Hypoxic Mixture as a Preoperative Strategy in Congenital Heart Disease with Pulmonary Overcirculation

Hypoxic Mixture as a Preoperative Strategy in Congenital Heart Disease with Pulmonary Overcirculation | 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 Research Article Hypoxic Mixture as a Preoperative Strategy in Congenital Heart Disease with Pulmonary Overcirculation María Gabriela Ramírez Guerrero¹, Diana Marcela Galván Canchila³, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9431166/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Although the use of a hypoxic mixture is uncommon, it appears to be a useful strategy in the preoperative management of congenital heart disease with pulmonary overcirculation physiology, which is considered a stabilizing step and a bridge to corrective or palliative surgery. Methodology This prospective observational study included 17 infants (< 1 year) with congenital heart disease and pulmonary overcirculation, who were managed preoperatively with a hypoxic mixture in 2024. Demographic and clinical data were analyzed to assess hemodynamic and blood gas changes within 24 h of therapy initiation. Paired t-test and repeated measures ANOVA were used (Stata 18.0®). Results Overall, 88.2% of the patients had biventricular congenital heart defects with pulmonary overcirculation physiology, most commonly aortic arch hypoplasia with ventricular septal defect. The hypoxic gas mixture concentration administered to over half of the patients was 16% (IQR 15–17). Pulse oximetry revealed significant changes from 6 h of therapy. pH and lactate levels demonstrated notable changes with the hypoxic mixture, as did urine output 12 h after therapy initiation. Conclusion The hypoxic mixture is a practical and versatile tool that impacts pulmonary flow control, indirectly demonstrating effects on hemodynamic and blood gas variables, serving as indicators of the balance between pulmonary and systemic flow (Qp/Qs). nitrogen pulmonary overcirculation pulmonary flow congenital heart disease hypoxic mixture Figures Figure 1 Figure 2 Introduction In children with univentricular and biventricular congenital heart defects, postnatal decrease in pulmonary vascular resistance leads to a hemodynamic imbalance characterized by the predominance of blood flow to the pulmonary circulation (left-to-right shunt), resulting in reduced systemic blood flow. This phenomenon is known as pulmonary overcirculation [1]. The hemodynamic consequences of pulmonary overcirculation depend on the magnitude of the shunt and the affected cardiac anatomy, which directly correlate with the volume of blood diverted from the systemic arterial vascular bed to the pulmonary vasculature [1,2]. Various strategies have been described to prevent pulmonary overcirculation and secondary shock, focusing on increasing pulmonary vascular resistance to regulate the Qp/Qs ratio (Qp: pulmonary blood flow / Qs: systemic blood flow), with a target value of ≤ 0.7 to optimize systemic perfusion. This ratio quantifies the hemodynamic balance between the two circulatory beds: a Qp/Qs ratio > 1 indicates pulmonary flow predominance, whereas a Qp/Qs ratio < 1 indicates greater systemic flow [3,4]. Mathematical models suggest that maintaining this ratio between 0.7 and 1 preserves adequate tissue oxygenation through sufficient systemic blood flow [5]. Among the most notable strategies are the use of prostaglandins, vasodilators, inotropes, red blood cell transfusions, positive airway pressure, as well as the application of hypoxic mixture (with inspired oxygen fraction [FiO₂] below 21%) and 3% carbon dioxide [4,5]. The hypoxic mixture was first used in animal models in 1996 by Reddy et al., who reported their experience administering hypoxic gas (10% FiO₂) to sheep after creating a shunt from the main artery to the pulmonary artery [6]. The active principle of this therapy is the effect of nitrogen, which displaces oxygen molecules, preventing their potent pulmonary vasodilator effect [7]. Regarding clinical evidence, a hypoxic mixture was first used in 1998 by Day et al. as a preoperative strategy in the management of hypoplastic left heart syndrome (HLHS), demonstrating its clinical efficacy. Since then, its use has expanded globally, with notable results in Japan, the United States, and Spain. However, evidence remains limited in Latin America, especially in patients with biventricular physiology, highlighting the need for further studies in this subgroup [6,8,9]. Hypoxic mixture is a safe, economical, and effective strategy that can be applied with or without mechanical ventilation [10]. It has been suggested to maintain an FiO₂ between 0.14 and 0.20 to induce pulmonary hypoxic vasoconstriction, increasing pulmonary vascular resistance and optimizing the Qp/Qs ratio. In patients with univentricular physiology, the target postductal oxygen saturation is 75–85%, whereas in biventricular patients, the goal is approximately 90%. A mixed venous saturation of 55–60% is recommended 7–11. This approach improves blood pressure, urine output, and tissue perfusion, preventing acidosis, coronary or cerebral ischemia, and multiorgan damage [10, 11]. However, concerns persist regarding the potential development of neurological complications secondary to cerebral hypoxia. Although several studies have evaluated cerebral oxygenation during this therapy, a safe FiO₂ threshold has not yet been established [10,12,13]. A recent meta-analysis identified only four studies that reported Near-Infrared Spectroscopy (NIRS) values before and after hypoxic mixture administration, with no statistically significant changes [8]. Although the hypoxic mixture has fallen out of use, in some centers, including those in low- and middle- income countries, critical care management for these patients relies on hypercapnia and hypoxic mixture as a bridge therapy to corrective or palliative surgery [8]. Therefore, the objective of the present study was to describe the effects of hypoxic mixture administration in pediatric patients with congenital heart disease and pulmonary overcirculation. Materials And Methods Population and study design An observational, descriptive, longitudinal, prospective study was conducted on a single group of 17 infants under 1 year old with congenital heart disease and pulmonary overcirculation physiology. These patients were admitted to a cardiovascular intensive care unit at a referral hospital in Colombia between July 1 and December 31, 2024. This study evaluated the use of a hypoxic mixture, which is part of the standard therapy for managing this patient group. Hemodynamic and blood gas variables were monitored before the initiation of the hypoxic mixture (Hour 0) and subsequently at hours 1, 6, 12, and 24 to assess the response to hypoxic mixture therapy, with the administered concentration varying according to each patient’s tolerance. Eligibility Criteria Inclusion Criteria Infants under 1 year old with congenital heart disease and pulmonary overcirculation who were admitted to the intensive care unit and required hypoxic mixture as part of the preoperative management of pulmonary overcirculation were included. The hypoxic mixture was administered via a high-flow nasal cannula, nasal CPAP, or invasive and noninvasive mechanical ventilation. Exclusion Criteria Pediatric patients requiring hypoxic mixture in the postoperative period of cardiovascular surgery and children with infectious or anatomical pulmonary pathologies. Variables Demographic variables, including age, sex, weight, gestational age, and associated comorbidities, were collected. Clinical variables were also recorded before and after the initiation of hypoxic mixture therapy (at times 0, 1, 6, 12, and 24 h), including heart rate, blood pressure (systolic, diastolic, and mean), oxygen saturation, and urine output (measured during the 12 h before and after therapy). Data Collection Data were collected from the medical records and telemetry logs of children who met the inclusion criteria. Information was recorded in a digital form (Google Forms) and then exported to Microsoft Excel® for cleaning and statistical analysis. Patient identities were protected using unique numerical codes assigned by the research team. Statistical Analysis Qualitative variables were described using absolute frequency. Quantitative variables with a normal distribution were analyzed using the mean and standard deviation; otherwise, the median and interquartile range were used. For bivariate analysis, the paired t-test or Wilcoxon test was applied, depending on the data distribution. For quantitative variables with a normal distribution, repeated measures ANOVA with Bonferroni correction was used, with statistical significance set at p < 0.05. All analyses were conducted using STATA 18.0 software (College Station, TX, USA). Ethical Considerations The principles of confidentiality and privacy established in the Declaration of Helsinki (13) were strictly followed to ensure the protection of personal and sensitive data. The research protocol was reviewed and approved by the hospital’s Research Ethics Committee. Results Seventeen infants under 1 year old diagnosed with congenital heart disease and pulmonary overcirculation physiology were included in this study. They were admitted to the pediatric cardiovascular intensive care unit between July and December 2024 and required hypoxic mixture therapy during the preoperative period. Regarding demographic characteristics, males predominated (10 /17 58.8%). The median age at the start of hypoxic mixture therapy was 11 days of life (IQR: 4–17), with an average weight of 2,990 g (SD ± 471). (Table 1 ) Table 1 Characteristics of the study population. Demographic and Clinical Characteristics n = 17 (%) Sex Male 10 (58.8) Female 7 (41.2) Age (days). Median (IQR) 11 (4–17) Weight (grams). Mean (SD) 2990 ( ± 471) Gestational age (weeks). Median (IQR) 37.3 (37–38) Genetic syndromes None 10 (58.8) Down syndrome 5 (29.4) DiGeorge syndrome 1 (5.9) Turner syndrome 1 (5.9) Type of congenital heart disease Biventricular 15 (88.2) Univentricular 2 (11.8) Type of respiratory support Invasive mechanical ventilation 7 (41.2) Nasal CPAP 6 (35.3) High-flow nasal cannula 4 (23.5) Positive end-expiratory pressure (PEEP) cm H₂O. Median (IQR) 8 (8–9) Fraction of inspired oxygen (FiO₂) 14% 4 (23.5) 15% 2 (11.8) 16% 3 (17.6) 17% 7 (41.2) 18% 1 (5.9) Days of hypoxic mixture therapy. Mean (SD) 7.5 ( ± 5.4) Type of inotropic support Milrinone 7 (41.1) Epinephrine 3 (17.7) Epinephrine +Milrinone 3 (17.7) None 4 (23.5) Use of prostaglandin Yes 4 (23.5) No 13 (76.5) IQR : Interquartile Range, SD : Standard Deviation, CPAP : Continuous Positive Airway Pressure, PEEP : Positive End−Expiratory Pressure, FiO₂ : Fraction of Inspired Oxygen . Twenty-nine point four percent of the patients had Down syndrome (5/17), followed by DiGeorge syndrome and Turner syndrome. Pulmonary overcirculation heart defects were classified as biventricular (15/17, 88.2%) and univentricular (2/17, 11.8%). The most common defect observed was aortic arch hypoplasia with a ventricular septal defect, followed by truncus arteriosus, atrioventricular canal, and patent ductus arteriosus. (Fig. 1 ) AAH: Aortic Arch Hypoplasia, TA: Truncus Arteriosus, AVC: Atrioventricular Canal, PDA: Patent Ductus Arteriosus, DORV: Double Outlet Right Ventricle, VSD: Ventricular Septal Defect, APW: Aortopulmonary Window, EA: Ebstein's anomaly, HLHS: Hypoplastic Left Heart Syndrome, SV: Single Ventricle, IAA: Interrupted Aortic Arch. The hypoxic mixture was administered as part of conventional pulmonary overcirculation management with an inspired oxygen fraction (FiO₂) between 14 and 17%, and the therapy lasted an average of 7.5 days (SD ± 5.4). The respiratory support devices used to deliver the hypoxic mixture were invasive mechanical ventilation (7/17, 41.2%), nasal CPAP, and high-flow nasal cannula. Milrinone was the most commonly used inotrope (7/17, 41.1%), followed by epinephrine. Prostaglandin, used to maintain systemic flow through the ductus arteriosus, was administered in (4/17) 23.5% of cases. (Table 1 ) Hemodynamic Response in Patients Undergoing Hypoxic Mixture Therapy Hemodynamic changes in children treated with hypoxic mixture were evaluated at five time points: before initiation (Hour 0) and at 1, 6, 12, and 24 h. Heart rate (HR) showed no significant differences across the evaluated time points (p = 0.22) or when comparing pre-therapy values with post-therapy values (p = 1.0). (Fig. 2 ) The following are shown: (a) heart rate (bpm), (b) systolic blood pressure (mmHg), (c) mean arterial pressure (mmHg), and (d) postductal oxygen saturation (%). Mean values with their corresponding confidence intervals are presented at each evaluation time point (hour 0, 1, 6, 12, and 24) Systolic blood pressure did not show significant differences in the mean values measured at the different intervals compared to therapy initiation (p = 0.062). However, a significant increase in systolic blood pressure was observed when comparing measurements at 6 and 12 h, with a higher mean value at 12 h (p = 0.048). Pulse oximetry showed significant changes after starting the hypoxic mixture (p < 0.00001), mainly between 0 and 6, 12, and 24 h. Urine output increased at 12 h after the start of hypoxic mixture therapy, with an average increase of 1.4 mL/kg/h (p = 0.04). (Table 2 ) Table 2 Hemodynamic changes associated with hypoxic mixture administration. Evaluation timelines n = 17 0 hours 1 hours 6 hours 12 hours 24 hours F p - value Heart Rate * 149 ( ± 18) 144 ( ± 16) 139 ( ± 17) 144 ( ± 11) 146 ( ± 8) 1.46 0.22 Systolic Arterial Pressure * 74 ( ± 13) 77 ( ± 12) 74 ( ± 11) 81 ( ± 9) 76 ( ± 12) 2.36 0.0062 Diastolic Arterial Pressure * 41( ± 11) 41( ± 10) 40 ( ± 9) 43 ( ± 9) 39 ( ± 8) 0.78 0.54 Mean Arterial Pressure * 51 ( ± 13) 52( ± 10) 50 ( ± 9) 54 ( ± 8) 50 ( ± 9) 1.30 0.27 Saturation of Oxygen * 96 ( ± 2) 93( ± 5) 90 ( ± 5) 88 ( ± 4) 88 ( ± 4) 18.67 < 0.001 n: sample size * Mean SD: Standard Deviation. F statistic in an ANOVA analysis that evaluates the differences in means between groups. Significant p−value less than 0.05 . Changes in venous blood gas were evaluated after 6 h of hypoxic mixture therapy, compared to baseline (Hour 0). Of the 17 patients in the study, only nine had central venous access inserted at the jugular or subclavian vein level for sampling. Venous blood gas analysis revealed a significant decrease in pH at 6 hours after initiation of the hypoxic mixture, with an average change of 0.073 units (p = 0.041; 95% CI: 0.003–0.14). The initial pH was higher than that recorded at 6 h. (Table 3 ) Table 3 Changes in blood gas and clinical parameters before and after hypoxic mixture therapy. Characteristic Before hypoxic mixture (0 HR) After hypoxic mixture (6HR) Δ Mean (CI 95%) t-test p-value pH. † 7.36 ( ± 0.064) 7.29 ( ± 0.091) 0.073 (0.003–0.14) 2.42 0.041 pCO₂. mmHg. † 49.46 ( ± 9.20) 59.29 ( ± 13.25) -9.83 (− 21.85–2.18 -1.88 0.095 pVO₂. mmHg. Median (IQR) ‡ 32.9 (28.1–35.6) 35.6 (31.8–40.2) -0.35 (-7.3–7.9) 22* 1.00 SVO₂. † 68.78 ( ± 14.27) 66.06 ( ± 11.96) 2.72 (-5.7–11.16) 0.74 0.47 HCO₃. mEq/L ‡ 29.30 (24.4–31.6) 29.1 (26.2–30.5) 0.55 (-1.4–129) 25 0.82 BE. mmol/L † 1.74 ( ± 3.65) 0.24 ( ± 4.37) 1.50 (− 0.04–3.04) 2.23 0.056 Lactate. mmol/L ‡ 1.89 (1.58–2.29) 1.39 (1.19–1.90) 0.47 (0.26–1.42) 45* 0.009 Qp/Qs. † 18.42 ( ± 13.65) 4.19 ( ± 3.79) 14.22 (2.53–25.90) 2.80 0.022 Urine output. mL/kg/hr. † 4.6 ( ± 2.2) 6 ( ± 1.8) -1.4 (− 2.77 − 0.06) -2.21 0.042 Pulse oximetry Postductal. † 96 ( ± 2) 88 ( ± 4.3) 6.3 (4.1–8.5) 6.03 0.0002 n: sample size, pCO₂: partial pressure of carbon dioxide, pVO₂: venous partial pressure of oxygen, SvO₂:venous oxygen saturation, HCO₃⁻: bicarbonate, HR: Hour, Δ: Delta, CI: confidence interval, IQR: Interquartile range, SD: Standard deviation, Mean difference (Δ) was analyzed using a paired t−test, * Median change (Δ) was assessed using the Wilcoxon signed−rank test. A p−value < 0.05 was considered statistically significant for both statistical tests. ** For urine output and postductal pulse oximetry, the sample size was 17. confidence interval, IQR : Interquartile range, SD : Standard deviation, † Mean SD, ‡ Median (IQR) No significant changes were observed in the pCO₂, venous pO₂, venous oxygen saturation, bicarbonate, or base excess. Lactate levels decreased, with a mean difference of 0.47 mmol/L (p = 0.009). Qp/Qs values showed an average decrease of 14.22 units at 6 hours compared to Hour 0 (95% CI: 2.53–25.90). Qp/Qs was calculated using venous saturation obtained from blood gas analysis, whereas arterial saturation was estimated using pulse oximetry. A hypothetical pulmonary arterial saturation of 95% was assumed for calculations. A reduction in pulse oximetry was observed 12 h after the start of the mixture, with an average decrease of 6 percentage points (p = 0.0002; 95% CI: 4–8). This variable was evaluated in all 17 patients in the study. Discussion In Colombia, the management of congenital heart diseases has advanced significantly; however, there is limited experience with therapies such as hypoxic mixture, and no local studies support their use. Therefore, this study was conducted at a high-complexity institution recognized as a referral center for congenital heart disease in Latin America. Since the 1990s, studies with limited populations have been reported, revealing gaps in the specific indications for the use of hypoxic mixture. Despite this, it has been proposed as a preoperative strategy for congenital heart diseases with univentricular physiology, especially hypoplastic left heart syndrome [8,9]. Although the use of hypoxic mixture is limited, it represents a potentially useful therapeutic strategy in low-resource countries by stabilizing children with conditions such as low birth weight or comorbidities that complicate the immediate correction or palliation of heart defects, in addition to the limited availability of cardiovascular surgery or interventional hemodynamics [8,11,14]. An important part of the studies has employed the hypoxic mixture in infants younger than 6 months, mainly term neonates with congenital heart diseases, mostly univentricular, such as hypoplastic left heart syndrome, Shone’s syndrome, and biventricular defects such as truncus arteriosus, atrioventricular canal, aortic coarctation, and tricuspid atresia [10, 14–16]. In contrast, most of the children included in this study were term neonates, with a predominance of biventricular heart diseases (88.2%) compared to univentricular heart diseases (11.8%), the most frequent being hypoplasia of the aortic arch with ventricular septal defect, followed by truncus arteriosus and atrioventricular canal. While the hypoxic mixture appears safe in term newborns, its use in preterm infants raises concerns, especially regarding possible adverse effects on neurological development, generating apprehension among neonatologists regarding its safety. However, Tan et al. applied this therapy to six preterm infants with gestational ages between 25 and 32 weeks and weights of nearly 1,200 grams, administering an 18% hypoxic mixture for 48 hours as preoperative management after ductal closure failure with indomethacin, and reported improvements in pH, systolic pressure, and urine output [10]. Additionally, there is no consensus on the FiO₂ concentration administered with the hypoxic mixture or on the duration of this therapy in children. Some authors have reported using FiO₂ concentrations between 15% and 20%, applied for periods ranging from 10 minutes to approximately 180 days in the preoperative stage 1,5,10,16. In our experience, hypoxic mixture was used with FiO₂ between 14% and 18%, with an average duration of 7.5 days (SD ± 5.4) and good tolerance. Devices used to administer hypoxic mixture include invasive mechanical ventilation, high-flow nasal cannulas, CPAP, and Hood chambers [10,14]. This therapy offers a relevant advantage over other strategies, such as 3% carbon dioxide, which generally requires invasive mechanical ventilation and sedation for use in the pediatric population [5]. In relation to hemodynamic and blood gas effects, significant changes have been documented in heart rate, blood pressure, oxygen saturation, and urine output, assessed at various time points after the initiation of hypoxic mixture therapy [15,16]. However, in this study, heart rate did not show a significant reduction over the first 24 h, findings consistent with those reported by Tabbutt et al. 5 with an average of 153 ± 4 bpm (p = 0.30), and by Ramamoorthy et al., who also found no significant differences when comparing the response to hypoxic mixture versus 3% carbon dioxide (152 ± 17 vs. 150 ± 20 bpm) [16]. Systolic blood pressure appears to respond favorably to the hypoxic mixture, with a significant increase when comparing values before therapy initiation with those obtained at 24 h [14]. Other researchers have reported an increase in blood pressure from 44 ± 8.8 mmHg to 55 ± 7 mmHg (p = 0.03) within 30 minutes after starting the mixture [10]. In our cohort, a significant increase in systolic pressure was observed at 12 h compared to 6 h post-initiation (p = 0.048). Meanwhile, Tabbutt et al. found improvement only with 2.7% CO₂ (68.5 ± 4.6 mmHg; p = 0.02), compared to the hypoxic mixture (61.2 ± 3.4 mmHg; p = 0.79) [5]. Likewise, pulse oximetry is a key aspect of evaluating the response to hypoxic mixture. In this study, significant differences were observed in postductal saturation levels at 6, 12, and 24 h after therapy initiation (p < 0.0001). These results are consistent with those of Thomas et al., who reported a significant decrease in saturation between 12 and 24 h (91.7 ± 6.6 vs. 86.0 ± 6.5; p < 0.005), in agreement with other studies [10,14]. In contrast, Tan et al. documented significant changes within the first 30 min of therapy (97 ± 4% vs. 94 ± 4%; p = 0.03) [10]. Urine output, considered a relevant clinical outcome and an indirect marker of systemic blood flow in patients under hypoxic mixture therapy, has shown significant increases between 8- and 24-hours post- therapy initiation [10]. Shime et al. reported improvements as early as the third hour after administration [15]. In our study, urine output was evaluated at 12 h, showing an average increase of 1.4 mL/kg/h compared to the baseline value before therapy initiation. In addition to its hemodynamic impact, the hypoxic mixture induces changes in blood gas parameters, including pH, lactate, PCO₂, and PaO₂, which are considered key markers of the Qp/Qs balance and an indirect measure of effective microcirculation [6]. Tabbutt et al. reported a significant increase in pH with the use of this therapy (p = 0.012) [5]; however, in our study, a decrease of 0.073 units was observed at 6 h after starting the hypoxic mixture. Similarly, lactate values decreased by 0.47 mmol/L at 6 h after initiating the hypoxic mixture, in contrast to the study by Thomas et al., who did not report significant changes in this parameter [14]. Although blood gas analysis allows estimation of the Qp/Qs ratio, its precise calculation requires data on pulmonary venous saturation, which represents a technical limitation [10]. Most studies have assumed a pulmonary venous saturation of 99%. Only two investigations have documented significant reductions in Qp/Qs after 24 h of hypoxic mixture therapy initiation (from 9.9 SD ± 13 to 3.3 SD ± 3.6) [14]. In our series, Qp/Qs was evaluated at 6 h, showing a decrease from 18.4 SD ± 13.6 to 4.9 SD ± 3.7, assuming a pulmonary venous saturation of 95% and using pulse oximetry as an estimator of arterial saturation due to the lack of arterial blood gas analysis. Finally, although the results of this study were based on parameters obtained through venous blood gas analysis, the findings were consistent with those reported in studies using arterial blood gas analysis, suggesting that both methodologies may be useful in the clinical evaluation of pulmonary overcirculation status and its effects on pulmonary flow and microcirculation, particularly in the context of Qp/Qs imbalance [14, 16]. While some concerns about the use of hypoxic mixture is grounded in the lack of solid evidence, this strategy has demonstrated relevant physiological effects with potential clinical impact in patients with pulmonary overcirculation. The lack of conclusive results may be attributed to the small sample size, which could explain the absence of significant differences in some outcomes [8]. Limitations One of the main limitations was the absence of evaluation of NIRS behavior, a key tool for assessing the neurological risk associated with hypoxemia, which requires complementing imaging studies for comprehensive interpretation. This study demonstrated relevant clinical and physiological changes following the administration of a hypoxic mixture, even with a small sample size, supporting the need for further multicenter research to consolidate its utility in managing pulmonary overcirculation and contribute to reducing morbidity and mortality associated with inadequate management of pulmonary overcirculation in contexts with limited access to timely cardiovascular surgery. Conclusions In resource-limited settings, hypoxic mixture therapy could be considered an effective and cost-efficient strategy to optimize hemodynamic management in patients with congenital heart disease and pulmonary overcirculation. Its application enables stabilization of the Qp/Qs ratio and improves systemic perfusion during the preoperative stage, particularly in the absence of immediate access to surgical or hemodynamic intervention. Declarations Conflict of interest: The authors declare no conflict of interest. Funding source: This study received no external funding. Author Contribution MGR, DMC, KMS, LMA contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by the authors, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Nagao H, Tanaka T (2021) The Effect of Hypoxic Gas Therapy Using Nitrogen Before Bilateral Pulmonary Artery Banding on Hemodynamics and Pulmonary Artery Development. 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Pediatr Res 58:521–524. https://doi.org/10.1203/01.pdr.0000176913.41568.9d World Medical Association (2024) WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. https://doi.org/10.1001/jama.2013.281053 Thomas L, Flores S, Wong J, Loomba R (2019) Acute Effects of Hypoxic Gas Admixtures on Pulmonary Blood Flow and Regional Oxygenation in Children Awaiting Norwood Palliation. Cureus 11:5693. https://doi.org/10.7759/cureus.5693 Shime N, Hashimoto S, Hiramatsu N, Oka T, Kageyama K, Tanaka Y (2000) Hypoxic gas therapy using nitrogen in the preoperative management of neonates with hypoplastic left heart syndrome. Pediatr Crit Care Med 1:38–41. https://doi.org/10.1097/00130478-200007000-00007 Ramamoorthy C, Tabbutt S, Dean Kurth C et al (2002) Effects of Inspired Hypoxic and Hypercapnic Gas Mixtures on Cerebral Oxygen Saturation in Neonates with Univentricular Heart Defects. Anesthesiology 96:283–288. https://doi.org/10.1097/00000542-200202000-00010 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9431166","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":628327571,"identity":"30cdb607-9e46-443c-b5c8-84b2b4c35b08","order_by":0,"name":"María Gabriela Ramírez Guerrero¹","email":"","orcid":"","institution":"Hospital Internacional de Colombia","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Gabriela Ramírez","lastName":"Guerrero¹","suffix":""},{"id":628327572,"identity":"80118b4c-0a00-474a-8b86-b3c98ed82e67","order_by":1,"name":"Diana Marcela Galván Canchila³","email":"","orcid":"","institution":"University of Santander","correspondingAuthor":false,"prefix":"","firstName":"Diana","middleName":"Marcela Galván","lastName":"Canchila³","suffix":""},{"id":628327573,"identity":"d577b99e-fd24-4363-a5c2-e6ec0e7eb5cb","order_by":2,"name":"Keyla Milena Meneses Silvera²","email":"","orcid":"","institution":"Fundación Cardiovascular de Colombia","correspondingAuthor":false,"prefix":"","firstName":"Keyla","middleName":"Milena Meneses","lastName":"Silvera²","suffix":""},{"id":628327574,"identity":"a6e5ceb5-46a0-4c98-a355-e5760e7319f5","order_by":3,"name":"Laura Isabel Manosalva Arciniegas²","email":"data:image/png;base64,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","orcid":"","institution":"Fundación Cardiovascular de Colombia","correspondingAuthor":true,"prefix":"","firstName":"Laura","middleName":"Isabel Manosalva","lastName":"Arciniegas²","suffix":""}],"badges":[],"createdAt":"2026-04-15 21:38:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9431166/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9431166/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107697024,"identity":"323ac847-d36a-442d-97d8-d9c487c1eedf","added_by":"auto","created_at":"2026-04-24 07:19:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":101130,"visible":true,"origin":"","legend":"\u003cp\u003eProfile of congenital heart diseases treated with hypoxic gas mixture\u003c/p\u003e\n\u003cp\u003eAAH: Aortic Arch Hypoplasia, TA: Truncus Arteriosus, AVC: Atrioventricular Canal, PDA: Patent Ductus Arteriosus, DORV: Double Outlet Right Ventricle, VSD: Ventricular Septal Defect, APW: Aortopulmonary Window, EA: Ebstein's anomaly, HLHS: Hypoplastic Left Heart Syndrome, SV: Single Ventricle, IAA: Interrupted Aortic Arch.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9431166/v1/b3902c115045e46caad80fd8.png"},{"id":107697025,"identity":"bd24bd89-c421-46b3-bf5b-2e6091d4c6a3","added_by":"auto","created_at":"2026-04-24 07:19:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":154078,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in clinical and hemodynamic variables before and after initiation of the hypoxic mixture\u003c/p\u003e\n\u003cp\u003eThe following are shown: (a) heart rate (bpm), (b) systolic blood pressure (mmHg), (c) mean arterial pressure (mmHg), and (d) postductal oxygen saturation (%). Mean values with their corresponding confidence intervals are presented at each evaluation time point (hour 0, 1, 6, 12, and 24)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9431166/v1/48793256eeb28704b9d1c833.png"},{"id":107707967,"identity":"911ccf20-3811-44f3-85ad-722879085619","added_by":"auto","created_at":"2026-04-24 09:21:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":570772,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9431166/v1/5bc12e62-83a2-4abe-a29f-7caf7cfac5f8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hypoxic Mixture as a Preoperative Strategy in Congenital Heart Disease with Pulmonary Overcirculation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn children with univentricular and biventricular congenital heart defects, postnatal decrease in pulmonary vascular resistance leads to a hemodynamic imbalance characterized by the predominance of blood flow to the pulmonary circulation (left-to-right shunt), resulting in reduced systemic blood flow. This phenomenon is known as pulmonary overcirculation [1].\u003c/p\u003e \u003cp\u003eThe hemodynamic consequences of pulmonary overcirculation depend on the magnitude of the shunt and the affected cardiac anatomy, which directly correlate with the volume of blood diverted from the systemic arterial vascular bed to the pulmonary vasculature [1,2].\u003c/p\u003e \u003cp\u003eVarious strategies have been described to prevent pulmonary overcirculation and secondary shock, focusing on increasing pulmonary vascular resistance to regulate the Qp/Qs ratio (Qp: pulmonary blood flow / Qs: systemic blood flow), with a target value of \u0026le;\u0026thinsp;0.7 to optimize systemic perfusion. This ratio quantifies the hemodynamic balance between the two circulatory beds: a Qp/Qs ratio\u0026thinsp;\u0026gt;\u0026thinsp;1 indicates pulmonary flow predominance, whereas a Qp/Qs ratio\u0026thinsp;\u0026lt;\u0026thinsp;1 indicates greater systemic flow [3,4]. Mathematical models suggest that maintaining this ratio between 0.7 and 1 preserves adequate tissue oxygenation through sufficient systemic blood flow [5].\u003c/p\u003e \u003cp\u003eAmong the most notable strategies are the use of prostaglandins, vasodilators, inotropes, red blood cell transfusions, positive airway pressure, as well as the application of hypoxic mixture (with inspired oxygen fraction [FiO₂] below 21%) and 3% carbon dioxide [4,5].\u003c/p\u003e \u003cp\u003eThe hypoxic mixture was first used in animal models in 1996 by Reddy et al., who reported their experience administering hypoxic gas (10% FiO₂) to sheep after creating a shunt from the main artery to the pulmonary artery [6]. The active principle of this therapy is the effect of nitrogen, which displaces oxygen molecules, preventing their potent pulmonary vasodilator effect [7].\u003c/p\u003e \u003cp\u003eRegarding clinical evidence, a hypoxic mixture was first used in 1998 by Day et al. as a preoperative strategy in the management of hypoplastic left heart syndrome (HLHS), demonstrating its clinical efficacy. Since then, its use has expanded globally, with notable results in Japan, the United States, and Spain. However, evidence remains limited in Latin America, especially in patients with biventricular physiology, highlighting the need for further studies in this subgroup [6,8,9].\u003c/p\u003e \u003cp\u003eHypoxic mixture is a safe, economical, and effective strategy that can be applied with or without mechanical ventilation [10]. It has been suggested to maintain an FiO₂ between 0.14 and 0.20 to induce pulmonary hypoxic vasoconstriction, increasing pulmonary vascular resistance and optimizing the Qp/Qs ratio. In patients with univentricular physiology, the target postductal oxygen saturation is 75\u0026ndash;85%, whereas in biventricular patients, the goal is approximately 90%. A mixed venous saturation of 55\u0026ndash;60% is recommended 7\u0026ndash;11. This approach improves blood pressure, urine output, and tissue perfusion, preventing acidosis, coronary or cerebral ischemia, and multiorgan damage [10, 11].\u003c/p\u003e \u003cp\u003eHowever, concerns persist regarding the potential development of neurological complications secondary to cerebral hypoxia. Although several studies have evaluated cerebral oxygenation during this therapy, a safe FiO₂ threshold has not yet been established [10,12,13]. A recent meta-analysis identified only four studies that reported Near-Infrared Spectroscopy (NIRS) values before and after hypoxic mixture administration, with no statistically significant changes [8].\u003c/p\u003e \u003cp\u003eAlthough the hypoxic mixture has fallen out of use, in some centers, including those in low- and middle- income countries, critical care management for these patients relies on hypercapnia and hypoxic mixture as a bridge therapy to corrective or palliative surgery [8]. Therefore, the objective of the present study was to describe the effects of hypoxic mixture administration in pediatric patients with congenital heart disease and pulmonary overcirculation.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePopulation and study design\u003c/h2\u003e \u003cp\u003eAn observational, descriptive, longitudinal, prospective study was conducted on a single group of 17 infants under 1 year old with congenital heart disease and pulmonary overcirculation physiology. These patients were admitted to a cardiovascular intensive care unit at a referral hospital in Colombia between July 1 and December 31, 2024.\u003c/p\u003e \u003cp\u003eThis study evaluated the use of a hypoxic mixture, which is part of the standard therapy for managing this patient group. Hemodynamic and blood gas variables were monitored before the initiation of the hypoxic mixture (Hour 0) and subsequently at hours 1, 6, 12, and 24 to assess the response to hypoxic mixture therapy, with the administered concentration varying according to each patient\u0026rsquo;s tolerance.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility Criteria Inclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInfants under 1 year old with congenital heart disease and pulmonary overcirculation who were admitted to the intensive care unit and required hypoxic mixture as part of the preoperative management of pulmonary overcirculation were included. The hypoxic mixture was administered via a high-flow nasal cannula, nasal CPAP, or invasive and noninvasive mechanical ventilation.\u003c/p\u003e\n\u003ch3\u003eExclusion Criteria\u003c/h3\u003e\n\u003cp\u003ePediatric patients requiring hypoxic mixture in the postoperative period of cardiovascular surgery and children with infectious or anatomical pulmonary pathologies.\u003c/p\u003e\n\u003ch3\u003eVariables\u003c/h3\u003e\n\u003cp\u003eDemographic variables, including age, sex, weight, gestational age, and associated comorbidities, were collected. Clinical variables were also recorded before and after the initiation of hypoxic mixture therapy (at times 0, 1, 6, 12, and 24 h), including heart rate, blood pressure (systolic, diastolic, and mean), oxygen saturation, and urine output (measured during the 12 h before and after therapy).\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eData were collected from the medical records and telemetry logs of children who met the inclusion criteria. Information was recorded in a digital form (Google Forms) and then exported to Microsoft Excel\u0026reg; for cleaning and statistical analysis. Patient identities were protected using unique numerical codes assigned by the research team.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eQualitative variables were described using absolute frequency. Quantitative variables with a normal distribution were analyzed using the mean and standard deviation; otherwise, the median and interquartile range were used. For bivariate analysis, the paired t-test or Wilcoxon test was applied, depending on the data distribution. For quantitative variables with a normal distribution, repeated measures ANOVA with Bonferroni correction was used, with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were conducted using STATA 18.0 software (College Station, TX, USA).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003e The principles of confidentiality and privacy established in the Declaration of Helsinki (13) were strictly followed to ensure the protection of personal and sensitive data. The research protocol was reviewed and approved by the hospital\u0026rsquo;s Research Ethics Committee.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSeventeen infants under 1 year old diagnosed with congenital heart disease and pulmonary overcirculation physiology were included in this study. They were admitted to the pediatric cardiovascular intensive care unit between July and December 2024 and required hypoxic mixture therapy during the preoperative period.\u003c/p\u003e \u003cp\u003eRegarding demographic characteristics, males predominated (10 /17 58.8%). The median age at the start of hypoxic mixture therapy was 11 days of life (IQR: 4\u0026ndash;17), with an average weight of 2,990 g (SD\u0026thinsp;\u0026plusmn;\u0026thinsp;471). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study population.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDemographic and Clinical Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;17 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (58.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (41.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (days). Median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (4\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight (grams). Mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2990 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;471)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational age (weeks). Median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.3 (37\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eGenetic syndromes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (58.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDown syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (29.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiGeorge syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTurner syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eType of congenital heart disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBiventricular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (88.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUniventricular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (11.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of respiratory support\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvasive mechanical ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (41.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNasal CPAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (35.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh-flow nasal cannula\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (23.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive end-expiratory pressure (PEEP) cm H₂O. Median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (8\u0026ndash;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003eFraction of inspired oxygen (FiO₂)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (23.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (11.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (41.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDays of hypoxic mixture therapy. Mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eType of inotropic support\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMilrinone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (41.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEpinephrine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (17.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEpinephrine +Milrinone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (17.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (23.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUse of prostaglandin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (23.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (76.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cb\u003eIQR\u003c/b\u003e: Interquartile Range, \u003cb\u003eSD\u003c/b\u003e: Standard Deviation, \u003cb\u003eCPAP\u003c/b\u003e: Continuous Positive Airway Pressure, \u003cb\u003ePEEP\u003c/b\u003e: Positive End\u0026minus;Expiratory Pressure, \u003cb\u003eFiO₂\u003c/b\u003e: Fraction of Inspired Oxygen\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTwenty-nine point four percent of the patients had Down syndrome (5/17), followed by DiGeorge syndrome and Turner syndrome. Pulmonary overcirculation heart defects were classified as biventricular (15/17, 88.2%) and univentricular (2/17, 11.8%). The most common defect observed was aortic arch hypoplasia with a ventricular septal defect, followed by truncus arteriosus, atrioventricular canal, and patent ductus arteriosus. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAAH: Aortic Arch Hypoplasia, TA: Truncus Arteriosus, AVC: Atrioventricular Canal, PDA: Patent Ductus Arteriosus, DORV: Double Outlet Right Ventricle, VSD: Ventricular Septal Defect, APW: Aortopulmonary Window, EA: Ebstein's anomaly, HLHS: Hypoplastic Left Heart Syndrome, SV: Single Ventricle, IAA: Interrupted Aortic Arch.\u003c/p\u003e \u003cp\u003eThe hypoxic mixture was administered as part of conventional pulmonary overcirculation management with an inspired oxygen fraction (FiO₂) between 14 and 17%, and the therapy lasted an average of 7.5 days (SD\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4).\u003c/p\u003e \u003cp\u003eThe respiratory support devices used to deliver the hypoxic mixture were invasive mechanical ventilation (7/17, 41.2%), nasal CPAP, and high-flow nasal cannula. Milrinone was the most commonly used inotrope (7/17, 41.1%), followed by epinephrine. Prostaglandin, used to maintain systemic flow through the ductus arteriosus, was administered in (4/17) 23.5% of cases. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eHemodynamic Response in Patients Undergoing Hypoxic Mixture Therapy\u003c/h2\u003e \u003cp\u003eHemodynamic changes in children treated with hypoxic mixture were evaluated at five time points: before initiation (Hour 0) and at 1, 6, 12, and 24 h. Heart rate (HR) showed no significant differences across the evaluated time points (p\u0026thinsp;=\u0026thinsp;0.22) or when comparing pre-therapy values with post-therapy values (p\u0026thinsp;=\u0026thinsp;1.0). (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe following are shown: (a) heart rate (bpm), (b) systolic blood pressure (mmHg), (c) mean arterial pressure (mmHg), and (d) postductal oxygen saturation (%). Mean values with their corresponding confidence intervals are presented at each evaluation time point (hour 0, 1, 6, 12, and 24)\u003c/p\u003e \u003cp\u003eSystolic blood pressure did not show significant differences in the mean values measured at the different intervals compared to therapy initiation (p\u0026thinsp;=\u0026thinsp;0.062). However, a significant increase in systolic blood pressure was observed when comparing measurements at 6 and 12 h, with a higher mean value at 12 h (p\u0026thinsp;=\u0026thinsp;0.048).\u003c/p\u003e \u003cp\u003ePulse oximetry showed significant changes after starting the hypoxic mixture (p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001), mainly between 0 and 6, 12, and 24 h. Urine output increased at 12 h after the start of hypoxic mixture therapy, with an average increase of 1.4 mL/kg/h (p\u0026thinsp;=\u0026thinsp;0.04). (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHemodynamic changes associated with hypoxic mixture administration.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvaluation timelines n\u0026thinsp;=\u0026thinsp;17\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 hours\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep - value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeart Rate\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e149 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e144 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e139 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e144 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e146 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSystolic Arterial Pressure\u003c/b\u003e \u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e74 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e77 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e74 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e81 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e76 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiastolic Arterial Pressure\u003c/b\u003e \u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e41(\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e41(\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e40 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e43 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e39 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean Arterial Pressure\u003c/b\u003e \u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e51 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e52(\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e50 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e54 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e50 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSaturation of Oxygen\u003c/b\u003e \u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e96 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e93(\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e90 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e88 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e88 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e18.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003en: sample size * Mean SD: Standard Deviation. F statistic in an ANOVA analysis that evaluates the differences in means between groups. Significant p\u0026minus;value less than 0.05\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eChanges in venous blood gas were evaluated after 6 h of hypoxic mixture therapy, compared to baseline (Hour 0). Of the 17 patients in the study, only nine had central venous access inserted at the jugular or subclavian vein level for sampling.\u003c/p\u003e \u003cp\u003eVenous blood gas analysis revealed a significant decrease in pH at 6 hours after initiation of the hypoxic mixture, with an average change of 0.073 units (p\u0026thinsp;=\u0026thinsp;0.041; 95% CI: 0.003\u0026ndash;0.14). The initial pH was higher than that recorded at 6 h. (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in blood gas and clinical parameters before and after hypoxic mixture therapy.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore hypoxic mixture\u003c/p\u003e \u003cp\u003e(0 HR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter hypoxic mixture\u003c/p\u003e \u003cp\u003e(6HR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eΔ Mean\u003c/p\u003e \u003cp\u003e(CI 95%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003et-test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003epH.\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.36 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.064)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.29 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.091)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.073 (0.003\u0026ndash;0.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.041\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003epCO₂. mmHg.\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.46 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.29 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;13.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-9.83 (\u0026minus;\u0026thinsp;21.85\u0026ndash;2.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003epVO₂. mmHg. Median (IQR)\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026Dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.9 (28.1\u0026ndash;35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.6 (31.8\u0026ndash;40.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.35 (-7.3\u0026ndash;7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSVO₂.\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.78 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;14.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.06 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;11.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.72 (-5.7\u0026ndash;11.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHCO₃. mEq/L\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026Dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.30 (24.4\u0026ndash;31.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.1 (26.2\u0026ndash;30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.55 (-1.4\u0026ndash;129)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBE. mmol/L\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.74 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;3.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.24 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;4.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.50 (\u0026minus;\u0026thinsp;0.04\u0026ndash;3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLactate. mmol/L\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026Dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.89 (1.58\u0026ndash;2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.39 (1.19\u0026ndash;1.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.47 (0.26\u0026ndash;1.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eQp/Qs.\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.42 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;13.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.19 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;3.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.22 (2.53\u0026ndash;25.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine output. mL/kg/hr.\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.6 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.4 (\u0026minus;\u0026thinsp;2.77\u0026thinsp;\u0026minus;\u0026thinsp;0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-2.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.042\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePulse oximetry Postductal.\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.3 (4.1\u0026ndash;8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.0002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003en: sample size, pCO₂: partial pressure of carbon dioxide, pVO₂: venous partial pressure of oxygen, SvO₂:venous oxygen saturation, HCO₃⁻: bicarbonate, HR: Hour, Δ: Delta, CI: confidence interval, IQR: Interquartile range, SD: Standard deviation, Mean difference (Δ) was analyzed using a paired t\u0026minus;test, * Median change (Δ) was assessed using the Wilcoxon signed\u0026minus;rank test. A p\u0026minus;value \u0026lt; 0.05 was considered statistically significant for both statistical tests. ** For urine output and postductal pulse oximetry, the sample size was 17.\u003c/b\u003e confidence interval, \u003cb\u003eIQR\u003c/b\u003e: Interquartile range, \u003cb\u003eSD\u003c/b\u003e: Standard deviation, \u003cb\u003e\u0026dagger; Mean SD, \u0026Dagger; Median (IQR)\u003c/b\u003e\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNo significant changes were observed in the pCO₂, venous pO₂, venous oxygen saturation, bicarbonate, or base excess. Lactate levels decreased, with a mean difference of 0.47 mmol/L (p\u0026thinsp;=\u0026thinsp;0.009).\u003c/p\u003e \u003cp\u003eQp/Qs values showed an average decrease of 14.22 units at 6 hours compared to Hour 0 (95% CI: 2.53\u0026ndash;25.90). Qp/Qs was calculated using venous saturation obtained from blood gas analysis, whereas arterial saturation was estimated using pulse oximetry. A hypothetical pulmonary arterial saturation of 95% was assumed for calculations.\u003c/p\u003e \u003cp\u003eA reduction in pulse oximetry was observed 12 h after the start of the mixture, with an average decrease of 6 percentage points (p\u0026thinsp;=\u0026thinsp;0.0002; 95% CI: 4\u0026ndash;8). This variable was evaluated in all 17 patients in the study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn Colombia, the management of congenital heart diseases has advanced significantly; however, there is limited experience with therapies such as hypoxic mixture, and no local studies support their use. Therefore, this study was conducted at a high-complexity institution recognized as a referral center for congenital heart disease in Latin America.\u003c/p\u003e \u003cp\u003eSince the 1990s, studies with limited populations have been reported, revealing gaps in the specific indications for the use of hypoxic mixture. Despite this, it has been proposed as a preoperative strategy for congenital heart diseases with univentricular physiology, especially hypoplastic left heart syndrome [8,9].\u003c/p\u003e \u003cp\u003eAlthough the use of hypoxic mixture is limited, it represents a potentially useful therapeutic strategy in low-resource countries by stabilizing children with conditions such as low birth weight or comorbidities that complicate the immediate correction or palliation of heart defects, in addition to the limited availability of cardiovascular surgery or interventional hemodynamics [8,11,14].\u003c/p\u003e \u003cp\u003eAn important part of the studies has employed the hypoxic mixture in infants younger than 6 months, mainly term neonates with congenital heart diseases, mostly univentricular, such as hypoplastic left heart syndrome, Shone\u0026rsquo;s syndrome, and biventricular defects such as truncus arteriosus, atrioventricular canal, aortic coarctation, and tricuspid atresia [10, 14\u0026ndash;16].\u003c/p\u003e \u003cp\u003eIn contrast, most of the children included in this study were term neonates, with a predominance of biventricular heart diseases (88.2%) compared to univentricular heart diseases (11.8%), the most frequent being hypoplasia of the aortic arch with ventricular septal defect, followed by truncus arteriosus and atrioventricular canal.\u003c/p\u003e \u003cp\u003eWhile the hypoxic mixture appears safe in term newborns, its use in preterm infants raises concerns, especially regarding possible adverse effects on neurological development, generating apprehension among neonatologists regarding its safety. However, Tan et al. applied this therapy to six preterm infants with gestational ages between 25 and 32 weeks and weights of nearly 1,200 grams, administering an 18% hypoxic mixture for 48 hours as preoperative management after ductal closure failure with indomethacin, and reported improvements in\u003c/p\u003e \u003cp\u003epH, systolic pressure, and urine output [10].\u003c/p\u003e \u003cp\u003eAdditionally, there is no consensus on the FiO₂ concentration administered with the hypoxic mixture or on the duration of this therapy in children. Some authors have reported using FiO₂ concentrations between 15% and 20%, applied for periods ranging from 10 minutes to approximately 180 days in the preoperative stage 1,5,10,16. In our experience, hypoxic mixture was used with FiO₂ between 14% and 18%, with an average duration of 7.5 days (SD\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4) and good tolerance.\u003c/p\u003e \u003cp\u003eDevices used to administer hypoxic mixture include invasive mechanical ventilation, high-flow nasal cannulas, CPAP, and Hood chambers [10,14]. This therapy offers a relevant advantage over other strategies, such as 3% carbon dioxide, which generally requires invasive mechanical ventilation and sedation for use in the pediatric population [5].\u003c/p\u003e \u003cp\u003eIn relation to hemodynamic and blood gas effects, significant changes have been documented in heart rate, blood pressure, oxygen saturation, and urine output, assessed at various time points after the initiation of hypoxic mixture therapy [15,16]. However, in this study, heart rate did not show a significant reduction over the first 24 h, findings consistent with those reported by Tabbutt et al. 5 with an average of 153\u0026thinsp;\u0026plusmn;\u0026thinsp;4 bpm (p\u0026thinsp;=\u0026thinsp;0.30), and by Ramamoorthy et al., who also found no significant differences when comparing the response to hypoxic mixture versus 3% carbon dioxide (152\u0026thinsp;\u0026plusmn;\u0026thinsp;17 vs. 150\u0026thinsp;\u0026plusmn;\u0026thinsp;20 bpm) [16].\u003c/p\u003e \u003cp\u003eSystolic blood pressure appears to respond favorably to the hypoxic mixture, with a significant increase when comparing values before therapy initiation with those obtained at 24 h [14]. Other researchers have reported an increase in blood pressure from 44\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 mmHg to 55\u0026thinsp;\u0026plusmn;\u0026thinsp;7 mmHg (p\u0026thinsp;=\u0026thinsp;0.03) within 30 minutes after starting the mixture [10]. In our cohort, a significant increase in systolic pressure was observed at 12 h compared to 6 h post-initiation (p\u0026thinsp;=\u0026thinsp;0.048). Meanwhile, Tabbutt et al. found improvement only with 2.7% CO₂ (68.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 mmHg; p\u0026thinsp;=\u0026thinsp;0.02), compared to the hypoxic mixture (61.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 mmHg; p\u0026thinsp;=\u0026thinsp;0.79) [5].\u003c/p\u003e \u003cp\u003eLikewise, pulse oximetry is a key aspect of evaluating the response to hypoxic mixture. In this study, significant differences were observed in postductal saturation levels at 6, 12, and 24 h after therapy initiation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). These results are consistent with those of Thomas et al., who reported a significant decrease in saturation between 12 and 24 h (91.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6 vs. 86.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5; p\u0026thinsp;\u0026lt;\u0026thinsp;0.005), in agreement with other studies [10,14]. In contrast, Tan et al. documented significant changes within the first 30 min of therapy (97\u0026thinsp;\u0026plusmn;\u0026thinsp;4% vs. 94\u0026thinsp;\u0026plusmn;\u0026thinsp;4%; p\u0026thinsp;=\u0026thinsp;0.03) [10].\u003c/p\u003e \u003cp\u003eUrine output, considered a relevant clinical outcome and an indirect marker of systemic blood flow in patients under hypoxic mixture therapy, has shown significant increases between 8- and 24-hours post- therapy initiation [10]. Shime et al. reported improvements as early as the third hour after administration [15]. In our study, urine output was evaluated at 12 h, showing an average increase of 1.4 mL/kg/h compared to the baseline value before therapy initiation.\u003c/p\u003e \u003cp\u003eIn addition to its hemodynamic impact, the hypoxic mixture induces changes in blood gas parameters, including pH, lactate, PCO₂, and PaO₂, which are considered key markers of the Qp/Qs balance and an indirect measure of effective microcirculation [6]. Tabbutt et al. reported a significant increase in pH with the use of this therapy (p\u0026thinsp;=\u0026thinsp;0.012) [5]; however, in our study, a decrease of 0.073 units was observed at 6 h after starting the hypoxic mixture. Similarly, lactate values decreased by 0.47 mmol/L at 6 h after initiating the hypoxic mixture, in contrast to the study by Thomas et al., who did not report significant changes in this parameter [14].\u003c/p\u003e \u003cp\u003eAlthough blood gas analysis allows estimation of the Qp/Qs ratio, its precise calculation requires data on pulmonary venous saturation, which represents a technical limitation [10]. Most studies have assumed a pulmonary venous saturation of 99%. Only two investigations have documented significant reductions in Qp/Qs after 24 h of hypoxic mixture therapy initiation (from 9.9 SD\u0026thinsp;\u0026plusmn;\u0026thinsp;13 to 3.3 SD\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6) [14]. In our series, Qp/Qs was evaluated at 6 h, showing a decrease from 18.4 SD\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6 to 4.9 SD\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7, assuming a pulmonary venous saturation of 95% and using pulse oximetry as an estimator of arterial saturation due to the lack of arterial blood gas analysis.\u003c/p\u003e \u003cp\u003eFinally, although the results of this study were based on parameters obtained through venous blood gas analysis, the findings were consistent with those reported in studies using arterial blood gas analysis, suggesting that both methodologies may be useful in the clinical evaluation of pulmonary overcirculation status and its effects on pulmonary flow and microcirculation, particularly in the context of Qp/Qs imbalance [14, 16].\u003c/p\u003e \u003cp\u003eWhile some concerns about the use of hypoxic mixture is grounded in the lack of solid evidence, this strategy has demonstrated relevant physiological effects with potential clinical impact in patients with pulmonary overcirculation. The lack of conclusive results may be attributed to the small sample size, which could explain the absence of significant differences in some outcomes [8].\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOne of the main limitations was the absence of evaluation of NIRS behavior, a key tool for assessing the neurological risk associated with hypoxemia, which requires complementing imaging studies for comprehensive interpretation.\u003c/p\u003e \u003cp\u003eThis study demonstrated relevant clinical and physiological changes following the administration of a hypoxic mixture, even with a small sample size, supporting the need for further multicenter research to consolidate its utility in managing pulmonary overcirculation and contribute to reducing morbidity and mortality associated with inadequate management of pulmonary overcirculation in contexts with limited access to timely cardiovascular surgery.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn resource-limited settings, hypoxic mixture therapy could be considered an effective and cost-efficient strategy to optimize hemodynamic management in patients with congenital heart disease and pulmonary overcirculation. Its application enables stabilization of the Qp/Qs ratio and improves systemic perfusion during the preoperative stage, particularly in the absence of immediate access to surgical or hemodynamic intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest:\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding source:\u003c/h2\u003e \u003cp\u003eThis study received no external funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMGR, DMC, KMS, LMA contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by the authors, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNagao H, Tanaka T (2021) The Effect of Hypoxic Gas Therapy Using Nitrogen Before Bilateral Pulmonary Artery Banding on Hemodynamics and Pulmonary Artery Development. Pediatr Cardiol 42:637\u0026ndash;642. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00246-020-02524-7\u003c/span\u003e\u003cspan address=\"10.1007/s00246-020-02524-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrushansky E, Burbano N, Morell V et al (2012) Preoperative Management in Patients with Single-ventricle Physiology. 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J Appl Physiol 104:1835\u0026ndash;1836. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1152/japplphysiol.00154.2008\u003c/span\u003e\u003cspan address=\"10.1152/japplphysiol.00154.2008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakami T, Yamamura H, Inai K et al (2005) Monitoring of Cerebral Oxygenation during Hypoxic Gas Management in Congenital Heart Disease with Increased Pulmonary Blood Flow. 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Cureus 11:5693. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7759/cureus.5693\u003c/span\u003e\u003cspan address=\"10.7759/cureus.5693\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShime N, Hashimoto S, Hiramatsu N, Oka T, Kageyama K, Tanaka Y (2000) Hypoxic gas therapy using nitrogen in the preoperative management of neonates with hypoplastic left heart syndrome. Pediatr Crit Care Med 1:38\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/00130478-200007000-00007\u003c/span\u003e\u003cspan address=\"10.1097/00130478-200007000-00007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamamoorthy C, Tabbutt S, Dean Kurth C et al (2002) Effects of Inspired Hypoxic and Hypercapnic Gas Mixtures on Cerebral Oxygen Saturation in Neonates with Univentricular Heart Defects. Anesthesiology 96:283\u0026ndash;288. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/00000542-200202000-00010\u003c/span\u003e\u003cspan address=\"10.1097/00000542-200202000-00010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"nitrogen, pulmonary overcirculation, pulmonary flow, congenital heart disease, hypoxic mixture","lastPublishedDoi":"10.21203/rs.3.rs-9431166/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9431166/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the use of a hypoxic mixture is uncommon, it appears to be a useful strategy in the preoperative management of congenital heart disease with pulmonary overcirculation physiology, which is considered a stabilizing step and a bridge to corrective or palliative surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective observational study included 17 infants (\u0026lt; 1 year) with congenital heart disease and pulmonary overcirculation, who were managed preoperatively with a hypoxic mixture in 2024. Demographic and clinical data were analyzed to assess hemodynamic and blood gas changes within 24 h of therapy initiation. Paired t-test and repeated measures ANOVA were used (Stata 18.0®).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, 88.2% of the patients had biventricular congenital heart defects with pulmonary overcirculation physiology, most commonly aortic arch hypoplasia with ventricular septal defect. The hypoxic gas mixture concentration administered to over half of the patients was 16% (IQR 15–17). Pulse oximetry revealed significant changes from 6 h of therapy. pH and lactate levels demonstrated notable changes with the hypoxic mixture, as did urine output 12 h after therapy initiation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe hypoxic mixture is a practical and versatile tool that impacts pulmonary flow control, indirectly demonstrating effects on hemodynamic and blood gas variables, serving as indicators of the balance between pulmonary and systemic flow (Qp/Qs).\u003c/p\u003e","manuscriptTitle":"Hypoxic Mixture as a Preoperative Strategy in Congenital Heart Disease with Pulmonary Overcirculation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-24 07:19:05","doi":"10.21203/rs.3.rs-9431166/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d72a1ecd-154b-4ace-ab30-e7821fb44c9c","owner":[],"postedDate":"April 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-24T07:19:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-24 07:19:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9431166","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9431166","identity":"rs-9431166","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}