A New HYPER-HIE Phenotype? Why Some Babies Develop High Blood Pressure After Therapeutic Hypothermia

https://youtu.be/mteWQT7ekI8

When a baby experiences a lack of oxygen around the time of birth—a condition known as hypoxic-ischemic encephalopathy (HIE)—the first few days are often focused on treating low blood pressure, poor heart function, and supporting the brain with therapeutic hypothermia. But what happens after cooling ends?

Our newly published case report describes something unexpected: two infants who developed significant systemic hypertension after rewarming, despite recovering heart function and improving lung disease. These observations led us to propose a new concept—the HYPER-HIE phenotype—a possible new cardiovascular pattern that may occur during recovery from HIE.

The Story Doesn't End After Cooling

Therapeutic hypothermia has transformed the care of babies with HIE, reducing brain injury and improving long-term outcomes. However, recovery after cooling is a dynamic process.

Traditionally, clinicians have focused on hypotension during the first days after birth. Surprisingly, much less attention has been paid to what happens after rewarming, when the cardiovascular system begins to recover.

In our report, both infants followed a remarkably similar pattern:

• severe HIE requiring therapeutic hypothermia

• early cardiovascular instability with pulmonary hypertension

• gradual improvement in heart function

• new-onset systemic hypertension several days later

This unexpected rise in blood pressure occurred after the cooling period rather than during the initial critical illness.

Looking Beyond Blood Pressure

High blood pressure is often assumed to be reassuring. After all, isn't it better than low blood pressure?

Not necessarily.

Using targeted neonatal echocardiography (TnECHO), we found that both infants had markedly elevated systemic vascular resistance (SVR) despite normal ventricular function.

This suggests that the heart had recovered—but the blood vessels remained tightly constricted.

In other words, a normal or high blood pressure does not necessarily mean good blood flow to the body's organs or the brain.

What Might Be Causing This?

Because this is a case report, we cannot prove exactly why this happens.

However, several biological mechanisms may contribute:

• persistent sympathetic nervous system activation

• elevated circulating catecholamines

• activation of the renin-angiotensin-aldosterone system (RAAS)

• altered vascular tone

• kidney injury following asphyxia

• cardiovascular adaptation after pulmonary hypertension resolves

These mechanisms likely interact to produce a high-afterload circulation, resulting in elevated blood pressure during recovery.

Introducing the HYPER-HIE Phenotype

Based on these observations, we propose the term:

HYPER-HIE

Hypertension Following Hypoxic-Ischemic Encephalopathy

The proposed phenotype is characterized by:

✔ Hypertension after rewarming

✔ Recovery of myocardial function

✔ Elevated systemic vascular resistance

✔ Resolution of pulmonary hypertension

✔ No structural cardiac explanation for hypertension

Recognizing this phenotype may help clinicians identify infants who require continued cardiovascular monitoring even after therapeutic hypothermia has ended.

Does Milrinone Work?

Both infants received milrinone, a medication that reduces afterload and improves blood flow.

Their blood pressure normalized while receiving treatment.

However, it is important to emphasize that our report cannot determine whether milrinone caused this improvement. The infants may have recovered naturally, and larger prospective studies will be required before treatment recommendations can be made.

Why This Matters

This paper is not simply about two interesting patients.

It challenges us to think differently about cardiovascular recovery after HIE.

Perhaps blood pressure alone is not enough.

Perhaps we should also measure:

• cardiac output

• systemic vascular resistance

• cerebral perfusion

• renal function

• phase-specific cardiovascular physiology

Understanding these changes could improve both cardiovascular care and brain protection during one of the most vulnerable periods of neonatal recovery.

The Bottom Line

Most clinicians caring for infants with HIE are vigilant for low blood pressure during therapeutic hypothermia.

Our report suggests that another pattern may emerge later—high blood pressure after rewarming, potentially driven by elevated systemic vascular resistance.

Whether this HYPER-HIE phenotype is common, how often it occurs, and how it should be treated remain unanswered questions.

What is clear is that the cardiovascular story of HIE does not end when cooling stops. By recognizing new recovery patterns and studying them systematically, we may identify opportunities to further improve outcomes for newborns recovering from hypoxic-ischemic encephalopathy

Reference: HYPER-HIE Phenotype: Postrewarming Systemic Hypertension Following Hypoxic-Ischemic Encephalopathy-A Case Report and Mechanistic Review. Surak A, Schmölzer GM. Case Rep Pediatr. 2026 Jul 25;2026:1742901. doi: 10.1155/crpe/1742901. eCollection 2026.

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