Hemodynamics in HIE and acute PH

Hemodynamic disturbances and considerations in HIE

Adapted from work by NeoBrainLab (Dr Pia Wintermark) and Dr Gabriel Altit - Posted February 7, 2026

Cardiorespiratory dysfunction is frequent in asphyxia and hypoxic ischemic encephalopathy (HIE) and contribute to mortality, brain injury and/or neurodevelopmental impairments.(1-3) Dopamine infusion remains the most commonly used agent to treat hypotension in North America.(4) However, based on pediatric and adult literature, experts and guidelines increasingly advocate against dopamine in shock, with other agents being considered more beneficial for their hemodynamics properties. In addition, the injured neonatal brain affected by HIE displays impaired cerebral autoregulation (5, 6), and the impact of CV medications may be different in this context. One retrospective cohort study demonstrated an association between CV medications and brain injury in neonates with HIE.(3) No trial has tested CV medications in neonates with HIE to optimize their hemodynamics, and, more crucially, their brain outcomes.

Cardiac and respiratory dysfunction (i.e., myocardial ischemia, vascular tone anomalies, acute pulmonary hypertension (PH), and hypoxemic respiratory failure) are frequent in neonates with HIE and contribute to the mortality, brain injury and/or their neurodevelopmental impairments.(1, 3, 7) The asphyxia event is often followed by a decrease in cardiac contractility (coronary ischemia)(8) and by an altered pulmonary/systemic vascular transition.(9, 10) This results in a decreased cardiac output.(11) Despite, the blood pressure (BP) is typically appearing “normal” initially secondary to a catecholamine surge by stress-response(12) and to a TH-induced vasoconstriction. Hypotension frequently unfolds due to a rapid fall in circulating catecholamines,(12) exposure to anti-seizure medications, autonomous dysfunction and adrenal ischemia. Due to hypotension and acute PH, neonates with HIE are frequently exposed to exogenous catecholamines and steroids during TH. Vasopressors, inotropes, pulmonary vasodilators, and steroids, referred under the umbrella term “CV medications”, are often used to restore hemodynamic stability. However, there is a near complete lack of evidence regarding which drug should be primarily administered to reduce mortality and morbidities, resulting in significant variations in practice. Beyond choice of medication, there are gaps in standardization related to important definitions (hypotension, acute PH), intervention thresholds and target goals (clinical vs. echocardiography-driven metrics), therapeutic escalation and de-escalation, and use of diagnostic and monitoring tools.(13) The optimal CV approach in the context of hypotension/shock in HIE remains a key knowledge gap and possible contributor to high mortality and morbidity rates.(1, 14) 

Therapeutic hypothermia alters pulmonary vascular resistance, promotes right-to-left shunting across fetal channels, and shifts the oxygen–hemoglobin dissociation curve to the left, thereby impairing oxygen unloading at the tissue level. In this setting, conventional monitoring with SpO2 and NIRS may become misleading. In addition, hypocapnia resulting from increased respiratory clearance in the presence of metabolic acidosis can further shift the dissociation curve leftward, compounding impairments in tissue oxygen delivery despite apparently adequate arterial oxygenation. Other critical concepts to keep in mind is the vulnerability of cerebral autoregulation and the delicate balance between cerebral perfusion pressure, coronary perfusion pressure, and systemic hemodynamics. In this context, both low-flow states and reperfusion can exacerbate brain injury. Careful attention to this balance is essential to uphold the principle of primum non nocere—avoiding overly aggressive interventions that may inadvertently increase cerebral blood flow in the setting of impaired autoregulation, thereby worsening reperfusion injury. This risk may be further amplified in the presence of cerebral venous congestion, which can independently contribute to secondary brain injury. Notably, infants with hypoxic-ischemic encephalopathy complicated by significant pulmonary hypertension may be exposed to elevated mean airway pressures or increased right-sided end-diastolic pressures, leading to raised central venous pressure and impaired cerebral venous drainage, with potential deleterious effects on cerebral perfusion and injury evolution.

Current cardiovascular (CV) therapies: Several CV medications are available to manage hypotension (low BP) and cardiac dysfunction in neonates with HIE. Rapid fluctuations in BP, especially of the preductal cerebral perfusion pressure, may be undesirable in these neonates.(13) During TH, the response to cardiovascular agents has been shown to shift from a β- to a more α-adrenergic response,(15) which potentially makes the agents with a predominant β-receptor effect less effective in optimizing cardiac output.(15) 

• Some studies have suggested that dopamine is better for these neonates, since it may (1) increase systolic blood pressure, and to a lesser extent, diastolic blood pressure; (2) prevent the loss of cerebral flow autoregulation;(16) (3) enable the clearance of lactate levels;(17) and (4) improve mortality or morbidity.(18) However, it may increase pulmonary vascular resistance, which is of concern since these infants often have concomitant acute PH, which may increase mortality or hypoxia – leading to worsening cerebral ischemia.(18) 

• Other studies have suggested that epinephrine has a more favorable profile, since it may improve systemic blood pressure without exacerbating PH.(19) However, epinephrine may fail to improve cardiac output due to a downregulation of the β-receptors.(20) It has been shown to increase lactic acid production,(17, 21) which has been linked to an increase in whole-body blood flow and a decrease in oxygen extraction.(21) This could be detrimental in HIE, since TH prevents secondary brain injury by reducing metabolic demand and reperfusion injury.(17) 

• Similarly, the shift in adrenergic response(15) may decrease the effects of dobutamine (a drug with predominantly β effects). The main metabolite of dobutamine, (+)-3-Omethyl-dobutamine, exerts an α-receptor inhibitory effect that decreases myocardial contractility and systemic vascular resistance(22) and worsens cardiac output. Also, dobutamine has no direct effect on cerebral blood flow in these neonates.(23, 24) Two studies reported that neonates developing more severe brain injury had a higher dobutamine dose.(21) 

• Agents such as norepinephrine or vasopressin act by vasoconstriction; these agents may improve acute PH profile (although in the context of high oxygen exposure, norepinephrine may actually increase pulmonary vascular tone - see Inotropes - Vasopressors - Cardiovascular Medications section), but do not provide inotropic support and may exacerbate left ventricle (LV) dysfunction, often present in the context of HIE. Vasopressin may worsen concomitant hyponatremia related to acute kidney injury and inappropriate secretion of anti-diuretic hormone frequently observed in the context of HIE. 

• In an era of personalized healthcare, experts are recommending an expanded utilization of targeted neonatal echocardiography (TNE) to guide a physiological-driven management. This approach aims to address the underlying CV phenotype through the application of physiological principles, serving as a valuable resource for potentially restoring homeostasis, fostering cerebral recovery, and preventing ongoing injury.(4, 25)

Special consideration for the injured neonatal brain: Perinatal hypoxic-ischemic insult initially leads to decreased blood flow to the brain (primary lesions), followed by a return of blood flow to an injured brain (hyperperfusion) and the initiation of a cascade of pathological pathways (secondary lesions or “reperfusion injury”).(26) This cascade includes an accumulation of extracellular glutamate with an excessive activation of glutamate receptors, calcium influx, and generation of reactive oxygen and nitrogen species, leading to cell death and definitive brain injury with long-term neurodevelopmental impairment.(26) This cascade is the primary target for neuroprotective interventions such as TH.(26) However, MRI studies of brain perfusion changes (arterial spin labeling) in neonates with HIE showed that systemic cooling using current clinical guidelines did not prevent increased brain perfusion during TH in all treated neonates,(27) explaining why TH does not prevent further injury in some neonates. Hypotension in HIE decreases cerebral blood flow and oxygen delivery, increases cerebral fractional tissue oxygen extraction, and decreases oxygen consumption.(5, 28-30) It has thus the potential to worsen brain injury, since the initial asphyxia event has already led to impaired cerebral vasoregulation.(28, 29) Hypotension further impairs the ability to autoregulate cerebral blood flow.(6, 29) The injudicious use of CV medications may cause abrupt BP changes, exacerbating brain ischemia in an heterogeneous and unpredictive manner secondary to the pressure passive cerebral perfusion state.(3)

Phenotypes of "Acute PH" possibly seen in HIE

Acute PH is often implied to be a failure to relax the pulmonary vasculature in the immediate post-natal transition secondary to various cardio-pulmonary insults or stressors. This often yields to "abnormally" high PVR which may cause RV dysfunction, low pulmonary blood flow, hypoxic respiratory failure due to extra-pulmonary right to left shunting. It is often complicated by adverse cardio-pulmonary interactions, ventilation-perfusion mismatch (such as in meconium aspiration syndrome), acidosis, shock and end-organ hypoperfusion. 

Acute PH in the newborn may present with diverse cardiovascular phenotypes, each representing a unique and dynamic physiology that requires constant vigilance and customized management. Targeted Neonatal Echocardiography (TNE) can be particularly valuable in deciphering the baby's condition and guiding therapeutic interventions. It’s crucial to remember that medications bring both intended effects and potential side effects. They should be carefully titrated and discontinued as soon as they are no longer required, as prolonged use may have unintended impacts on the body and cardiovascular system.

Cooling alters pulmonary vascular resistance, promotes right-to-left shunting across fetal channels, and shifts the oxygen–hemoglobin dissociation curve to the left (see oxygen-hemoglobin dissociation curve), impairing oxygen unloading at the tissue level. In this context, conventional monitoring may become misleading.

Acute PH (Classical "PPHN") with preserved or mildly depressed cardiac function and unrestrictive ductus

These patients often have maintained RV systolic function thanks to the ductus that is "wide open" and allows to "pop-off" the right ventricle in the context of supra-systemic pulmonary vascular resistances, leading to right to left ductal shunting. The baby is blue but at least not gray as they are able to maintain perfusion, at the expense of hypoxemia. There is often low pulmonary venous return, oligemia on the chest radiography. Desaturation is of secondary to right to left atrial shunting (pre-ductal desaturation) and right to left ductal shunting (post-ductal desaturation with differential of saturations). The low pulmonary blood flow leads to decreased LA preload, which favours the right to left atrial shunt. The size of inter-atrial shunt and the relationship between RV and LV end-diastolic pressures dictates the magnitude of the atrial shunt, and the amount of hypoxic blood entering the systemic circulation at that level (making the baby more profoundly desaturated at the pre-ductal level). The wide ductus shunts away the flow from the RV output towards the systemic circulation, decreasing pulmonary blood flow. Qp < Qs, but at least systemic blood flow is maintained (better to have a blue baby than a gray baby with weak pulses and end-organ perfusion compromise). Core strategy should be to promote the fall of PVR in order to reverse the phenotype.  The pre-ductal saturations are dependent on the atrial level shunt, as well as the pulmonary venous saturations (which may be decreased if there is a component of pulmonary parenchymal disease and ventilation perfusion mismatch). 

Management:

1. Ensure appropriate ventilation, but avoid hypocapnia (cerebral vasoconstriction) 

   1. Surfactant for RDS or Meconium Aspiration Syndrome

   2. Appropriate pulmonary recruitment (being aware that increasing MAP can be problematic in terms of cardio-respiratory interactions; high MAP can increase RV afterload and decrease cardiac preload).

2. Sedation/Analgesia may be indicated to avoid reactive increase in PVR 

3. Oxygen should be administered to aim 90-95% saturation. Oxygen is a pulmonary vasodilator but also toxic when exposed in excess. 

   1. Due to right to left shunt, there is a threshold at which FiO2 increase has no impact and excessive O2 may cause lung injury by reactive oxygen species 

4. Despite optimization of status, still high PVR and hypoxic:

   1. iNO is one of the only agent studied in RCT for hypoxic respiratory failure (often with acute PH / PPHN) in the term and near-term newborns

   2. Wean if not working; Wean once phenotype changes/resolves (implies reassessments)

5. Increasing data that vasopressors like vasopressin and norepinephrine may improve the PVR/SVR ratio in acute PH

6. PGE may be considered once PDA becomes restrictive as a pop-off for the RV (if there is RV failure), see below. 

7. Hydrocortisone should be considered in certain situations

   1. We do not recommend necessarily to base on cortisol level - Challenge with cortisol is the aspect of relative adrenal insufficiency. What is the normal values of cortisol in the context of significant stress. We know that some of these babies may have adrenal ischemia, hemorrhage, immaturity or sepsis which may all overwhelm the adrenal function and response. I personally do not rely solely on cortisol values and often consider hydrocortisone in babies with significant hemodynamic derangements. 

   2. Appropriate response to stress essential for maintenance of hemodynamic stability. Glucocorticosteroids  adrenergic receptors in smooth muscles, inhibits NO synthase expression and ↓ reuptake of norepinephrine leading to an increase in vascular tone and support of myocardial function. Effective in increasing BP and decrease inotropic support. No study: improved clinical outcomes with steroids in newborn shock 

   3. Hydrocortisone normalizes PDE-5 activity in pulmonary artery smooth muscle cells from lambs with PPHN

Acute PH (Classical "PPHN") with significantly depressed cardiac function and restrictive ductus

With a closing ductus and supra-systemic pulmonary vascular resistance (PVR), the right ventricle (RV) experiences an increasing afterload that it eventually cannot overcome. The patent ductus arteriosus (PDA) is too small to equalize pressures. Consequently, the RV is forced to maintain output against high PVR, initially causing a marked rise in pulmonary arterial pressures. This elevated afterload results in RV dysfunction and adverse interactions between the RV and left ventricle (LV). These patients are at high risk of progressively impaired left atrial (LA) preload and LV output, as well as progressive drop in  which can lead to profound hypotension and poor systemic perfusion. Eventually, the RV cannot compensate and there is significant drop in RV output, increase in RV end diastolic pressure. This leads to either backflow into the systemic veins (hepatomegaly, retrograde flow in the IVC, subhepatic veins and SVC - which can raise the post-capillary pressure of the cerebral vasculature), or it can lead to increased magnitude of the shunt at the atrial level (depending on the size of the inter-atrial shunt). These patients more "blue" if the volume accross the foramen ovale increases. They become more gray if the foramen ovale is restrictive. For these patients, addressing the elevated PVR must be coupled with cardiac support and potentially re-opening the ductus.

Management:

• Same as previous for high PVR, but here there is also is a component of significant RV systolic +/- diastolic dysfunction. 

  • Consider inotropic support: Dobutamine, Epinephrine

  • Milrinone can lead to significant hypotension. Can be considered if good urine output and normal BP. However, takes time to act, and may have accumulation if poor urine output as it is renally excreted. In our practice we do not use a bolus and we start at a lower dose (0.2 to 0.3 mcg/kg/min)

• PGE should be considered if the duct is restrictive to pop-off the right ventricle (if it is failing). This is ackowledging that it is at the expense of post-ductal hypoxemia. However, better to have perfusion and flow maintained and be "blue", than be gray with poor systemic blood flow. 

Acute PH with a closed duct 

See the section on the premature prenatal closure of the ductus.

Management and information:

• In this context there PDA is closed and there has been likely pre-natal ductal closure. As such, there is RV remodelling (hypertrophy), which leads to high RV end-diastolic pressure and a significant volume of hypoxic blood entering the systemic circulation at the level of the atrium, leading to pre-ductal desaturation. Pre and post-ductal saturation are the same because there is no duct! The RV may be failing. While these patients may remain with lower saturations for a while because of the R-L shunt at the atrial level, it is important to be patient. Agents like iNO and milrinone may be used to relax the pulmonary vascular bed. Inotropy may be necessary to support the RV function (dobutamine or epinephrine). Occasionally in significant RV hypertrophy, one may consider rate-control (such as esmolol). However, beta-blockers may also have some degree of myocardial depression and one should be particularly cautious in that context. 

• If the duct has been closed for a long time, it is unlikely that PGE will function as a strategy to re-open it.

  • If the ductus has been closed for an extended period in utero (e.g., weeks), intimal thickening, fibrosis, and remodeling may make it refractory to PGE1. If closure was recent or incomplete, PGE1 may still be theoretically effective in reopening the PDA.

• Milrinone may be considered to help the RV relax if the baby is not hypotensive and has good urine output (because it tends to renaly accumulate and can cause significant systemic vasodilation) - Reference.

• Ishida H, Kawazu Y, Kayatani F, Inamura N. Prognostic factors of premature closure of the ductus arteriosus in utero: a systematic literature review. Cardiology in the Young. 2017;27(4):634-638. doi:10.1017/S1047951116000871

  • "We analysed the data of 116 patients from 39 articles. Of these, 12 (10.3%) died after birth or in utero. Fetal or neonatal death was significantly correlated with fetal hydrops (odds ratio=39.6, 95% confidence interval=4.6–47.8) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.2–15.1). Persistent pulmonary hypertension was observed in 33 cases (28.4%), and was also correlated with fetal hydrops (odds ratio=4.2, 95% confidence interval=1.3–4.6) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.6–6.0). Interestingly, maternal drug administration was not correlated with the risk of death and persistent pulmonary hypertension."

  • "Persistent pulmonary hypertension of the newborn was observed in 33 cases (28.4%), 14 of which required mechanical ventilation (42.4%), including five patients who received nitric oxide inhalation. Fisher’s exact tests revealed that persistent pulmonary hypertension was significantly correlated with fetal hydrops (p=0.015; odds ratio 4.2, 95% confidence interval 1.3–4.6) and fetal right heart dilatation (p=0.0014; odds ratio 8.6, 95% confidence interval 1.4–22.1), but not with maternal drug administration (p=0.245) and fetal tricuspid regurgitation (p=0.108)." ... "Patients who could survive the perinatal period, regardless of persistent pulmonary hypertension, had no neurological or cardiac complications for at least 1–10 months; however, 11 patients (9.5%) had mild right ventricular hypertrophy or tricuspid regurgitation without any clinical symptoms, as detected by follow-up echocardiography at 1–6 months of age."

LV dysfunction

Many patients with hypoxic-ischemic encephalopathy (HIE) are at risk of left ventricular (LV) dysfunction, which is often multi-factorial in origin. Contributing factors include poor coronary perfusion, myocardial hypoxia, acidosis, electrolyte imbalances (e.g., sodium, potassium, calcium), energy substrate insufficiency (e.g., oxygen, glucose), elevated systemic vascular resistance due to vascular constriction that maintains pressure in the context of low flow, anemia (as seen in cases like fetal-maternal hemorrhage or acute bleeding such as intra-ventricular or subgaleal hemorrhages, placenta previa, or abruptio), kidney injury, adverse cardiopulmonary interactions, and inflammatory conditions (e.g., concomitant sepsis, chorioamnionitis). 

Severe LV dysfunction in these patients can lead to extremely low LV output. In such cases, the right ventricle (RV) may assume a systemic role, providing systemic blood flow, with the ductus arteriosus becoming crucial, similar to a hypoplastic left heart syndrome (HLHS) or coarctation physiology. In this context, inhaled nitric oxide (iNO) should be avoided as it may divert blood from systemic circulation. Pulmonary vasodilators can similarly increase pulmonary flow, risking flash pulmonary edema due to heightened post-capillary congestion from elevated left atrial pressure. Elevated LV end-diastolic pressures often result in a left-to-right shunt at the atrial level, with these patients typically showing "normal" pre-ductal saturations and desirable pre- and post-ductal saturation differences. The pre-ductal saturations are dependent on the atrial level shunt, as well as the pulmonary venous saturations (which may be decreased if there is a component of pulmonary parenchymal disease and ventilation perfusion mismatch). 

If the PDA is small, restrictive, or closed, severe LV dysfunction may manifest as shock with poor perfusion, weak pulses, tachycardia, mottling, prolonged capillary refill, low urine output, and marked acidosis due to impaired end-organ perfusion. Management strategies vary by severity, but significant LV dysfunction may require inotropic support (e.g., epinephrine, dobutamine) and prostaglandin E (PGE) to maintain ductal patency, thereby sustaining systemic blood flow which may depend on RV output. Milrinone should be used with caution if there is poor urinary output as it tends to renally accumulate and can cause hypotension by systemic vascular resistance drop. Milrinone takes a few hours to have effect due to its longer half-life. 

In summary, management of significant LV dysfunction involves:

- Inotropic support (e.g., epinephrine, dobutamine; occasionally milrinone) to strengthen cardiac output.

- Avoiding pulmonary vasodilators to prevent exacerbating systemic steal, especially when a right-to-left ductal shunt is essential for systemic flow.

- Maintaining ductal patency with PGE when systemic circulation relies on RV output to ensure adequate systemic blood flow.

Functional pulmonary valvular atresia/stenosis

Functional pulmonary atresia happens when the RV function is so impacted that the RVO is extremely low, and pulmonary blood flow becomes dependent on the left to right shunt at the level of the ductus. Paradoxically, these patients may have differential of saturation once the RV function improves and output becomes sufficient through the RVOT to have some bidirectional or right to left component to the ductal shunt. These patients are often quite blue with similar saturations pre-post ductal. They have significant volume of hypoxic blood entering at the atrial level (depending on the size of their foramen ovale and RV end-diastolic pressure). They may have significant hepatomegaly. These patients may benefit from PGE to provide pulmonary blood flow, which increases the LA pressure by pulmonary venous return and decreasing the atrial shunt in the Right to Left direction. They also benefit from RV inotropic support and pulmonary vasodilation if the primary cause is high PVR. Some infants with this phenotype have significant RV hypertrophy and only PGE with adequate filling (and sometimes rate control: esmolol and/or sedation-analgesia to avoid fast heart rate) may be sufficient. 

Biventricular dysfunction

In the case of significant biventricular dysfunction, the goal is to provide inotropic support. Here epinephrine and dobutamine are agents to consider. These patients are often hypotensive and hypoxic, they have low LV and RV output. Hydrocortisone may be added to provide some degree of adrenal support in certain cases. 

In all these cases, if medical management fails, one shall consider alternatives such as ECMO (and occasionally removing TH depending on the patient and the local practice).

Cardiovascular Medications

More under the inotropic and vasopressors section

Cardiopulmonary assessment and diagnostic approach in HIE - Dr. Regan Giesinger Clinical Cardiopulmonary Physiology for the Care of the Sick Newborn Course - November 2024 

Presentation - Role of TNE in HIE - World Congress of Cardiology - 2024