Subclinical Epilectic Seizures in Infants After Cardiac Surgery: Risk Factors and Association With Neurologic and Non-Neurologic Outcomes

Subclinical Epilectic Seizures in Infants After Cardiac Surgery: Risk Factors and Association With Neurologic and Non-Neurologic Outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Subclinical Epilectic Seizures in Infants After Cardiac Surgery: Risk Factors and Association With Neurologic and Non-Neurologic Outcomes Marco Ranucci, Massimo Mastrangelo, Federica Sperandeo, Martina Lodovici, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7867114/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Jan, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Background. Neonates and infants undergoing cardiac surgery are prone to cerebral injuries. Neuromonitoring with continuous conventional electroencephalography (cEEG) and/or amplitude integrated electroencephalography (aEEG) is able to detect subclinical abnormal cerebral patterns, especially seizures, which have been found to correlate with medium-long term neurocognitive deficits. The endpoints of this study are (i) to define a risk model for epilectic seizures (ES) and (ii) to investigate the relationship between ES and neurologic and non-neurologic outcomes. Methods . Retrospective analysis of 373 neonates and infants < year undergone cardiac surgery and receiving a pre/postoperative combined cEEG/aEEG exam. The risk factors for postoperative ES were investigated and pooled in a predictive model, and postoperative ES were assessed for association with neurologic and non-neurologic (major morbidity) postoperative patterns. Results. The independent risk factors for postoperative ES were the complexity of surgery (RACHS-2 score), an open sternum, and the hematocrit at the arrival in the intensive care unit. The predictive model based on these factors yielded a good discrimination (c-statistics 0.81). Postoperative ES were significantly associated with major non-neurologic morbidity, but once corrected for other confounding factors they lost significance. Conversely, postoperative ES were the only predictor of cerebral injuries, with an odds ratio of 8.0 (95% confidence interval 2.25-28.3, P=0.003). Conclusions. Postoperative ES are associated with an hemodynamic compromise and low arterial oxygen content, with a consequent inadequate oxygen delivery to the brain and other organs. In presence of these factors, EEG monitoring is useful for the early diagnosis of cerebral injuries in patients sedated and paralyzed. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience conventional electroencephalography amplitude integrated electroencephalography congenital heart surgery neonates infants seizures Figures Figure 1 Figure 2 Introduction Neurologic sequalae after cardiac surgery with or without cardiopulmonary bypass (CPB) in neonates and infants are relatively common. Early postoperative events include stroke, intraparenchymal hemorrhage, coma due to generalized hypoperfusion, and in neonates new brain injury is reported in up to 60% of the cases. 1 Long-term neuropsychological and cognitive deficits have been reported at variable rates in children with congenital heart disease (CHD) undergone cardiac surgery. 2 – 4 Neurological monitoring during and after cardiac surgery includes Near-Infrared Spectroscopy (NIRS) 5 , 6 , transcranial ultrasound 7 and Doppler 8 , and electroencephalography (EEG) 9 , 10 In this setting, the gold standard for epilectic seizures (ES) detection is the continuous conventional EEG (cEEG) but the amplitude-integrated EEG (aEEG) is more commonly applied before and after cardiac operation. aEEG is particularly useful to detect ES and background cerebral activity in neonates with different hypoxic-ischemic lesions. 11 , 12 In cardiac surgery patients subclinical ES were associated with early impairment of neurological outcome in arterial switch correction 13 , 14 Patients with hypoplastic left ventricle palliation and preoperative ES had long term neurocognitive impairment 15 . Overall, it seems well established that subclinical ES before and especially after cardiac surgery in neonates and infants are associated with bad short and long term neurological outcomes. 16 – 18 A recent guideline of the American Clinical Neurophysiology Society considers the neonates undergoing cardiac surgery for CHD as a risk category for subclinical ES, with a conditional recommendation (moderate quality of evidence) for continuous EEG monitoring. 19 Despite this, continuous EEG monitoring before and after cardiac surgery in congenital heart patients is far from being a routine clinical practice, and some authors have questioned the role of this technique 20 The purpose of this study is to investigate the clinical role of combined continuous conventional and amplitude EEG (cEEG/aEEG) monitoring in the setting of neonates and infants ≤ 1 year undergoing cardiac surgery for correction or palliation of CHD. The primary endpoint is the development of a risk model for subclinical ES after surgery to be applied for the selection of the patients deserving this technique, and the secondary endpoint is the determination of the outcome of patients experiencing subclinical ES after surgery. Methods Retrospective study based on our local database plus analysis of the cEEG/aEEG and clinical data recorded in our files. The sample size was based on the primary endpoint (development of a predictive model for postoperative ES). We considered a null hypothesis (no discrimination of the risk model) a c-statistics of 0.60 for, and a negation of the null hypothesis (satisfying discrimination of the risk model) a c-statistics of 0.80. The prevalence of postoperative ES was settled at 8.5% based on the existing literature. 13 With an alpha value of 0.01 and a beta value of 0.20, the sample size is 350 patients. The research was conducted at the IRCCS Policlinico San Donato, a Clinical Research Hospital partially funded by the Italian Ministry of Health. In this Institution, from January 2020 through May 2025 we have started a neurologic monitoring of neonates and infants ≤ 1 year, scheduled for surgical repair/palliation of congenital heart defects, by applying a video-cEEG/aEEG 21 . A total of 540 patients in this age segment were operated at our Institution, and due to the limited (2 devices) availability of the cEEG/aEEG in the intensive care unit (ICU) and the ward, 373 patients received a complete monitoring before and after surgery. This sample size satisfies the requirements of the power analysis. Preoperative cEEG/aEEG was performed either in the ward or ICU, usually within 24 hours before surgery. Postoperative cEEG/aEEG in the ICU was started from 2 hours up to 12 hours after completion of surgery and for at least 7 hours after surgery. For the purposes of the present analysis, we considered the pre and-postoperative cEEG/aEEG performed in the ICU. cEEG/aEEG data collection and definitions The combined cEEG/aEEG recordings were obtained with a Micromed 21-channel synchronized video-EEG machine (Micromed SystemPlus, Mogliano Veneto, Italy) at bedside in the neonatal/pediatric cardiac surgery ICU of our Institution. This device has a software which also displays in the monitor the aEEG traces in real time. The aEEG was derived from a two-channel recorder (C3-T3, C4-T4) and was displayed on a conventional semi-logarithmic scale (linear from 0 to 10 mV and logarithmic from 10 to 100 mV). The signal was then compressed to a rate of 6 cm/h. The electrodes were applied according to the International 10–20 System modified for neonates. In addition to scalp electrodes, extracerebral channels including electrocardiogram, electrooculogram, and surface electromyography were non-routinely monitored. Most postoperative traces were performed without video monitoring considering that the great majority of the patients were pharmacologically sedated and paralyzed. All the tracings were analyzed off-line by an experienced electroencephalographer and a neurologist (M.M.) according to standardized criteria. 22 In neonates, electrographic ES were adjudicated according to the following criteria: (i) a series of abnormal repetitive discharges with (ii) a demonstrable onset, time course with evolution in frequency and morphology, and (iii) a conclusion. The minimum duration of each ES was arbitrarily defined as 10 seconds, as historically reported by Clancy and Legido. 23 In infants, an ES was defined as a transient occurrence of abnormal excessive or synchronous neuronal activity in the brain with a clear start and finish. 24 Finally, the status epilecticus (SE) was defined as continuous ES lasting for 30 consecutive minutes, or ES recurrence present in > 50% of a 1-hour recording. 25 Clinical data collection and definitions The following preoperative data were retrieved from our institutional database: demographics; laboratory exams (serum creatinine, serum bilirubin, and hematocrit [HCT]); previous cerebrovascular events; evidence of ES at the preoperative cEEG/aEEG exam; type of surgery (single or double ventricle; with or without aortic arch procedure) and weight of surgery based on the RACHS-2 score. 26 CPB details included: on pump or off-pump; roller or centrifugal pump; priming volume; priming nature; nadir temperature on CPB; nadir hematocrit on CPB; CPB duration; aortic cross-clamp duration. Data at the arrival in the ICU included an arterial blood gas analysis with measurement of mean arterial pressure; central venous pressure; heart rate; HCT; temperature; and arterial blood lactate. The outcome was assessed in terms of neurologic complications (ischemic/hemorrhagic stroke; coma) adjudicated based on clinical signs and documented by imaging; and non-neurologic complications defined as a composite outcome of major morbidity. Major morbidity was adjudicated in presence of one or more of the following: acute kidney injury (defined base on the pROCK criteria 27 ); surgical revision; need for tracheostomy, deep sternal wound infection; need for extracorporeal membrane oxygenation (ECMO). Statistical analysis Categorical data are presented as number (%); continuous variables are presented as mean (standard deviation) or median (interquartile range) according to the normality of distribution. At an univariate analysis, the differences between groups (with or without ES) were investigated with a Pearson’s chi squared for binary variables and a Student’s t test or nonparametric tests for continuous variables. Multivariable logistic regression analyses were applied to identify the independent association of different variables with the dependent variable of interest (ES and neurologic/non neurologic morbidities), producing odds ratios with 95% confidence interval. The predictive model for ES was tested for accuracy (discrimination) and calibration. A receiver operating characteristics (ROC) analysis was applied producing a c-statistics, where an acceptable discrimination was defined for a c-statistics 0.70–0.75, a good discrimination for a c-statistics > 0.75 and ≤ 0.8, and a very good discrimination for a c-statistics > 0.8. The c-statistics was reported with the 95% confidence interval. This value was subsequently checked with a bootstrapping process (1,000 iterations). Different cut-off values were investigated for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Calibration of the model was checked with the Hosmer-Lemeshow statistics and calibration plot. All the statistical analyses were conducted using computerized statistical programs (SPSS 20.0, IBM, Chicago, IL, GraphPad, GraphPad Software, Inc, San Diego, CA, MedCalc, MedCalc Software, Ostend, Belgium). A p-value < 0.05 was considered significant for all the statistical tests. Ethics statements The Ethics Committee of San Raffele Hospital approved this study (CET331-2025) and waived the need for a written informed consent and all the parents of the patients gave a general consent for the scientific treatment of clinical data in an anonymous form. The study was conducted according to the relevant existing guidelines. Data availability All data are in a local repository and available at reasonable request Results The EEG monitoring was initiated after a median time of 4 hours (interquartile range 2–8 hours) after arrival in the ICU, and was continued for a median time of 18 hours (interquartile range 14–22 hours). Overall, 23 patients (6.2%) developed postoperative ES, and 11 (2.9%) exhibited a pattern of an SE. Before surgery, 11 (2.9%) patients had ES (3 with SE), and 3 (0.8%) showed both pre and postoperative ES. Table 1 reports the preoperative details of the patient population, including demographics, laboratory exams, co-morbidities, operative and CPB details, and early data at the arrival in the ICU. Patients with ES had a number of factors significantly different from patients without ES: a higher rate of pre-surgery subclinical ES; a lower baseline HCT, a higher RACHS-2 score, a higher rate of aortic arch surgery, a longer CPB duration, a higher rate of patients where the sternum was left open, a higher arterial lactate value and a lower HCT at the arrival in the ICU. To identify the factors independently associated with postoperative subclinical ES, the above listed factors were entered into a multivariable, stepwise forward logistic regression, whose details are shown in table 2. The independent factors associated with postoperative subclinical ES were: a higher RACHS-2, the open sternum, and a lower HCT at the arrival in the ICU. Based on the parameters reported in table 2, a predictive equation was developed and is reported in Fig. 1 . This relationship had a good calibration (Hosmer-Lemeshow test chi squared 9.2, P = 0.325) between expected and observed ES events, and a very good discrimination, with a c-statistics of 0.816 (95% confidence interval 0.75–0.88, P = 0.001) (Fig. 2 ). Based on the parameters of this equation, different cut-offs were identified, with the respective sensitivity, specificity, NPV and PPV shown in table 3. The univariate association between cEEG/aEEG ES and neurologic / non-neurologic outcomes is reported in table 4. ES are significantly (P = 0.005) associated with neurologic outcome at the univariate analysis; within a multivariable logistic regression model no other perioperative factor was associated with the neurologic outcome, and the ES remained the only factor independently associated with the neurologic outcome, showing an odds ratio of 8.0 for any kind of postoperative neurologic events. ES are significantly associated with non-neurologic major morbidity and with some of its components (tracheostomy, surgical revision, ECMO) and with hospital mortality. However, after correction for other possible factors associated with major morbidity (RACHS-2, open sternum, and CPB duration), the presence of postoperative cEEG/aEEG-documented ES does not maintain its properties as a factor significantly and independently associated with major morbidity. Discussion The prevalence of postoperative ES The rate of postoperative ES (6.2%) found in our series is consistent with what reported by other authors in similar series. Actually, the reported rate of postoperative ES greatly varies depending on the age and type of procedure (basically, with or without deep hypothermic cardiac arrest [DHCA]). In series limited to neonates, a higher rate is reported, with a prevalence of 18% in patients with hypoplastic left heart syndrome submitted to Norwood operation 17 and 17–19% in neonates undergoing any kind of cardiac surgery. 1 , 28 When infants of higher age and/or surgery of any kind are included, the rate of postoperative ES is lower: 2.5% in infants and children 20 ; ; 7.4% in neonates receiving cardiac surgery of any type 16 , 8–13% in neonates and infants receiving any kind of cardiac surgery. 13 , 29 In a setting similar to our series, the reported postoperative ES rate is 7%. 4 Of notice, the studies reporting the highest rate (20–30%) of subclinical ES are those including ECMO patients only. 30 – 32 Globally, given the relatively low rate of postoperative ES, and the requirement of considerable technical and human resources for implementing a program of cEEG/aEEG monitoring, the need for selection criteria appears motivated and is the object of our primary endpoint. Risk factors and risk model For our primary endpoint, we found 3 factors being independently associated with postoperative ES: RACHS-2, open sternum, and ECMO at the arrival in the ICU. The risk factors for postoperative ES have been previously investigated by other authors 3 , 4 , 13 and a risk model has been proposed. 16 Latal and associates 4 found that only some ICU outcome parameter (length of mechanical ventilation and ICU stay) were associated with ES, while CPB duration, lowest temperature on CPB, and peak lactate were not. In a series of neonates and infants, Gaynor and associates 13 found a significant association between postoperative ES and type of surgery (namely, aortic arch and DHCA), DHCA duration, and CPB duration. Interestingly, they could not find any association with delayed sternal closure or need for ECMO, but in both cases there was a non-significant trend that would probably become significant in a larger series. Finally, the most relevant study appears to be that of Naim and associates 16 , who developed and validated a predictive risk model in a large series of neonates. The ES prevalence was 7.9% in the derivation cohort and 6.3% in the validation cohort. In their multivariable model, the independent factors for postoperative ES were the gestational age, the head circumference, a single ventricle, DHCA duration, use of nitric oxide in the operating room (OR), cardiac arrest, ECMO, and open sternum in the OR. The derivation cohort had a good discrimination (c-statistics 0.77), but in the validation cohort this value decreased to a poor c-statistics of 0.61. There are major differences between our approach and those applied by the other authors. The first and most important is the use of a combined cEEG and aEEG in all the patients. It is commonly accepted that aEEG has a lower sensitivity for seizure detection in neonates with respect to cEEG 33 . The combined use of both techniques allows to overcome this limitation of the aEEG. We did collect a number of variables that were not considered in other studies. Among them, the preoperative and CPB characteristics included the preoperative serum creatinine and bilirubin and nadir HCT, type and volume of priming solution on CPB. The complexity of surgery was defined according to the RACHS-2 and the clinical (hematocrit, heart rate mean arterial and venous pressure, open sternum and ECMO), respiratory (PaO 2 and PaCO 2 ) and metabolic (pH, HCO 3 − , arterial lactates) conditions of the patients immediately at the arrival in the ICU were included in the analysis. As a consequence, our multivariable risk model included variables not considered by other authors (RACHS-2 and HCT at the arrival in the ICU) together with open sternum that was already observed in other studies. 16 Overall, our model offers interpretative insights: the 3 factors are representative of the complexity of surgery (RACHS-2) but even indirectly representative of the cardiac output (open sternum) and of the arterial oxygen content (HCT). The combination of these 2 parameters is the oxygen delivery (DO 2 ). In neonates and small infants, the cardiac output cannot be directly measured, and therefore the DO 2 as well. Therefore, the following considerations on DO 2 are a speculation based on indirect data. The open sternum is certainly a marker of a low cardiac function, and the HCT is a marker of the oxygen content. The combination of a low cardiac output and low hematocrit results in a low DO 2 . There are other data supporting this interpretation: at the univariate analysis the arterial lactates are significantly higher in patients with postoperative ES, therefore suggesting an inadequate DO 2 . Actually, a large study 29 could identify two predictors significantly and independently associated with postoperative ES, both clearly an expression of an inadequate cardiac output: arterial lactates and use of inotropic drugs. Other studies considered ECMO and open sternum as independent predictors of postoperative ES. 16 It is therefore possible to consider the postoperative ES as a consequence of a low cerebral DO 2 , even taking into account the temporal sequence (all the risk factors occur before the ES adjudication). Actually, other reports in different settings have shown a relationship between neonatal seizures and cerebral oxygenation assessed with the NIRS. 34 ES and outcome For our secondary endpoint, we found a univariate association between postoperative ES and neurologic complications. In a multivariable analysis, patients with postoperative ES had an 8-times higher risk of cerebral injury, yielding a PPV of 30% and an NPV of 95%. Non-neurologic bad outcomes, (major morbidity and mortality) were associated with postoperative ES in a univariate analysis, but after correction for potential confounders, only CPB duration, RACHS-2, and open sternum remained independently associated with major morbidity. So, the interpretation again focuses on the complexity of the procedure and a poor cardiac contractility. It is reasonable to attribute the higher rate of major morbidity to a poor hemodynamic state, with the postoperative ES being a marker of this condition. The great majority of the existing studies linked postoperative ES to long-term clinical conditions (neurocognitive impairment), but others addressed the hospital outcome. The link between EEG alterations and cerebral injury was denied by some authors 20 , but confirmed by others 1 , 14 , 29 in the surgical setting and in the ECMO setting. 31 , 35 Other non-neurologic bad outcomes have been reported in terms of longer mechanical ventilation and ICU stay 4 , 32 and mortality 17 . Is there a clinically relevant role of EEG monitoring in the setting of cardiac surgery in neonates and infants, and when should we consider to apply this technique? It must be admitted that the majority of the predictive risk models in medicine and surgery are actually of little clinical impact, being based on non-modifiable risk factors and rarely suggesting specific strategies. However, in this case the decision-making process could be facilitated by our risk analysis. Actually, there are suggestive risk factors, and possible cut-offs are presented in table 3: the important value to be considered in order not to miss the detection of postoperative ES is the NPV; a predictive cut-off at 35% probability maintains a good NPV (94%) and an acceptable PPV of 33% (about 5 times higher than the overall prevalence). Given the fact that EEG monitoring is not a routine technique, and that it requires a considerable amount of resources, a tool for selecting patients who most likely could benefit from this monitoring has a relevant impact. Considering the clinical role, postoperative ES have little or null usefulness as early signs of major morbidity. Actually, they are linked to a pattern of impaired hemodynamics, but the clinical signs of this pattern usually are evident immediately after the admission to the ICU, and often in the OR, and the postoperative ES are more a consequence than an early sign of impaired circulation and inadequate DO 2 . Things are different for neurologic injuries. As a matter of fact, the association between postoperative ES and cerebral injuries is strong, and they are the only independent factor linked to these complications. Considering that the great majority of neonates and infants are deeply sedated and paralyzed within the first 24 hours or postoperative days (especially in case of open sternum and ECMO), they cannot exhibit the clinical signs of cerebral injuries. In this setting, the finding of postoperative ES may prompt specific diagnostic imaging procedures, allowing an early diagnosis. This, in turn, may trigger therapeutic interventions aimed to contain the damage of a cerebral injury. There are limitations in our study. As per every retrospective study, the adjudication of clinical morbidity may not be totally reliable. Additionally, our risk model has not been validated in external series, and may lack some risk factors not retrievable from our database nor the patients’ files. Finally, there was no strict criteria for timing of first recording and duration of recording; practical issues (i.e. late arrival in the ICU) were determinant of this. As a consequence, we cannot exclude that an earlier and longer EEG monitoring could detect a higher rate of subclinical seizures. Conclusions Postoperative ES are a marker of an impaired circulatory pattern, probably through an inadequate oxygen supply to the brain. Their independent association with cerebral injury allows an early recognition of this complication. Abbreviations aEEG amplitude electroencephalography cEEG: conventional electroencephalography CHD: congenital heart disease CPB: cardiopulmonary bypass DHCA: deep hypothermic cardiac arrest DO 2 : oxygen delivery ECMO: extracorporeal membrane oxygenation ES: epilectic seizures HCT: hematocrit ICU: intensive care unit NIRS; near-infrared spectroscopy NPV: negative predictive value OR: operating room PPV: positive predictive value RACHS: risk stratification for congenital heart surgery ROC: receiver operating characteristics SE: status epilecticus Declarations The study was approved by the local Ethics Committee of Ospedale San Raffaele (CET331-2025) and, given the retrospective nature, written informed consent was waived. All data are in a local repository and available at reasonable request The authors declare that they have no conflict of interest The study was funded by institutional funds Author Contribution M.R. designed the study , led the data analysis, and wrote the first draft of the article; M.M. interpreted the EEG tracings; F.S. interpreted the EEG tracings; M.L. participated in literature retrieval and data analysis; R.L. participated in literature review and data analysis; T.A. critically revised the manuscript; M.A. participated in data collection and analysis; A.B. participated in data collection and analysis; A.G. critically revised the manuscript; G.I. participated in data collection and interpretation. Data Availability All data are in a local repository and available at reasonable request References Claessens, N. H. P. et al. Amplitude-Integrated Electroencephalography for Early Recognition of Brain Injury in Neonates with Critical Congenital Heart Disease. J. 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Rakshasbhuvankar, A. A., Nagarajan, L., Zhelev, Z. & Rao, S. C. Amplitude-integrated electroencephalography compared with conventional video-electroencephalography for detection of neonatal seizures. Cochrane Database Syst. Rev. 2025:11;8(8). Martini, S., Paoletti, V., Faldella, G. & Corvaglia, L. Cerebral Oxygenation Patterns during Electroclinical Neonatal Seizures. Neuropediatrics 50 , 408–409 (2019). Hanalioglu, D. et al. Neurophysiologic Features Reflecting Brain Injury During Pediatric ECMO Support. Neurocrit Care . 40 , 759–768 (2024). Tables Table 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table14.docx Cite Share Download PDF Status: Published Journal Publication published 09 Jan, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 01 Dec, 2025 Reviews received at journal 25 Nov, 2025 Reviews received at journal 21 Nov, 2025 Reviewers agreed at journal 31 Oct, 2025 Reviewers agreed at journal 31 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers invited by journal 29 Oct, 2025 Editor assigned by journal 29 Oct, 2025 Editor invited by journal 26 Oct, 2025 Submission checks completed at journal 23 Oct, 2025 First submitted to journal 23 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Ranucci","email":"data:image/png;base64,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","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":true,"prefix":"","firstName":"Marco","middleName":"","lastName":"Ranucci","suffix":""},{"id":538187707,"identity":"7301b49f-de80-43d3-a946-33876417919b","order_by":1,"name":"Massimo Mastrangelo","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Mastrangelo","suffix":""},{"id":538187708,"identity":"b7ddd8c8-5850-4065-add2-3b4151bdb41c","order_by":2,"name":"Federica Sperandeo","email":"","orcid":"","institution":"Alma Mater Studiorum – University of Bologna","correspondingAuthor":false,"prefix":"","firstName":"Federica","middleName":"","lastName":"Sperandeo","suffix":""},{"id":538187709,"identity":"4e26400f-dbc4-4a63-90d9-2a8225888f7f","order_by":3,"name":"Martina Lodovici","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Lodovici","suffix":""},{"id":538187710,"identity":"4f2985f3-26c6-4ff7-b448-f15d58a92efb","order_by":4,"name":"Rossana Lamastra","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Rossana","middleName":"","lastName":"Lamastra","suffix":""},{"id":538187711,"identity":"4f44a915-09df-4514-8731-a1d25bc5bed9","order_by":5,"name":"Tommaso Aloisio","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Tommaso","middleName":"","lastName":"Aloisio","suffix":""},{"id":538187712,"identity":"186deaee-f7a1-40ee-8d7f-c879096fbe9b","order_by":6,"name":"Martina Anguissola","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Anguissola","suffix":""},{"id":538187713,"identity":"0a966c3d-a049-4942-b9c3-5033e8128691","order_by":7,"name":"Alessandro Barbaria","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Barbaria","suffix":""},{"id":538187714,"identity":"31e6ccae-6255-4e47-86da-9deaf88b5b7d","order_by":8,"name":"Alessandro Giamberti","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Giamberti","suffix":""},{"id":538187715,"identity":"7838075a-f9ca-4a8f-8dd7-2344f237a470","order_by":9,"name":"Giuseppe Isgrò","email":"","orcid":"","institution":"IRCCS Policlinico San Donato, San Donato Milanese (Milan)","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"","lastName":"Isgrò","suffix":""}],"badges":[],"createdAt":"2025-10-15 10:38:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7867114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7867114/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-026-35059-7","type":"published","date":"2026-01-09T15:59:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95521798,"identity":"d89dc8ad-196c-44e3-8c08-8547d9fa6804","added_by":"auto","created_at":"2025-11-10 09:26:48","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":137894,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptEEGSciRep.docx","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/43f95178e1ef53af2acef430.docx"},{"id":95521793,"identity":"1bf98a23-295a-4dd1-9c87-d6f22388f5ac","added_by":"auto","created_at":"2025-11-10 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09:26:48","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":88001,"visible":true,"origin":"","legend":"","description":"","filename":"18e1c556fbd144f685d1c31730aafd4c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/d01e9ad1c4eba975156ca9a8.xml"},{"id":95521799,"identity":"23f852d7-3ed4-4bed-9551-b9a3468d1ceb","added_by":"auto","created_at":"2025-11-10 09:26:48","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99025,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/bbe8f5304c931ec1be053297.html"},{"id":95521792,"identity":"e76ccdb4-dcd2-4a1b-9f19-b912c316538e","added_by":"auto","created_at":"2025-11-10 09:26:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":24373,"visible":true,"origin":"","legend":"\u003cp\u003eCalibration plot of expected vs. observed epilectic seizures\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/6724e60cd38cf74b550449b5.png"},{"id":95521795,"identity":"3c3fae55-b896-4d52-b76d-9f89e94ae45a","added_by":"auto","created_at":"2025-11-10 09:26:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52852,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristics analysis of the discrimination properties of the risk model. Data in the text\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/df651a7d1478dd63a77a7fb6.png"},{"id":100070117,"identity":"7d9abd74-42cd-4b53-ba2a-fe41b5c050c2","added_by":"auto","created_at":"2026-01-12 16:16:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":716475,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/e43a5aac-8e6c-4881-ab85-f109d5877a2d.pdf"},{"id":95521794,"identity":"0dcc7469-c7d2-497e-90cc-27e4e71fe25e","added_by":"auto","created_at":"2025-11-10 09:26:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20696,"visible":true,"origin":"","legend":"","description":"","filename":"Table14.docx","url":"https://assets-eu.researchsquare.com/files/rs-7867114/v1/c431dbc8a5f4346253278f9a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSubclinical Epilectic Seizures in Infants After Cardiac Surgery: Risk Factors and Association With Neurologic and Non-Neurologic Outcomes\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurologic sequalae after cardiac surgery with or without cardiopulmonary bypass (CPB) in neonates and infants are relatively common. Early postoperative events include stroke, intraparenchymal hemorrhage, coma due to generalized hypoperfusion, and in neonates new brain injury is reported in up to 60% of the cases.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Long-term neuropsychological and cognitive deficits have been reported at variable rates in children with congenital heart disease (CHD) undergone cardiac surgery.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eNeurological monitoring during and after cardiac surgery includes Near-Infrared Spectroscopy (NIRS)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, transcranial ultrasound\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and Doppler\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, and electroencephalography (EEG)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e In this setting, the gold standard for epilectic seizures (ES) detection is the continuous conventional EEG (cEEG) but the amplitude-integrated EEG (aEEG) is more commonly applied before and after cardiac operation. aEEG is particularly useful to detect ES and background cerebral activity in neonates with different hypoxic-ischemic lesions.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e In cardiac surgery patients subclinical ES were associated with early impairment of neurological outcome in arterial switch correction\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Patients with hypoplastic left ventricle palliation and preoperative ES had long term neurocognitive impairment\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Overall, it seems well established that subclinical ES before and especially after cardiac surgery in neonates and infants are associated with bad short and long term neurological outcomes.\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e A recent guideline of the American Clinical Neurophysiology Society considers the neonates undergoing cardiac surgery for CHD as a risk category for subclinical ES, with a conditional recommendation (moderate quality of evidence) for continuous EEG monitoring.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Despite this, continuous EEG monitoring before and after cardiac surgery in congenital heart patients is far from being a routine clinical practice, and some authors have questioned the role of this technique\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe purpose of this study is to investigate the clinical role of combined continuous conventional and amplitude EEG (cEEG/aEEG) monitoring in the setting of neonates and infants\u0026thinsp;\u0026le;\u0026thinsp;1 year undergoing cardiac surgery for correction or palliation of CHD. The primary endpoint is the development of a risk model for subclinical ES after surgery to be applied for the selection of the patients deserving this technique, and the secondary endpoint is the determination of the outcome of patients experiencing subclinical ES after surgery.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eRetrospective study based on our local database plus analysis of the cEEG/aEEG and clinical data recorded in our files.\u003c/p\u003e\u003cp\u003eThe sample size was based on the primary endpoint (development of a predictive model for postoperative ES). We considered a null hypothesis (no discrimination of the risk model) a c-statistics of 0.60 for, and a negation of the null hypothesis (satisfying discrimination of the risk model) a c-statistics of 0.80. The prevalence of postoperative ES was settled at 8.5% based on the existing literature.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e With an alpha value of 0.01 and a beta value of 0.20, the sample size is 350 patients.\u003c/p\u003e\u003cp\u003eThe research was conducted at the IRCCS Policlinico San Donato, a Clinical Research Hospital partially funded by the Italian Ministry of Health. In this Institution, from January 2020 through May 2025 we have started a neurologic monitoring of neonates and infants\u0026thinsp;\u0026le;\u0026thinsp;1 year, scheduled for surgical repair/palliation of congenital heart defects, by applying a video-cEEG/aEEG\u003csup\u003e21\u003c/sup\u003e. A total of 540 patients in this age segment were operated at our Institution, and due to the limited (2 devices) availability of the cEEG/aEEG in the intensive care unit (ICU) and the ward, 373 patients received a complete monitoring before and after surgery. This sample size satisfies the requirements of the power analysis. Preoperative cEEG/aEEG was performed either in the ward or ICU, usually within 24 hours before surgery. Postoperative cEEG/aEEG in the ICU was started from 2 hours up to 12 hours after completion of surgery and for at least 7 hours after surgery. For the purposes of the present analysis, we considered the pre and-postoperative cEEG/aEEG performed in the ICU.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ecEEG/aEEG data collection and definitions\u003c/h2\u003e\u003cp\u003eThe combined cEEG/aEEG recordings were obtained with a Micromed 21-channel synchronized video-EEG machine (Micromed SystemPlus, Mogliano\u003c/p\u003e\u003cp\u003eVeneto, Italy) at bedside in the neonatal/pediatric cardiac surgery ICU of our Institution. This device has a software which also displays in the monitor the aEEG traces in real time.\u003c/p\u003e\u003cp\u003eThe aEEG was derived from a two-channel recorder (C3-T3, C4-T4) and was displayed on a conventional semi-logarithmic scale (linear from 0 to 10 mV and logarithmic from 10 to 100 mV). The signal was then compressed to a rate of 6 cm/h. The electrodes were applied according to the International 10\u0026ndash;20 System modified for neonates. In addition to scalp electrodes, extracerebral channels including electrocardiogram, electrooculogram, and surface electromyography were non-routinely monitored. Most postoperative traces were performed without video monitoring considering that the great majority of the patients were pharmacologically sedated and paralyzed.\u003c/p\u003e\u003cp\u003eAll the tracings were analyzed off-line by an experienced electroencephalographer and a neurologist (M.M.) according to standardized criteria.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e In neonates, electrographic ES were adjudicated according to the following criteria: (i) a series of abnormal repetitive discharges with (ii) a demonstrable onset, time course with evolution in frequency and morphology, and (iii) a conclusion. The minimum duration of each ES was arbitrarily defined as 10 seconds, as historically reported by Clancy and Legido. \u003csup\u003e23\u003c/sup\u003e In infants, an ES was defined as a transient occurrence of abnormal excessive or synchronous neuronal activity in the brain with a clear start and finish.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Finally, the \u003cem\u003estatus epilecticus\u003c/em\u003e (SE) was defined as continuous ES lasting for 30 consecutive minutes, or ES recurrence present in \u0026gt;\u0026thinsp;50% of a 1-hour recording.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical data collection and definitions\u003c/h3\u003e\n\u003cp\u003eThe following preoperative data were retrieved from our institutional database: demographics; laboratory exams (serum creatinine, serum bilirubin, and hematocrit [HCT]); previous cerebrovascular events; evidence of ES at the preoperative cEEG/aEEG exam; type of surgery (single or double ventricle; with or without aortic arch procedure) and weight of surgery based on the RACHS-2 score.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e CPB details included: on pump or off-pump; roller or centrifugal pump; priming volume; priming nature; nadir temperature on CPB; nadir hematocrit on CPB; CPB duration; aortic cross-clamp duration. Data at the arrival in the ICU included an arterial blood gas analysis with measurement of mean arterial pressure; central venous pressure; heart rate; HCT; temperature; and arterial blood lactate.\u003c/p\u003e\u003cp\u003eThe outcome was assessed in terms of neurologic complications (ischemic/hemorrhagic stroke; coma) adjudicated based on clinical signs and documented by imaging; and non-neurologic complications defined as a composite outcome of major morbidity. Major morbidity was adjudicated in presence of one or more of the following: acute kidney injury (defined base on the pROCK criteria\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e); surgical revision; need for tracheostomy, deep sternal wound infection; need for extracorporeal membrane oxygenation (ECMO).\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eCategorical data are presented as number (%); continuous variables are presented as mean (standard deviation) or median (interquartile range) according to the normality of distribution. At an univariate analysis, the differences between groups (with or without ES) were investigated with a Pearson\u0026rsquo;s chi squared for binary variables and a Student\u0026rsquo;s t test or nonparametric tests for continuous variables. Multivariable logistic regression analyses were applied to identify the independent association of different variables with the dependent variable of interest (ES and neurologic/non neurologic morbidities), producing odds ratios with 95% confidence interval. The predictive model for ES was tested for accuracy (discrimination) and calibration. A receiver operating characteristics (ROC) analysis was applied producing a c-statistics, where an acceptable discrimination was defined for a c-statistics 0.70\u0026ndash;0.75, a good discrimination for a c-statistics\u0026thinsp;\u0026gt;\u0026thinsp;0.75 and\u003c/p\u003e\u003cp\u003e\u0026le;\u0026thinsp;0.8, and a very good discrimination for a c-statistics\u0026thinsp;\u0026gt;\u0026thinsp;0.8. The c-statistics was reported with the 95% confidence interval. This value was subsequently checked with a bootstrapping process (1,000 iterations). Different cut-off values were investigated for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Calibration of the model was checked with the Hosmer-Lemeshow statistics and calibration plot. All the statistical analyses were conducted using computerized statistical programs (SPSS 20.0, IBM, Chicago, IL, GraphPad, GraphPad Software, Inc, San Diego, CA, MedCalc, MedCalc Software, Ostend, Belgium). A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant for all the statistical tests.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEthics statements\u003c/h3\u003e\n\u003cp\u003e The Ethics Committee of San Raffele Hospital approved this study (CET331-2025) and waived the need for a written informed consent and all the parents of the patients gave a general consent for the scientific treatment of clinical data in an anonymous form.\u003c/p\u003e\u003cp\u003e The study was conducted according to the relevant existing guidelines.\u003c/p\u003e\n\u003ch3\u003eData availability\u003c/h3\u003e\n\u003cp\u003eAll data are in a local repository and available at reasonable request\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe EEG monitoring was initiated after a median time of 4 hours (interquartile range 2\u0026ndash;8 hours) after arrival in the ICU, and was continued for a median time of 18 hours (interquartile range 14\u0026ndash;22 hours).\u003c/p\u003e\u003cp\u003eOverall, 23 patients (6.2%) developed postoperative ES, and 11 (2.9%) exhibited a pattern of an SE. Before surgery, 11 (2.9%) patients had ES (3 with SE), and 3 (0.8%) showed both pre and postoperative ES.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;1 reports the preoperative details of the patient population, including demographics, laboratory exams, co-morbidities, operative and CPB details, and early data at the arrival in the ICU. Patients with ES had a number of factors significantly different from patients without ES: a higher rate of pre-surgery subclinical ES; a lower baseline HCT, a higher RACHS-2 score, a higher rate of aortic arch surgery, a longer CPB duration, a higher rate of patients where the sternum was left open, a higher arterial lactate value and a lower HCT at the arrival in the ICU.\u003c/p\u003e\u003cp\u003eTo identify the factors independently associated with postoperative subclinical ES, the above listed factors were entered into a multivariable, stepwise forward logistic regression, whose details are shown in table 2. The independent factors associated with postoperative subclinical ES were: a higher RACHS-2, the open sternum, and a lower HCT at the arrival in the ICU.\u003c/p\u003e\u003cp\u003eBased on the parameters reported in table 2, a predictive equation was developed and is reported in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This relationship had a good calibration (Hosmer-Lemeshow test chi squared 9.2, P\u0026thinsp;=\u0026thinsp;0.325) between expected and observed ES events, and a very good discrimination, with a c-statistics of 0.816 (95% confidence interval 0.75\u0026ndash;0.88, P\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eBased on the parameters of this equation, different cut-offs were identified, with the respective sensitivity, specificity, NPV and PPV shown in table 3.\u003c/p\u003e\u003cp\u003eThe univariate association between cEEG/aEEG ES and neurologic / non-neurologic outcomes is reported in table 4. ES are significantly (P\u0026thinsp;=\u0026thinsp;0.005) associated with neurologic outcome at the univariate analysis; within a multivariable logistic regression model no other perioperative factor was associated with the neurologic outcome, and the ES remained the only factor independently associated with the neurologic outcome, showing an odds ratio of 8.0 for any kind of postoperative neurologic events.\u003c/p\u003e\u003cp\u003eES are significantly associated with non-neurologic major morbidity and with some of its components (tracheostomy, surgical revision, ECMO) and with hospital mortality. However, after correction for other possible factors associated with major morbidity (RACHS-2, open sternum, and CPB duration), the presence of postoperative cEEG/aEEG-documented ES does not maintain its properties as a factor significantly and independently associated with major morbidity.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eThe prevalence of postoperative ES\u003c/h2\u003e\u003cp\u003eThe rate of postoperative ES (6.2%) found in our series is consistent with what reported by other authors in similar series. Actually, the reported rate of postoperative ES greatly varies depending on the age and type of procedure (basically, with or without deep hypothermic cardiac arrest [DHCA]). In series limited to neonates, a higher rate is reported, with a prevalence of 18% in patients with hypoplastic left heart syndrome submitted to Norwood operation\u003csup\u003e17\u003c/sup\u003e and 17\u0026ndash;19% in neonates undergoing any kind of cardiac surgery.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e When infants of higher age and/or surgery of any kind are included, the rate of postoperative ES is lower: 2.5% in infants and children\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e;\u003c/sup\u003e; 7.4% in neonates receiving cardiac surgery of any type\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, 8\u0026ndash;13% in neonates and infants receiving any kind of cardiac surgery.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e In a setting similar to our series, the reported postoperative ES rate is 7%.\u003csup\u003e4\u003c/sup\u003e Of notice, the studies reporting the highest rate (20\u0026ndash;30%) of subclinical ES are those including ECMO patients only.\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eGlobally, given the relatively low rate of postoperative ES, and the requirement of considerable technical and human resources for implementing a program of cEEG/aEEG monitoring, the need for selection criteria appears motivated and is the object of our primary endpoint.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eRisk factors and risk model\u003c/h2\u003e\u003cp\u003eFor our primary endpoint, we found 3 factors being independently associated with postoperative ES: RACHS-2, open sternum, and ECMO at the arrival in the ICU.\u003c/p\u003e\u003cp\u003eThe risk factors for postoperative ES have been previously investigated by other authors \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and a risk model has been proposed.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Latal and associates\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e found that only some ICU outcome parameter (length of mechanical ventilation and ICU stay) were associated with ES, while CPB duration, lowest temperature on CPB, and peak lactate were not. In a series of neonates and infants, Gaynor and associates\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e found a significant association between postoperative ES and type of surgery (namely, aortic arch and DHCA), DHCA duration, and CPB duration. Interestingly, they could not find any association with delayed sternal closure or need for ECMO, but in both cases there was a non-significant trend that would probably become significant in a larger series. Finally, the most relevant study appears to be that of Naim and associates\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, who developed and validated a predictive risk model in a large series of neonates. The ES prevalence was 7.9% in the derivation cohort and 6.3% in the validation cohort. In their multivariable model, the independent factors for postoperative ES were the gestational age, the head circumference, a single ventricle, DHCA duration, use of nitric oxide in the operating room (OR), cardiac arrest, ECMO, and open sternum in the OR. The derivation cohort had a good discrimination (c-statistics 0.77), but in the validation cohort this value decreased to a poor c-statistics of 0.61.\u003c/p\u003e\u003cp\u003eThere are major differences between our approach and those applied by the other authors.\u003c/p\u003e\u003cp\u003eThe first and most important is the use of a combined cEEG and aEEG in all the patients. It is commonly accepted that aEEG has a lower sensitivity for seizure detection in neonates with respect to cEEG\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. The combined use of both techniques allows to overcome this limitation of the aEEG. We did collect a number of variables that were not considered in other studies. Among them, the preoperative and CPB characteristics included the preoperative serum creatinine and bilirubin and nadir HCT, type and volume of priming solution on CPB. The complexity of surgery was defined according to the RACHS-2 and the clinical (hematocrit, heart rate mean arterial and venous pressure, open sternum and ECMO), respiratory (PaO\u003csub\u003e2\u003c/sub\u003e and PaCO\u003csub\u003e2\u003c/sub\u003e) and metabolic (pH, HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e, arterial lactates) conditions of the patients immediately at the arrival in the ICU were included in the analysis. As a consequence, our multivariable risk model included variables not considered by other authors (RACHS-2 and HCT at the arrival in the ICU) together with open sternum that was already observed in other studies.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOverall, our model offers interpretative insights: the 3 factors are representative of the complexity of surgery (RACHS-2) but even indirectly representative of the cardiac output (open sternum) and of the arterial oxygen content (HCT). The combination of these 2 parameters is the oxygen delivery (DO\u003csub\u003e2\u003c/sub\u003e). In neonates and small infants, the cardiac output cannot be directly measured, and therefore the DO\u003csub\u003e2\u003c/sub\u003e as well. Therefore, the following considerations on DO\u003csub\u003e2\u003c/sub\u003e are a speculation based on indirect data. The open sternum is certainly a marker of a low cardiac function, and the HCT is a marker of the oxygen content. The combination of a low cardiac output and low hematocrit results in a low DO\u003csub\u003e2\u003c/sub\u003e. There are other data supporting this interpretation: at the univariate analysis the arterial lactates are significantly higher in patients with postoperative ES, therefore suggesting an inadequate DO\u003csub\u003e2\u003c/sub\u003e. Actually, a large study\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e could identify two predictors significantly and independently associated with postoperative ES, both clearly an expression of an inadequate cardiac output: arterial lactates and use of inotropic drugs. Other studies considered ECMO and open sternum as independent predictors of postoperative ES.\u003csup\u003e16\u003c/sup\u003e It is therefore possible to consider the postoperative ES as a consequence of a low cerebral DO\u003csub\u003e2\u003c/sub\u003e, even taking into account the temporal sequence (all the risk factors occur before the ES adjudication). Actually, other reports in different settings have shown a relationship between neonatal seizures and cerebral oxygenation assessed with the NIRS.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eES and outcome\u003c/h2\u003e\u003cp\u003eFor our secondary endpoint, we found a univariate association between postoperative ES and neurologic complications. In a multivariable analysis, patients with postoperative ES had an 8-times higher risk of cerebral injury, yielding a PPV of 30% and an NPV of 95%. Non-neurologic bad outcomes, (major morbidity and mortality) were associated with postoperative ES in a univariate analysis, but after correction for potential confounders, only CPB duration, RACHS-2, and open sternum remained independently associated with major morbidity. So, the interpretation again focuses on the complexity of the procedure and a poor cardiac contractility. It is reasonable to attribute the higher rate of major morbidity to a poor hemodynamic state, with the postoperative ES being a marker of this condition.\u003c/p\u003e\u003cp\u003eThe great majority of the existing studies linked postoperative ES to long-term clinical conditions (neurocognitive impairment), but others addressed the hospital outcome. The link between EEG alterations and cerebral injury was denied by some authors\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, but confirmed by others\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e in the surgical setting and in the ECMO setting.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Other non-neurologic bad outcomes have been reported in terms of longer mechanical ventilation and ICU stay\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e and mortality\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIs there a clinically relevant role of EEG monitoring in the setting of cardiac surgery in neonates and infants, and when should we consider to apply this technique? It must be admitted that the majority of the predictive risk models in medicine and surgery are actually of little clinical impact, being based on non-modifiable risk factors and rarely suggesting specific strategies. However, in this case the decision-making process could be facilitated by our risk analysis. Actually, there are suggestive risk factors, and possible cut-offs are presented in table 3: the important value to be considered in order not to miss the detection of postoperative ES is the NPV; a predictive cut-off at 35% probability maintains a good NPV (94%) and an acceptable PPV of 33% (about 5 times higher than the overall prevalence). Given the fact that EEG monitoring is not a routine technique, and that it requires a considerable amount of resources, a tool for selecting patients who most likely could benefit from this monitoring has a relevant impact.\u003c/p\u003e\u003cp\u003eConsidering the clinical role, postoperative ES have little or null usefulness as early signs of major morbidity. Actually, they are linked to a pattern of impaired hemodynamics, but the clinical signs of this pattern usually are evident immediately after the admission to the ICU, and often in the OR, and the postoperative ES are more a consequence than an early sign of impaired circulation and inadequate DO\u003csub\u003e2\u003c/sub\u003e. Things are different for neurologic injuries. As a matter of fact, the association between postoperative ES and cerebral injuries is strong, and they are the only independent factor linked to these complications. Considering that the great majority of neonates and infants are deeply sedated and paralyzed within the first 24 hours or postoperative days (especially in case of open sternum and ECMO), they cannot exhibit the clinical signs of cerebral injuries. In this setting, the finding of postoperative ES may prompt specific diagnostic imaging procedures, allowing an early diagnosis. This, in turn, may trigger therapeutic interventions aimed to contain the damage of a cerebral injury.\u003c/p\u003e\u003cp\u003eThere are limitations in our study. As per every retrospective study, the adjudication of clinical morbidity may not be totally reliable. Additionally, our risk model has not been validated in external series, and may lack some risk factors not retrievable from our database nor the patients\u0026rsquo; files. Finally, there was no strict criteria for timing of first recording and duration of recording; practical issues (i.e. late arrival in the ICU) were determinant of this. As a consequence, we cannot exclude that an earlier and longer EEG monitoring could detect a higher rate of subclinical seizures.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePostoperative ES are a marker of an impaired circulatory pattern, probably through an inadequate oxygen supply to the brain. Their independent association with cerebral injury allows an early recognition of this complication.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eaEEG amplitude electroencephalography\u003c/p\u003e\n\u003cp\u003ecEEG: conventional electroencephalography\u003c/p\u003e\n\u003cp\u003eCHD: congenital heart disease\u003c/p\u003e\n\u003cp\u003eCPB: cardiopulmonary bypass\u003c/p\u003e\n\u003cp\u003eDHCA: deep hypothermic cardiac arrest\u003c/p\u003e\n\u003cp\u003eDO\u003csub\u003e2\u003c/sub\u003e: oxygen delivery\u003c/p\u003e\n\u003cp\u003eECMO: extracorporeal membrane oxygenation\u003c/p\u003e\n\u003cp\u003eES: epilectic seizures\u003c/p\u003e\n\u003cp\u003eHCT: hematocrit\u003c/p\u003e\n\u003cp\u003eICU: intensive care unit\u003c/p\u003e\n\u003cp\u003eNIRS; near-infrared spectroscopy\u003c/p\u003e\n\u003cp\u003eNPV: negative predictive value\u003c/p\u003e\n\u003cp\u003eOR: operating room\u003c/p\u003e\n\u003cp\u003ePPV: positive predictive value\u003c/p\u003e\n\u003cp\u003eRACHS: risk stratification for congenital heart surgery\u003c/p\u003e\n\u003cp\u003eROC: receiver operating characteristics\u003c/p\u003e\n\u003cp\u003eSE: status epilecticus\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe study was approved by the local Ethics Committee of Ospedale San Raffaele (CET331-2025) and, given the retrospective nature, written informed consent was waived.\u003c/p\u003e\u003cp\u003eAll data are in a local repository and available at reasonable request\u003c/p\u003e\u003cp\u003eThe authors declare that they have no conflict of interest\u003c/p\u003e\u003cp\u003eThe study was funded by institutional funds\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.R. designed the study , led the data analysis, and wrote the first draft of the article; M.M. interpreted the EEG tracings; F.S. interpreted the EEG tracings; M.L. participated in literature retrieval and data analysis; R.L. participated in literature review and data analysis; T.A. critically revised the manuscript; M.A. participated in data collection and analysis; A.B. participated in data collection and analysis; A.G. critically revised the manuscript; G.I. participated in data collection and interpretation.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data are in a local repository and available at reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eClaessens, N. H. P. et al. Amplitude-Integrated Electroencephalography for Early Recognition of Brain Injury in Neonates with Critical Congenital Heart Disease. \u003cem\u003eJ. Pediatr.\u003c/em\u003e \u003cb\u003e202\u003c/b\u003e, 199\u0026ndash;205e1 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiller, G. \u0026amp; Vogel, H. Structural evidence of injury or malformation in the brains of children with congenital heart disease. \u003cem\u003eSemin Pediatr. Neurol.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 20\u0026ndash;26 (1999).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eClaessens, N. H. P. et al. Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease. \u003cem\u003eDev. Med. Child. Neurol.\u003c/em\u003e \u003cb\u003e60\u003c/b\u003e, 1052\u0026ndash;1058 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLatal, B. et al. 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S., Scharfman, H. E. \u0026amp; deCurtis, M. How can we identify ictal and interictal abnormal activity? \u003cem\u003eAdv. Exp. Med. Biol.\u003c/em\u003e \u003cb\u003e813\u003c/b\u003e, 3\u0026ndash;23 (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWusthoff, C. J. Diagnosing neonatal seizures and status epilepticus. \u003cem\u003eJ. Clin. Neurophysiol.\u003c/em\u003e \u003cb\u003e30\u003c/b\u003e, 115\u0026ndash;121 (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAllen, P. et al. Risk Stratification for Congenital Heart Surgery for ICD-10 Administrative Data (RACHS-2). \u003cem\u003eJ. Am. Coll. Cardiol.\u003c/em\u003e \u003cb\u003e79\u003c/b\u003e, 465\u0026ndash;478 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXu, X. et al. A New Criterion for Pediatric AKI Based on the Reference Change Value of Serum Creatinine. \u003cem\u003eJ. Am. Soc. Nephrol.\u003c/em\u003e \u003cb\u003e29\u003c/b\u003e, 2432\u0026ndash;2442 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGunn, J. K., Beca, J., Hunt, R. W., Olischar, M. \u0026amp; Shekerdemian, L. S. Perioperative amplitude-integrated EEG and neurodevelopment in infants with congenital heart disease. \u003cem\u003eIntensive Care Med.\u003c/em\u003e \u003cb\u003e38\u003c/b\u003e, 1539\u0026ndash;1547 (2012).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin, R. et al. Perioperative EEG background and discharge abnormalities in children undergoing cardiac surgery: a prospective single-centre observational study. \u003cem\u003eBr. J. Anaesth.\u003c/em\u003e \u003cb\u003e131\u003c/b\u003e, 360\u0026ndash;372 (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChahine, A. et al. Continuous Amplitude-Integrated Electroencephalography During Neonatal and Pediatric Extracorporeal Membrane Oxygenation. \u003cem\u003eJ. Clin. Neurophysiol.\u003c/em\u003e \u003cb\u003e40\u003c/b\u003e, 317\u0026ndash;324 (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin, J. J. et al. Electrographic Seizures in Children and Neonates Undergoing Extracorporeal Membrane Oxygenation. \u003cem\u003ePediatr. Crit. Care Med.\u003c/em\u003e \u003cb\u003e18\u003c/b\u003e, 249\u0026ndash;257 (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKohne, J. G., MacLaren, G., Shellhaas, R. A., Benedetti, G. \u0026amp; Barbaro, R. P. Variation in electroencephalography and neuroimaging for children receiving extracorporeal membrane oxygenation. \u003cem\u003eCrit. Care\u003c/em\u003e. \u003cb\u003e27\u003c/b\u003e, 23 (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRakshasbhuvankar, A. A., Nagarajan, L., Zhelev, Z. \u0026amp; Rao, S. C. Amplitude-integrated electroencephalography compared with conventional video-electroencephalography for detection of neonatal seizures. \u003cem\u003eCochrane Database Syst. Rev.\u003c/em\u003e 2025:11;8(8).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartini, S., Paoletti, V., Faldella, G. \u0026amp; Corvaglia, L. Cerebral Oxygenation Patterns during Electroclinical Neonatal Seizures. \u003cem\u003eNeuropediatrics\u003c/em\u003e \u003cb\u003e50\u003c/b\u003e, 408\u0026ndash;409 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanalioglu, D. et al. Neurophysiologic Features Reflecting Brain Injury During Pediatric ECMO Support. \u003cem\u003eNeurocrit Care\u003c/em\u003e. \u003cb\u003e40\u003c/b\u003e, 759\u0026ndash;768 (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"conventional electroencephalography, amplitude integrated electroencephalography, congenital heart surgery, neonates, infants, seizures","lastPublishedDoi":"10.21203/rs.3.rs-7867114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7867114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground. \u003c/em\u003eNeonates and infants undergoing cardiac surgery are prone to cerebral injuries. Neuromonitoring with continuous conventional electroencephalography (cEEG) and/or amplitude integrated electroencephalography (aEEG) is able to detect subclinical abnormal cerebral patterns, especially seizures, which have been found to correlate with medium-long term neurocognitive deficits. The endpoints of this study are (i) to define a risk model for epilectic seizures (ES) and (ii) to investigate the relationship between ES and neurologic and non-neurologic outcomes. \u003cem\u003eMethods\u003c/em\u003e. Retrospective analysis of 373 neonates and infants \u0026lt; year undergone cardiac surgery and receiving a pre/postoperative combined cEEG/aEEG exam. The risk factors for postoperative ES were investigated and pooled in a predictive model, and postoperative ES were assessed for association with neurologic and non-neurologic (major morbidity) postoperative patterns. \u003cem\u003eResults. \u003c/em\u003eThe independent risk factors for postoperative ES were the complexity of surgery (RACHS-2 score), an open sternum, and the hematocrit at the arrival in the intensive care unit. The predictive model based on these factors yielded a good discrimination (c-statistics 0.81). Postoperative ES were significantly associated with major non-neurologic morbidity, but once corrected for other confounding factors they lost significance. Conversely, postoperative ES were the only predictor of cerebral injuries, with an odds ratio of 8.0 (95% confidence interval 2.25-28.3, P=0.003). \u003cem\u003eConclusions.\u003c/em\u003e Postoperative ES are associated with an hemodynamic compromise and low arterial oxygen content, with a consequent inadequate oxygen delivery to the brain and other organs. In presence of these factors, EEG monitoring is useful for the early diagnosis of cerebral injuries in patients sedated and paralyzed.\u003c/p\u003e","manuscriptTitle":"Subclinical Epilectic Seizures in Infants After Cardiac Surgery: Risk Factors and Association With Neurologic and Non-Neurologic Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 09:26:43","doi":"10.21203/rs.3.rs-7867114/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-01T06:09:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-25T19:32:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T22:18:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"263767779249941429130725985212114267875","date":"2025-10-31T15:37:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30747240820326438875732324736225092395","date":"2025-10-31T15:22:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21466381208563416974137860091035579279","date":"2025-10-29T20:24:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"322804251550883019301977442892292581800","date":"2025-10-29T15:04:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-29T14:53:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-29T14:50:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-27T03:46:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-23T07:57:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-23T07:54:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"12696e43-27d1-4387-8fb6-4070863c063a","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":57709959,"name":"Health sciences/Diseases"},{"id":57709960,"name":"Health sciences/Medical research"},{"id":57709961,"name":"Health sciences/Neurology"},{"id":57709962,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-01-12T16:11:16+00:00","versionOfRecord":{"articleIdentity":"rs-7867114","link":"https://doi.org/10.1038/s41598-026-35059-7","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-01-09 15:59:31","publishedOnDateReadable":"January 9th, 2026"},"versionCreatedAt":"2025-11-10 09:26:43","video":"","vorDoi":"10.1038/s41598-026-35059-7","vorDoiUrl":"https://doi.org/10.1038/s41598-026-35059-7","workflowStages":[]},"version":"v1","identity":"rs-7867114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7867114","identity":"rs-7867114","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}