Risk Factors for Neurological Injury Following Neonatal Cardiac Surgery are Multi-Factorial and Interrelated Making Interventional Targets Difficult to Identify

Susan Nicolson, Lindsey Loveland, Viviane Nasr, James DiNardo

Original article

Starr JP, Karamlou T, Steele A, Artis AS, Rajeswaran J, Salim Hammoud M, Gates RN. Temperature and Neurologic Outcomes in Neonates Undergoing Cardiac Surgery: A Society of Thoracic Surgeons Study. J Am Coll Cardiol. 2024 Jul 30;84(5):450-463. doi: 10.1016/j.jacc.2024.04.059. PMID: 39048277.

Editorial Comment:

DiNardo JA. Nadir Temperature During Neonatal Cardiac Surgery and Neurologic Outcome. J Am Coll Cardiol. 2024 Jul 30;84(5):464-466. doi: 10.1016/j.jacc.2024.05.040. PMID: 39048278.

There is variability in the incidence of postoperative neurologic injury in neonates after cardiac surgery (2-11%).  Early injury impacts long-term neurodevelopmental outcomes, with mild to severe impairment in 30-50% of patients.  Investigators continue to examine modifiable factors to mitigate such injury.  Over time there has been a gradual reduction in the nadir of intraoperative temperature (NIT) during neonatal cardiac surgery.  This is in part due to increased use of cerebral perfusion (CP) to perfuse the brain and provide systemic flow during deep hypothermia to minimize the adverse effects of deep hypothermic circulatory arrest (DHCA).   Utilization of CP has resulted in the use of warmer temperatures despite no accepted standard for temperature, CP flow or pH management. Studies comparing DHCA to CP have found equivocal results regarding neurological outcomes.^1,2    Starr and colleagues³ sought to access the association between NIT and early neurologic outcomes.  Retrospective analysis was done on 24,345 neonates (<30 days of age) undergoing cardiac procedures at 125 centers with wide variability in the use and details of cardiopulmonary bypass (CPB), DHCA, and CP whose data was entered into The Society for Thoracic Surgeons - Congenital Heart Database between 2010-2019.  The primary outcome was a binary collapsed composite composed of persistent neurologic deficit at discharge, seizure and/or stroke.  Neonates with one of these events were classified as having experienced the primary endpoint.  NIT was analyzed categorically at deep hypothermia (<20 degrees C), moderate hypothermia (20.1-28.0 degrees C), mild hypothermia (28.1-34.0 degrees C) and normothermia (>34.1 degrees C).  Temperatures were obtained from rectal, bladder or nasopharyngeal sites, each with their inherent issues. Neonates with temperatures < 15 degrees C were excluded.

Over the study interval NIT for the entire group increased from 23.9 degrees C to 25.6 degrees C. Use of DHCA decreased from 40% to 36% and the use of CP increased from 26% to 35%.  Only about half of the procedures included in the analysis required any substantial period of either DHCA or CP

Major neurological injury was found in 4.9% of the cohort, with variations based on surgical procedure.  The discrete patient and procedural factors that increased the risk of major neurologic injury were younger gestational age, younger age at surgery, undergoing Norwood procedure, longer CPB times and the presence of non-cardiac anomalies or chromosomal abnormalities.  After adjusting for risk NIT was not associated with major neurologic injury overall, but a lower NIT showed protective effect in neonates undergoing the Norwood procedure.  For neonates undergoing the Norwood procedure the odds ratio of neurologic injury was 2.2 time greater for procedures using normothermic perfusion than for those using deep hypothermia.  The risk of neurologic injury was mitigated by use of CP. 

Variable NIT does not address the important issue of the proportion of the operative procedure spent at the target temperature.  This study also fails to address the other components of cerebral and systemic perfusion management and their association with neurologic injury (see table).  The complex interplay between variables, of which NIT is but one, have not been sufficiently investigated by these authors or elsewhere. 

When attention is paid to oxygen delivery on CPB, the choice of NIT is significantly less important as regards risk of neurologic injury during procedures performed entirely on CPB than it is for procedures where isolation of the cerebral circulation using DHCA or CP or both is required for a bloodless surgical field.⁴  The one subgroup in whom lower core temperature was protective highlights the fact that temperature and perfusion strategies may need to be tailored to specific neonates and procedures.

To date no single intervention has been found to be superior to hypothermia in ameliorating or preventing ischemic injury to organs during periods of reduced or absent blood flow.  The trend to use higher NIT during neonatal cardiac surgery, particularly those in whom DHCA or CP is anticipated warrants close attention.  It would be a mistake to minimize the neuroprotective effects of hypothermia without careful analysis of how other changes in the conduct of DHCA or CP could either exacerbate or mitigate the neurologic injury associated with a higher NIT.

Table.  Management Considerations for DHCA and CP⁵

DHCA

Duration of cooling and rewarming on CPB in conjunction with DHCA

·       pH-stat or alpha-stat acid base management

·       use of normoxia or hyperoxia before and after DHCA

·       target hematocrit and oxygen delivery during procedure

Acceptable duration of DHCA at target NIT

·       NIRS - cerebral oxygen saturation decay slope and nadir

·       periods of DHCA interposed between period of reperfusion on CPB

CP

Flow rate for CP

·       empiric flow rate or rate guided by one of more of the following to prevent insufficient or excessive CBF

-          ipsilateral subclavian artery pressure

-          bilateral or unilateral transcranial Doppler flow in middle cerebral artery

-          bilateral or unilateral NIRS assessment of cerebral oxygen saturation

-          assessment of EEG activity

·       pH-stat or alpha-stat acid base management

·       use of normoxia or hyperoxia during CP

·       target hematocrit and oxygen delivery during procedure

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References:

1.           Algra SO, Jansen NJ, van der Tweel I, et al. Neurological injury after neonatal cardiac surgery: a randomized, controlled trial of 2 perfusion techniques. Circulation 2014;129(2):224-33. (In eng). DOI: 10.1161/circulationaha.113.003312.

2.           Goldberg CS, Bove EL, Devaney EJ, et al. A randomized clinical trial of regional cerebral perfusion versus deep hypothermic circulatory arrest: outcomes for infants with functional single ventricle. The Journal of thoracic and cardiovascular surgery 2007;133(4):880-7. (In eng). DOI: 10.1016/j.jtcvs.2006.11.029.

3.           Starr JP, Karamlou T, Steele A, et al. Temperature and Neurologic Outcomes in Neonates Undergoing Cardiac Surgery: A Society of Thoracic Surgeons Study. Journal of the American College of Cardiology 2024;84(5):450-463. (In eng). DOI: 10.1016/j.jacc.2024.04.059.

4.           Bojan M, Gioia E, Di Corte F, et al. Lower limit of adequate oxygen delivery for the maintenance of aerobic metabolism during cardiopulmonary bypass in neonates. British journal of anaesthesia 2020;124(4):395-402. (In eng). DOI: 10.1016/j.bja.2019.12.034.

5.           DiNardo JA. Nadir Temperature During Neonatal Cardiac Surgery and Neurologic Outcome. Journal of the American College of Cardiology 2024;84(5):464-466. (In eng). DOI: 10.1016/j.jacc.2024.05.040.