Comparable Prognosis in Different Neonatal Histidine-Tryptophan-Ketoglutarate Dosage Management

Neonatal heart surgery is a high-stakes procedure: surgeons must repair congenital defects while protecting an immature heart from damage during cardioplegic arrest—the temporary pause of the heart using a solution called cardioplegia. One widely used option is histidine-tryptophan-ketoglutarate (HTK), a crystalloid solution that halts cardiac activity and preserves tissue. But for newborns, there’s been a critical gap in guidance: how much HTK is safe to use?

Until now, most HTK dosing guidelines were based on adults or older children (40–60 mL/kg). But neonates have smaller hearts, fragile blood vessels, and unique physiology—making it hard to balance dose, pressure, and perfusion time. If clinicians stick to the standard dose, perfusion pressure might be too low to reach all parts of the heart. If they increase pressure to improve coverage, they risk using more HTK than recommended.

A 2021 study from Fuwai Hospital in Beijing sought to answer this question. Researchers retrospectively analyzed data from 146 neonates (under 28 days old) who underwent on-pump heart surgery with single-shot HTK perfusion. Their goal: compare outcomes between standard-dose (SD) HTK (40–60 mL/kg) and high-dose (HD) HTK (>60 mL/kg) and evaluate whether higher doses are safe for newborns.

Study Design: Balancing Variables for Reliable Results

The team divided patients into two groups based on HTK dose:

Standard-dose (SD): 63 neonates (40 mL/kg < HTK ≤ 60 mL/kg)
High-dose (HD): 83 neonates (HTK > 60 mL/kg)

To account for baseline differences (e.g., weight, surgery complexity, procedure time) that could skew results, they used propensity score matching (PSM)—a statistical tool that creates 1:1 pairs of patients with similar characteristics. After matching, 44 pairs remained—each with identical weights, ages, surgery risks, and procedure times.

The team tracked key outcomes:

Heart protection: Cardiac enzymes (markers of heart damage, like CK-MB), echocardiography (heart function/size), and complications (arrhythmias, low cardiac output syndrome).
Recovery: Ventilation time, ICU stay, hospital stay, and blood product use.
Safety: Electrolyte levels (sodium, potassium), hematocrit (red blood cell count), and extracardiac complications (infection, reintubation).

Key Results: High-Dose HTK Is Just as Safe as Standard Dose

After PSM, the two groups showed no significant differences in nearly every measure of safety and effectiveness:

1. Heart Protection Was Identical

Cardiac enzymes: Pre- and post-operative levels of CK, CK-MB, and lactate dehydrogenase (LDH)—markers of heart injury—were the same.
Complications: Rates of arrhythmias, low cardiac output syndrome, or delayed sternal closure were identical.
Spontaneous re-beating: 100% of patients in both groups had their hearts restart naturally after clamp removal—no extra intervention needed.

2. Recovery and Safety Matched

Electrolytes: No differences in sodium, potassium, or calcium levels—even with higher HTK doses. Concerns about hyponatremia (low sodium) were unfounded.
Blood products: Use of red blood cells, platelets, and plasma was similar between groups.
Recovery times: Ventilation duration (≈50 hours), ICU stay (≈5–6 days), and hospital stay (≈13–14 days) were identical.

3. Long-Term Heart Function Was Comparable

Follow-up echocardiograms at 1 month, 3–6 months, and 1 year showed no differences in left ventricular ejection fraction (how well the heart pumps) or end-diastolic dimension (heart size). The only minor difference was a slightly larger left ventricle in the HD group at 1 month—but this resolved over time.

Why This Matters: Flexibility for Clinicians, Safety for Newborns

HTK works by two key mechanisms:

Low sodium/calcium: Reduces cell swelling and calcium overload, which damage the heart during ischemia.
Strong buffer (histidine): Neutralizes acid buildup from anaerobic metabolism, extending protection without repeated dosing.

For neonates, adequate perfusion pressure is critical—small coronary arteries mean HTK must reach every part of the heart to prevent damage. This study confirms that increasing HTK dose to maintain pressure doesn’t compromise safety.

Importantly, the team addressed two major concerns with high-dose HTK:

Hyponatremia: No significant drop in sodium levels, even with higher doses. HTK is iso-osmotic (matches body fluid pressure), so it doesn’t cause dangerous fluid shifts.
Hemodilution: A cell saver removed excess HTK, and ultrafiltration concentrated blood after surgery—keeping hematocrit (red blood cell count) within safe ranges.

Limitations to Consider

Like all retrospective studies, this one has caveats:

Bias: Retrospective design means researchers relied on existing data, not random assignment. PSM reduced bias but couldn’t eliminate it entirely.
Small sample: Only 146 patients (88 after PSM) from a single center—results may not generalize to all hospitals.
Missing data: The team couldn’t compare exact perfusion times or pressures between groups, which could affect outcomes.

Conclusion: High-Dose HTK Is a Safe Option for Neonates

For clinicians performing neonatal heart surgery, this study is a game-changer. High-dose HTK (>60 mL/kg) is just as safe and effective as the standard dose—providing flexibility to adjust dosing for better perfusion without risking complications.

The results fill a critical gap in neonatal care, where every milliliter of cardioplegia matters. While larger, multi-center randomized trials are needed to confirm these findings, this work gives surgeons confidence to tailor HTK use to each baby’s unique needs.

This study was conducted by Li-Ting Bai, Yuan-Yuan Tong, Jin-Ping Liu, and colleagues from the Department of Cardiopulmonary Bypass and State Key Laboratory of Cardiovascular Disease at Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. It was published in the Chinese Medical Journal in 2021.

To read the full study, visit doi.org/10.1097/CM9.0000000000001643

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