Hypothermia vs Normothermia in neonatal Arterial Switch Operation – Clinical outcomes and Myocardial preservation

doi:10.21203/rs.3.rs-4831073/v1

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Hypothermia vs Normothermia in neonatal Arterial Switch Operation – Clinical outcomes and Myocardial preservation

https://doi.org/10.21203/rs.3.rs-4831073/v1

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Objectives:

This study aims to compare the immediate postoperative clinical and laboratory outcomes, specifically focusing on the extent of cardiomyocyte death, between hypothermic (28°C) and normothermic (34–36°C) cardiopulmonary bypass in neonates undergoing arterial switch operation.

Methods:

A retrospective analysis was conducted on neonates who underwent arterial switch operation at the Edmond and Lily Safra Children's Hospital between July 2017 and December 2018. Patients were divided into two groups based on the cardiopulmonary bypass temperature strategy. Clinical, demographic, biochemical, and surgical data were collected, including cell-free DNA concentrations at multiple time points. Statistical analyses were performed to compare the outcomes between the two groups.

Results:

The study included 27 patients, with 12 in the hypothermia group and 15 in the normothermia group. Significant differences were found in cardiopulmonary bypass and aortic cross-clamp times, with longer durations in the nypothermia group (p < 0.001). Postoperative maximal lactate and Troponin-I levels were higher in the hypothermia group (p = 0.028 and p < 0.001, respectively). The normothermia group showed a higher incidence of acute kidney injury (p = 0.004). No significant differences were observed in total cell-free DNA levels between the groups, except for higher cardiac cell-free DNA at 24 hours in the hypothermia group (p = 0.002).

Conclusions:

Normothermia during cardiopulmonary bypass is associated with shorter operative times, lower metabolic stress, and reduced myocardial injury compared to hypothermia. Despite a higher incidence of acute kidney injury, normothermia demonstrates comparable safety and may offer benefits in myocardial preservation during neonatal arterial switch operation.

Cardiopulmonary Bypass

Transposition of the Great Arteries

Arterial Switch Operation

Hypothermia

Normothermia

Myocardial Preservation

The management of cardiopulmonary bypass (CPB) temperature during pediatric cardiac surgery, particularly for neonates, represents a critical juncture in the evolution of surgical techniques aimed at optimizing patient outcomes [1–5]. The debate between the use of hypothermic and normothermic strategies has been longstanding, rooted in the historical preference for hypothermia to reduce metabolic demand and enhance safety margins during unforeseen complications [1–3].

Hypothermia during CPB, traditionally favored for its role in lowering metabolic rates and protecting vital organs against ischemic injuries, has been a cornerstone in pediatric cardiac surgery [4, 5]. The rationale behind this approach is to afford a margin of safety against ischemic damage by reducing the body's oxygen requirements, a strategy that has also been linked to a diminution in the inflammatory response to CPB. However, the adverse effects of hypothermia, affecting a broad spectrum of tissues and organ systems, have been increasingly recognized for their potential to negatively impact clinical outcomes [6].

In contrast, normothermia during CPB has been progressively explored as an alternative method, with the hypothesis that maintaining physiological body temperatures might mitigate some of the detrimental effects associated with hypothermic bypass, including coagulopathy, vasoconstriction, and altered pharmacokinetics [7–10]. Early studies in adults suggested improved clinical outcomes and reduced organ dysfunction with normothermic CPB compared to hypothermic strategies, prompting inquiries into its applicability in pediatric populations [9].

Transposition of the great arteries (TGA) is a congenital pediatric cardiac defect arising from an embryological discordance between the aorta and pulmonary trunk. In the United States, the prevalence of TGA is 4.7 per 10,000 live births with national estimation of 1900 annual cases. TGA accounts for three percent of all congenital heart disease and 20 percent of cyanotic heart disease [10].

The arterial switch operation (ASO) has emerged as the established method for repairing TGA, yielding promising early and sustained outcomes. Initially introduced by Adib Jatene and Magdi Yacoub in the mid-1970s, ASO has evolved into a consistently replicable surgical approach. In the contemporary setting, the perioperative mortality rate associated with ASO ranges from 2.0–7.5%, influenced by factors such as the anatomical intricacy, the preoperative condition of the patients, and the specifics of coronary anatomy [11, 12]. At first the standard perioperative strategy consisted of deep hypothermic circulatory arrest (DHCA). With more experience, however, this strategy was modified to use deep hypothermic low-flow bypass with DHCA reserved for concomitant aortic arch pathology only [13]. Supported by refinements in CPB techniques and routine neonatal surgical management in recent years there are growing opinions for using CPB with full flow normothermia during ASO [14, 15]. However, only few data on early and late results comparing CPB under different temperature protocols are available thus far [16–18].

This study seeks to explore the immediate post operative clinical and laboratory outcomes with special attention to the magnitude of cardiomyocyte death as expressed by tissue specific cell free DNA (cfDNA) in normothermic versus hypothermic CPB ASO patients.

Study Design and Population: This retrospective study was designed to compare the outcomes between neonates undergoing ASO managed under two distinct temperature protocols: hypothermia (HT-CPB, 28°C) and normothermia (NT-CPB, 34–36°C). The study cohort consisted neonates who underwent ASO with CPB at the Edmond and Lily Safra Children's Hospital between July, 2017 and December, 2018 with previously collected cfDNA levels. Inclusion criteria for the cfDNA data-bank were pediatric patients (age < 18 years) undergoing cardiac surgery with CPB. Patients were excluded if they had pre-existing conditions that could independently affect cfDNA concentrations, such as systemic infections or autoimmune diseases. Temperature strategy was determined according to the surgeon preferences.

Data Collection

Clinical, demographic, biochemical and surgical data were collected for each patient, including gender, diagnosis, age, weight, pre-operative mechanical ventilation (MV), use of prostaglandin E (PGE), oxygen saturation (O2Sat) and balloon atrial septostomy (BAS). Intraoperative data such as CPB time, aortic cross-clamp time (XCLMP) and minimum temperature were also recorded. Post operative maximal lactate, maximal Troponin-I, maximal vasoactive inotropic score (VIS), MV duration, acute kidney injury (AKI) using Kidney Disease Improving Global Outcomes (KDIGO) score, pediatric intensive care unit (PICU) length of stay (LOS) as well as extracorporeal membrane oxygenation (ECMO) use and death. cfDNA concentrations before surgery as well as at PICU admission after the surgery (Time 0), 6 hours (Time 6), 12 hours (Time 12), and 24 hours (Time 24) post-surgery for both total and cardiac cfDNA.

Statistical Analysis

Continuous variables, including cfDNA concentrations and patient characteristics, were summarized using mean and standard deviation (SD) for normally distributed data, and median with interquartile range (25%-75%) for non-normally distributed data. Categorical variables, such as gender, diagnosis, and KDIGO status, were presented as counts and percentages.

The study groups (HT-CPB vs. NT-CPB) were compared using independent samples t-tests for continuous variables and chi-square tests for categorical variables. Interval changes in cfDNA concentrations (Time 6 - Time 0, Time 12 - Time 6, Time 24 - Time 12) were calculated and analyzed to understand the dynamics of cfDNA release and clearance over time. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using Python's scientific computing libraries.

Ethics

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) at Sheba Medical Center. Informed consent was obtained from parents or legal guardians. All patient data were de-identified to ensure confidentiality.

A total of 27 patients, with 12 (44%) in the HT-CPB group and 15 (56%) in the NT-CPB group. The gender distribution showed 58% males in the HT-CPB group and 40% in the NT-CPB group. No statistically significant differences were observed in the demographic and pre-operative characteristics between the groups (Table 1).

Table 1

Demographic and pre-operative characteristics of the Hypothermia and Normothermia groups.
Parameter		HT-CPB (n = 12)	NT-CPB (n = 15)	P Value
Gender, male		7 (58%)	6 (40%)	0.634
Diagnosis	TGA	9 (75%)	12 (80%)	1.000
Diagnosis	TGA/VSD	3 (25%)	3 (20%)	1.000
Pre-Operative MV		3 (25%)	3 (20%)	1.000
Pre-Operative PGE		9 (75%)	0 (0%)	0.150
Pre-Operative BAS		0 (0%)	3 (20%)	0.304
Pre-Operative O2Sat (%)		80.92 (6.78)	81.20 (4.72)	0.899
Operation Weight (gram)		3008.33 (481.36)	3168.00 (553.95)	0.438
Operation Age (days)		6.75 (3.65)	8.27 (3.26)	0.265
HT-CPB, Hypothermia during Cardiopulmonary bypass; NT-CPB, Normothermia during Cardiopulmonary bypass; TGA, Transposition of the Great Arteries; VSD, Ventricular Septal Defect; MV, Mechanical Ventilation; PGE, Prostaglandin; BAS, Balloon Atrial Septostomy
Parameters are presented as mean (standard deviation) or counts(percentages) unless stated otherwise.

Intra-Operative characteristics

Significant differences were noted in the duration of CPB and XCLMP, with the HT-CPB group showing longer durations compared with the NT-CPB group (116.00 ± 20.15 min vs 71.93 ± 28.49 min and 96.92 ± 21.66 min vs 54.73 ± 32.24 min respectively), p < 0.001 for both parameters.

Post-operative characteristics

Maximal lactate and Troponin-I levels were significantly higher in the HT-CPB group compared to the NT-CPB group (p = 0.028 and p < 0.001, respectively). There was a significant difference (p = 0.004) in the distribution of KDIGO scores between the groups with higher incidence in the NT-CPB group. The vasoactive inotropic score (VIS) and MV time were higher in the HT-CPB group, although not reaching statistical significance for VIS (p = 0.065). There were no differences in PICU LOS. No cases of delayed sternal closure, ECMO support or death were recorded in any group. Both intra-operative and post-operative characteristics are presented in Table 2.

Table 2

Intra-operative and post-operative characteristics of the Hypothermia and Normothermia groups.
Parameter	HT-CPB (n = 12)	NT-CPB (n = 15)	P Value
CPB (min)	116.00 (20.15)	71.93 (28.49)	< 0.001
XCLMP (min)	96.92 (21.66)	54.73 (32.24)	< 0.001
Max Lactate (mg/dL)	65.33 (12.43)	51.00 (18.11)	0.028
Max Troponin (	15.37 (1.55)	10.57 (2.83)	< 0.001
Max VIS	17.87 (5.75)	14.47 (3.35)	0.065
MV time (hours)	34.83 (12.83)	28.47 (12.60)	0.207
KDIGO	0: 9 (75%) 1: 3 (25%) 2: 0 (0%)	0: 2 (13.33%) 1: 11 (73.33%) 2: 2 (13.33%)	0.004
Delayed sternal closure	0 (0%)	0 (0%)	1.000
ECMO support	0 (0%)	0 (0%)	1.000
PICU LOS (days)	7.25 (1.14)	7 (1.41)	0.620
Death	0 (0%)	0 (0%)	1.000
HT-CPB, Hypothermia during Cardiopulmonary bypass; NT-CPB, Normothermia during Cardiopulmonary bypass; MV, Mechanical Ventilation; XCLMP, Aortic Cross Clamp; VIS, Vasoactive Inotropic Score; KDIGO, Kidney Disease Improving Global Outcomes; ECMO, Extracorporeal Membrane Oxygenator; PICU, Pediatric Intensive Care Unit; LOS, Length of Stay
Parameters are presented as mean (standard deviation) or counts (percentages) unless stated otherwise.

Cell-free DNA Dynamics

cfDNA dynamics, detailed in Table 3, revealed no significant difference in all time points for total cfDNA levels between the HT-CPB and NT-CPB groups. However, the interval change in total cfDNA from time 6 to 0 hours was significantly different (p = 0.034), with the HT-CPB group showing an increase and the NT-CPB group a decrease in number of copies/ml. Cardiac cfDNA levels also did not differ significantly at the measured time points between groups, except at 24 hours, where the HT-CPB group exhibited significantly higher levels than the NT-CPB group (p = 0.002) (Fig. 1).

Table 3

Comparison of cell free DNA dynamics between the Hypothermia and Normothermia groups.
Parameter	HT-CPB (n = 12)	NT-CPB (n = 15)	P Value
Total cell free DNA (copies/ml)
Time 0	44605.08 (34343.41)	41420.14 (22258.14)	0.773
Time 6	51035.55 (58044.90)	27877.14 (10845.04)	0.141
Time 12	12541.03 (10136.92)	11421.49 (4695.58)	0.706
Time 24	9350.96 (4449.82)	8131.24 (3615.49)	0.439
Interval 6 − 0	6430.47 (28064.73)	-13543.00 (18231.08)	0.034
Interval 12 − 6	-38494.52 (48169.77)	-16455.65 (10639.38)	0.096
Interval 24 − 12	-3190.08 (7151.75)	-3290.25 (4787.98)	0.966
Cardiac cell free DNA (copies/ml)
Time 0	5960.78 (3907.27)	6356.51 (3754.62)	0.791
Time 6	6601.87 (7996.76)	4687.13 (2256.91)	0.383
Time 12	1361.35 (466.09)	1185.95 (521.88)	0.372
Time 24	783.20 (482.23)	343.53 (41.52)	0.002
Interval 6 − 0	641.09 (4246.98)	-1669.38 (3305.06)	0.124
Interval 12 − 6	-5240.52 (7686.55)	-3501.17 (2158.37)	0.409
Interval 24 − 12	-578.15 (613.25)	-842.42 (511.03)	0.233
HT-CPB, Hypothermia during Cardiopulmonary bypass; NT-CPB, Normothermia during Cardiopulmonary bypass
All parameters are presented as mean (standard deviation).

Comparing the cell-free DNA levels between two groups of neonates undergoing Arterial Switch Operations, demonstrated that cfDNA levels in the normothermia group were similar to those in the hypothermia group. This indicates that from the cardiac preservation perspective, normothermia is a viable alternative.

The management of cardiopulmonary bypass temperature during pediatric cardiac surgery has been a subject of ongoing debate, with varying practices across institutions [19–21]. Our study aimed to compare the outcomes of normothermic with hypothermic CPB in pediatric patients undergoing the arterial switch operation, with and without VSD closure. Both CPB and XCLMP durations were longer and maximal lactate and troponin-I were higher in the HT-CPB group. Maximal VIS and duration of MV were also higher in this group but without statistical significance. All that in the light of indifferent cardiomyocyte damage as evident by the level of cfDNA.

Intra-operative Parameters

The observation that normothermia during CPB resulted in shorter CPB and XCLMP compared to hypothermia invites a nuanced discussion about the potential mechanisms as well as implications of these findings. While surgeon differences may contribute to the duration of the surgery, the time needed to safely cool and subsequently rewarm the patient must be factored into the total CPB time. The traditional rationale for hypothermia in CPB has been its neuroprotective effects through reduced metabolic demand (7,20,21). However, if normothermia can achieve shorter operative times without compromising patient safety or outcome, it may prompt a reevaluation of temperature management practices during CPB.

Hemodynamic Stability and Recovery [9, 22–24].

Normothermia was associated with improved hemodynamic stability, as evidenced by lower maximal lactate levels and a trend towards lower VIS in the NT-CPB group [25]. This suggests better myocardial function and less dependence on inotropic support, potentially translating to a quicker recovery. In addition, our findings indicate that troponin levels, while elevated post-operatively in both groups, suggest a nuanced interplay between CPB temperature and myocardial preservation [15]. The comparative analysis revealed lower troponin release in the normothermic group. This pattern may suggest that normothermia, by maintaining closer alignment with physiological body temperatures, potentially aids in preserving myocardial integrity during the stress of cardiac surgery which leads to favorable hemodynamics post-surgery. This is in line with the observation of shorter MV time for normothermic patients, indicating not just a faster recovery trajectory but also an implication of cost-effectiveness and reduced healthcare resource utilization.

Higher KDIGO Scores in Normothermia

The higher incidence of AKI in patients undergoing normothermic CPB, as indicated by KDIGO scores, contrasts with the otherwise compelling advantages of normothermia, including reduced oxidative stress, improved myocardial protection, and enhanced clinical outcomes [23, 24]. This discrepancy underscores the complex interplay between CPB temperature management and renal outcomes. AKI in the context of CPB is multifactorial, influenced by factors such as hemodynamic instability, inflammatory responses, and oxidative stress, all of which can affect renal perfusion and function [26]. The higher KDIGO scores in the normothermia group suggest a potential vulnerability of the kidneys under normothermic conditions that merits further investigation.

The Novelty of cfDNA Dynamics in temperature management.

The novel investigation into cfDNA as a marker for cellular damage during CPB represents a significant leap in understanding the physiological underpinnings of temperature management strategies in pediatric cardiac surgery [27–29]. cfDNA levels, which rise in response to cellular injury, offer a unique window into the systemic impact of surgical interventions. The comparative analysis of cfDNA levels between NT-CPB and HT-CPB groups underscores a critical insight: normothermia maintains cellular integrity to a degree previously underestimated. By demonstrating the non-inferiority of normothermia in preventing cell death, this research may support the narrative shift towards a broader appreciation of physiological resilience under normothermic conditions. This pioneering perspective encourages a rethinking and reevaluation of clinical practices, advocating for further research of normothermic approach as not only a viable but an advantageous strategy for managing patients undergoing CPB.

Future Research Directions

The potential superiority or at least non-inferiority of normothermia in neonatal arterial switch operations invites further exploration. Future research should endeavor to include larger, multi-center datasets to affirm these findings' generalizability and investigate long-term outcomes beyond the immediate postoperative period, including central nervous system function and neurodevelopmental outcome which have not been addressed at out study. Additionally, a more granular analysis of the mechanisms underpinning normothermia's effects could uncover actionable insights for refining surgical protocols and enhancing patient care.

Our analysis provides cautious insight towards support of normothermia (34–36°C) as a viable and potentially superior temperature management strategy during neonatal arterial switch operation, compared to hypothermia (28°C) from the hemodynamic and cardiac preservation stand point. Given its comparable safety profile regarding cellular stress along with the theoretical benefits derived from broader clinical and laboratory studies, normothermia emerges as an appealing option for neonatal cardiac care. Personalized decision-making, grounded in a deep understanding of each patient's clinical landscape, remains paramount as the field moves towards optimizing outcomes in this vulnerable population.

Competing Interests:

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethics approval:

The study protocol (cfDNA bank) was approved by the Chaim Sheba Medical Center Institutional Review Board (#4993-18-SMC). Informed consent was obtained from parents or legal guardians.

Funding:

The authors did not receive support from any organization for the submitted work.

Author Contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by U.P., A.M., H.A. and S.W. D.M. and A.E.S. supervised and consulted during preparation of the manuscript. The first draft of the manuscript was written by Y.L., Y.S., H.Z. and E.K. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at the Hebrew University of Jerusalem, Israel.

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You are reading this latest preprint version

Hypothermia vs Normothermia in neonatal Arterial Switch Operation – Clinical outcomes and Myocardial preservation

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Conclusions:

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Results

Discussion

Conclusion

Declarations

Competing Interests:

Funding:

Author Contribution

Data Availability

References

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Status:

Version 1