The direct effect of TH on the cardiovascular system includes the following:

• Moderate bradycardia resulting from the decreased effect of the parasympathetic system on cardiac function. Indeed, sinus bradycardia leads to reduced stroke volume and decreased requirement for energy by the myocardium. In turn, administration of inotropes increase metabolic requirements.
• Additionally, TH leads to increased PVR, potentially resulting in a clinical picture of persistent pulmonary hypertension in the neonate (PPHN) or its exacerbation in cases of pre-existing raised PVR. In animal studies, TH was associated with increased PVR, while an increased risk of PPHN with TH was not found in RCTs.
• The resulting RV dysfunction and reduced stroke capacity of the RV leads to reduced pulmonary venous return and therefore inferior filling and stroke volume of the LV. A consequence of the effects of TH mentioned above and of an episode of HI in the perinatal period is therefore exacerbation of respiratory and circulatory failure.

Impact of the warming process on the cardiovascular system following administration of hypothermia

The impact of the warming phase on the cardiovascular system has not been well documented and currently very little data was published on this topic. Physiologically warming accelerates the heartbeat and improves stroke volume, although the mean blood pressure may fall or remain unchanged as a result of lowering of the diastolic component, which in turn affects metabolism and drug clearance, including clearance of cardiovascular medications. The warming phase, following conclusion of hypothermic treatment, affects the selection of further medicinal therapy in terms of vasopressors, inotropes and of fluid therapy. Furthermore, studies have shown that neonates are more at risk of convulsive episodes during the warming phase. In a study of 160 neonates, 9% experienced intra- or periventricular haemorrhage. Neonates require more precise observation in terms of haemodynamic instability during the warming phase.

Inclusion Criteria:

1. Neonates with gestation age ≥35, whith episode of PA and who were qualified for TH according to the Standards of Medical care of Neonates in Poland (10) was enrolled to the SG
2. Healthy, neonates with gastation >37 0/7 < 41 6/7, who underwent ECHO for reasons such as difficult adaptation, gestational diabetes of the mother etc. was enrolled to the CG.

Exclusion Criteria:

1. Congenital cardiac abnormalities
2. Genetic abnormalities
3. Absence of parental or guardian consent for participation in the study
4. SGA <10 centiles

This is a multicentre, prospective, case-control, observational study. The number of subjects under observation will be 113 neonates. The enrolment, intervention and assessment schedule is presented in tabel.

Initial echocardiography and cerebral and abdominal ultrasonography will be conducted according to physician recommendation by two neonatologist.

The study procedure will be explained to patient's guardians who will also receive an information leaflet. Guardians will then be asked to provide two copies of informed consent.