Hemodynamic Effects of Arginine-Vasopressin After Pediatric Cardiac Surgery

Hemodynamic Effects of Arginine-Vasopressin After Pediatric Cardiac Surgery | 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 Hemodynamic Effects of Arginine-Vasopressin After Pediatric Cardiac Surgery Ilias Iliopoulos, Saul Flores, Matthew Coghill, Wonshill Koh, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7653444/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 Background: Arginine-vasopressin is widely used for treatment of vasodilatory and mixed shock after pediatric cardiac surgery. Although a favorable effect on blood pressure has been documented, data on organ perfusion and tissue oxygen balance remain limited. Methods: We prospectively evaluated an observational cohort of 49 children after reparative cardiac surgery. Median age was 8 months (interquartile range 5 to 59 months) and weight 11.0 kg (interquartile range 7.2 to 26.3 kg). Patients who received arginine-vasopressin (n=23) for hypotension were compared with patients of similar surgical complexity who did not (n=26), using regression analysis. Results: Vasopressin dose was independently associated with an increase in systolic blood pressure (p<0.01), an increase in cerebral oxygen extraction (p=0.04), and an increase in renal oxygen extraction (p<0.01). No statistical difference was observed between treated and non-treated patients in diastolic blood pressure, blood lactate, or urine output. Conclusions: Arginine-vasopressin therapy restores blood pressure in hypotensive children after cardiac surgery but may have unfavorable effects on tissue oxygenation. Arginine-vasopressin pediatric cardiac surgery postoperative cardiac care congenital heart disease Figures Figure 1 Figure 2 Figure 3 Introduction Arginine-vasopressin is an endogenous peptide hormone; however, in clinical practice it is administered in synthetic form to treat hypotension in many groups of critically ill patients, including pediatric cardiac populations. A subset of children develops vasodilatory shock with preserved cardiac function after cardiopulmonary bypass and respond well to exogenous administration of intravenous arginine-vasopressin. It has been suggested that these patients have absolute or relative vasopressin deficiency and exhibit a favorable hemodynamic response to low-dose vasopressin (that will not otherwise cause vasoconstriction in healthy subjects), indicating a replacement effect of vasopressin. However, treatment of hypotension after cardiac surgery frequently requires escalation to higher doses of vasopressin that may instigate vasoconstriction with unknown effects on cardiac output, oxygen consumption, and tissue oxygen balance. Materials and Methods Children undergoing corrective cardiac surgery with cardiopulmonary bypass and surgical complexity defined as RACHS-1 score ≥ 3 or tetralogy of Fallot repair from April 2016 until July 2018 were eligible. Surgical complexity was defined based on RACHS-1 category and intraoperative hemodynamic predictors of vasopressor requirement. Patients undergoing palliative operations or treated with arginine-vasopressin within 24h prior to surgery were excluded. Patients receiving steroids within the last 30 days, etomidate within the last 3 days, or with known endocrine abnormalities were excluded to avoid hypothalamic-adrenal axis confounding. Patients that received arginine-vasopressin (Vasostrict, Par Pharmaceutical Inc., Spring Valley, New York, United States of America) within the first 48h after cardiac surgery (treated group) were compared with patients who did not (non-treated group). The non-treated group consisted of patients who either did not develop postoperative hypotension or were treated with alternative vasopressors chosen according to the clinical judgement of the care team. Otherwise, operative and anesthetic management were according to standard of care per the respective clinical team. All patients received intraoperative methylprednisolone 30mg/kg (max 500mg) in the cardiopulmonary bypass pump prime as per standard clinical practice. Clinical and inotropic management (choice of vasopressors, timing, dose of initiation and dose escalation) was at discretion of the clinical team. All patients received the standard of care as per current institutional practice regardless of study participation. Enrolled patients were studied for 48h after completion of cardiopulmonary bypass. Clinical and demographic characteristics, hemodynamic data (heart rate, blood pressure, urine output, central venous pressure, fluid balance) and markers of oxygenation and end organ perfusion (oxygen saturation, near infrared spectroscopy, arteriovenous difference of oxygen, blood lactate) were obtained. All data were extracted by trained research personnel and recorded on standardized study specific case report forms. Data were anonymized and manually entered in web-based secure REDCap database, created specifically for this study. Prior to analysis, data were reviewed for missingness and plausibility. Variable definitions Arteriovenous difference of oxygen was defined as the difference between the systemic oxygen saturation (by pulse oximetry) and the average of cerebral and somatic near infrared spectroscopy. Cerebral and renal oxygen extraction ratio was calculated based on systemic oxygen saturation and cerebral and renal near infrared spectroscopy: systemic saturation – cerebral (or renal) near infrared spectroscopy / cerebral (or renal) infrared spectroscopy. Near infrared spectroscopy was continuously monitored with an INVOS 5100C (Medtronic, Minneapolis, MN) monitor. The vasoactive inotropic score was modified to exclude arginine-vasopressin: 100 × epinephrine dose (mcg/kg/min) + 100 × norepinephrine dose (mcg/kg/min) 10 × milrinone dose (mcg/kg/min). 12 Dopamine and dobutamine were not used based on institutional practice. The study received approval by the Institutional Review Board of Cincinnati Children’s Hospital Medical Center (ID:1891–2014). Parental informed consent and assent from patients older than 11 years of age was obtained prior to study enrollment. Data analysis A time series regression analysis was performed to model the relationships between cerebral oxygen extraction ratio and the set of independent variables. Each predictor was included in a linear regression model with cerebral oxygen extraction ratio as the outcome variable. Data were preprocessed to include only those time points where cerebral oxygen extraction ratio was measured, and corresponding predictor values were aligned according to the time of measurement. Missing values in medication doses were imputed using the median values calculated from available data. The regression model was built using Ordinary Least Squares regression to estimate the coefficients for each predictor while controlling for all other variables in the model. Statistical significance was assessed at a p-value of less than 0.05. The model's fit was evaluated using R-squared and Adjusted R-squared values to ascertain the proportion of variance in cerebral oxygen extraction ratio explained by the predictors. The F-statistic was used to determine the overall significance of the regression model. Diagnostic checks were performed to assess potential multicollinearity among predictors, using variance inflation factors and condition numbers. Results We enrolled 49 patients in this study. Median age was 8 months (interquartile range 5 to 59 months) and weight 11.0 kg (interquartile range 7.2 to 26.3 kg). For the arginine-vasopressin treated patients, most frequent cardiac operations were tetralogy of Fallot repair (n = 9), atrioventricular septal defect repair (n = 4) and double outlet right ventricle repair (n = 2). For the non-arginine-vasopressin group, most frequent cardiac operations were atrioventricular septal defect repair (n = 5), tetralogy of Fallot repair (n = 4), and Ross operation (n = 3). Complete list of operations performed in both group is provided in Table 1 . Arginine-vasopressin therapy was used within 48h after surgery for 23 patients. Twenty-six patients did not receive arginine-vasopressin after surgery and there were used as a comparison group. Baseline comparison of clinical and operative characteristics of both groups is demonstrated in in Table 2. Table 1 Cardiac operations Arginine-vasopressin group (n = 23) No arginine vasopressin group (n = 26) Tetralogy of Fallot repair (n = 9) Atrioventricular septal defect repair (n = 5) Atrioventricular septal defect repair (n = 4) Tetralogy of Fallot repair (n = 4) Double outlet right ventricle repair (n = 2) Ross operation (n = 3) Aortic arch reconstruction/ interrupted aortic arch repair (n = 2) Right ventricular to pulmonary artery conduit replacement (n = 3) Truncus arteriosus repair (n = 1) Double outlet right ventricle repair (n = 2) Arterial switch operation (n = 1) Double switch operation (n = 2) Double switch operation (n = 1) Mitral valve surgery (n = 3) Mitral valve repair (n = 1) Aortic root replacement (n = 1) Repair of anomalous coronary artery (n = 1) Aortic valve repair (n = 1) Right ventricular to pulmonary artery conduit replacement (n = 1) Total anomalous pulmonary venous return repair (n = 1) Aortic coarctation repair (n = 1) Table . General characteristics of arginine-vasopressin treated vs. non treated patients Variable [i] Vasopressin (n=23) No vasopressin (n=26) p-value Female gender 12 (52%) 13 (50%) 1.000 Age (years) 0.48 (0.50 to 0.82) 4.30 (0.50 to 10.63) < 0.001 Weight (kg) 6.9 (5.1 to 8.3) 14.9 (5.4 to 28.7) 0.003 CPB[ii] time (min) 165 (137.5 to 212.5) 176 (126 to 205) 0.851 Cross clamp time (min) 123 (88.5 to 171) 106 (87 to 154) 0.356 DHCA (min)[iii] 4 (17%) 2 (8%) 0.550 [i] Variables presented as count/frequencies or median/interquartile range [ii] CPB=Cardiopulmonary bypass [iii] DHCA= Deep hypothermic circulatory arrest In the vasopressin group, the median dose at CICU admission was 0.2 milliunits//kg/min, peaked at 1 and 2 hours at approximately 0.7 milliunits/kg/min, and then decreased to 0.1 milliunits/kg/min at 48 hours. The time-series regression conducted to model systolic blood pressure resulted in an R-squared of 0.842, indicating that 84.2% of the variability in systolic blood pressure was explained by the model. The p-value for the model was < 0.001, indicating that the model was statistically significant. Systolic blood pressure was associated with age, weight, and vasopressin dose [constant = 50.865 (p = 0.000) and coefficients = − 0.518 (p = 0.000), 0.072 (p = 0.005) and 0.231 (p = 0.031) respectively]. The mean systolic blood pressure trends in both groups are depicted in Fig. 1. The time-series regression conducted to model cerebral oxygen extraction ratio resulted in an R-squared of 0.628, indicating that 62.8% of the variability in systolic blood pressure was explained by the model. The p-value for the model was < 0.254, indicating that the model was not statistically significant. Cerebral oxygen extraction ratio was associated with vasopressin dose [constant = 29.141 (p = 0.086) with coefficient = 13.867 (p = 0.043)]. The cerebral oxygen extraction ratio in both groups is depicted in Fig. 2. The time-series regression conducted to model renal oxygen extraction ratio resulted in an R-squared of 0.932, indicating that 93.2% of the variability in systolic blood pressure was explained by the model. The p-value for the model was 0.00421, indicating that the model was statistically significant. Renal oxygen extraction ratio was associated with age, vasopressin dose and time [constant = 27.970 (p = 0.016) with coefficient = − 0.0305 (p = 0.034), 21.609 (p = 0.002) and 0.438 (p = 0.015) respectively]. The cerebral oxygen extraction ratio in both groups is depicted in Fig. 3. Discussion Our study demonstrated that arginine-vasopressin therapy is associated with improved systolic blood pressure but unfavorable changes in oxygen balance of important end organs such as the brain and kidneys. Both cerebral and renal oxygen extraction increased, suggesting that oxygen delivery or oxygen consumption in these end organs changed in an undesirable direction. Additionally, we confirmed associations of age and weight with systolic blood pressure. Interestingly, no statistical differences were observed in systolic or diastolic blood pressure, urine output, or blood lactate between hypotensive patients treated with vasopressin and the non-treated group, indicating that arginine-vasopressin successfully restored clinical hemodynamics. Peripheral vasodilation in the setting of preserved ventricular function, or mixed circulatory compromise with a significant vasodilatory component, has been well documented in postoperative pediatric cardiac population. 2 , 3 Several factors associated with cardiopulmonary bypass such as hypothermia and inflammatory response can cause vasodilation and, in this setting, arginine-vasopressin therapy at doses necessary to restore vascular tone (but avoid excessive vasoconstriction) is a reasonable option that is supported by significant published evidence. A recent meta-analysis of studies in the pediatric cardiac population indicated that arginine-vasopressin improved systolic and diastolic blood pressure and was associated with lower heart rate. 8 The neonatal subset benefited further from a significant decrease in catecholamine score and fluid balance. 8,13 Traditional therapies such as administration of volume expanders and catecholamines are associated with significant morbidity and adverse outcomes such as volume overload, arrhythmias and increase in global and myocardial oxygen consumption. Arginine-vasopressin therapy has emerged in the recent years as a reasonable alternative that will likely obviate some of the undesired effects of catecholamines. Indeed, a recent multicenter registry study indicated that vasopressin was the only vasoactive agent with increased use in recent years. 1 Our study corroborates the existing literature with regards of the positive effect on systolic blood pressure, urine output and clinical hemodynamics. We found that despite augmentation of blood pressure arginine-vasopressin was associated with unfavorable change in end organ oxygen balance. The finding of increased oxygen extraction in both brain and kidneys is problematic. There is physiologic concern that excessive vasoconstriction caused by arginine -vasopressin can potentially have deleterious effects in cardiac output, oxygen delivery and oxygen balance despite restoring blood pressure and clinical hemodynamic parameters. This is a more important consideration for patients with impaired ventricular function. Furthermore, animal experiments indicate that arginine-vasopressin can decrease cardiac output with mechanisms unrelated to loading conditions and increase mortality in an ischemia-reperfusion model in mice, a finding that might be relevant for the population of children after cardiopulmonary bypass. 14 Prior clinical studies have yielded conflicting results. In a single center retrospective report, clinical response to arginine-vasopressin was unrelated to baseline ventricular function. 15 Similarly, clinical reports advocate for use of arginine-vasopressin as a “cleaner inotrope” in pediatric patients with heart failure to avoid the side effects and morbidity associated with catecholamine use. 16 On the other hand, studies evaluating end organ perfusion and oxygen balance have also demonstrated similar findings to our study. In a small cohort of 20 children after congenital heart surgery, arginine-vasopressin was not associated with any improvement in organ perfusion. 9 Moreover, a single center study evaluating the effect of arginine-vasopressin in clinical and oximetric parameters in neonates following stage 1 palliation indicated that improvement in blood pressure was accompanied with an increase in cerebral and renal oxygen extraction for the subset of patients with Sano modification. 10 It was presumed that the increase in systemic vascular resistance induced by arginine-vasopressin resulted in increased pulmonary blood flow and systemic steal. Our study population consisted of only biventricular patients without residual shunts, therefore a change in Qp;Qp ratio cannot be the explanation for our findings. Our study was not designed to offer a mechanistic explanation for the change in oxygen balance. It plausible that the increase in systemic vascular resistance has resulted in a decrease cardiac output and oxygen transport but our data cannot support this speculation. Data on the effect of arginine-vasopressin on oxygen consumption are very limited. Nonetheless, animal experiments have suggested that arteriolar vasoconstriction induced by clinical doses of arginine-vasopressin might increase vessel wall oxygen consumption. 17 Contrarily, animal data exist that suggest a decrease in oxygen consumption associated with arginine-vasopressin. 18 , 19 Given the uncertainty of the specific actions of vasopressin in the microcirculation and the effect on tissue oxygen balance, clinical vigilance is warranted. In the clinical use of arginine-vasopressin avoidance of high doses that can instigate excessive vasoconstriction and monitoring of global and regional tissue oxygen balance is justified. 9 Our study has several limitations. Firstly, it is a small single center observational study, and its findings might not be generalizable. The design was observational; therefore, the clinical management was not protocolized and decisions on vasoactive management were entirely at the discretion of the clinical team. However, our institutional practice dictates that epinephrine is kept at low inotropic doses and vasopressin is the vasopressor of choice for hypotensive patients. Therefore, the non- arginine-vasopressin group consisted of non-hypotensive patients (only 2 patients were treated with norepinephrine in this group), and it is not a true control group. However, we observed similar slope of progress for all clinical hemodynamics (heart rate, blood pressure, blood lactate) for both groups reasonably supporting the conclusion that arginine-vasopressin restored clinical hemodynamics in the hypotensive patients. Another significant limitation is that oxygen balance data are derived from near infrared spectroscopy which is an imperfect monitor and is characterized by wide limits of agreement with measured central venous saturations. 20 Despite its limitations near infrared spectroscopy has become the standard of care in postoperative management of pediatric cardiac patients and it is the only available monitor of continuous real time oximetric data of regional circulations. 21 Finally, our cohort was a convenience cohort, and we missed potentially eligible patients during the study period. Summarizing, arginine-vasopressin therapy is associated with favorable effects in blood pressure and restores clinical hemodynamics in hypotensive postoperative pediatric cardiac patients with biventricular circulation. In addition, it is associated with an increase in cerebral and renal oxygen extraction, necessitating oxygen balance monitoring with its clinical use. Further studies in multicenter cohorts are required to confirm validity and generalizability of these findings. Declarations Financial Support This research received no financial support. Conflicts of Interest None Ethical Standards All study procedures complied with the ethical standards of the Helsinki Declaration and has been approved by Institutional Research Board of Cincinnati Children’s Medical Center. Author Contribution All the authors helped with design and completion of the study. In addition all authors participated in the writing of the main manuscript, preparing figures and tables. All authors reviewed the final document. Acknowledgement The authors acknowledge the staff of the Heart Institute Research Core at Cincinnati Children’s Hospital Medical Center for the regulatory, data management and statistical support provided. References Loomba RS, Flores S. Use of vasoactive agents in postoperative pediatric cardiac patients: Insights from a national database. Congenit Heart Dis . 2019;14(6):1176-1184. doi:10.1111/chd.12837 Lechner E, Hofer A, Mair R, Moosbauer W, Sames-Dolzer E, Tulzer G. Arginine-vasopressin in neonates with vasodilatory shock after cardiopulmonary bypass. Eur J Pediatr . 2007;166(12). doi:10.1007/s00431-006-0400-0 Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation . 1999;100(19 SUPPL.). doi:10.1161/01.cir.100.suppl_2.ii-182 Mastropietro CW, Davalos MC, Seshadri S, Walters HL, Delius RE. Clinical response to arginine vasopressin therapy after paediatric cardiac surgery. Cardiol Young . 2013;23(3). doi:10.1017/S1047951112000996 Mastropietro CW, Rossi NF, Clark JA, et al. Relative deficiency of arginine vasopressin in children after cardiopulmonary bypass. Crit Care Med . 2010;38(10). doi:10.1097/CCM.0b013e3181eed91d Morrison WE, Simone S, Conway D, Tumulty J, Johnson C, Cardarelli M. Levels of vasopressin in children undergoing cardiopulmonary bypass. Cardiol Young . 2008;18(2). doi:10.1017/S1047951108001881 Burton GL, Kaufman J, Goot BH, Da Cruz EM. The use of Arginine Vasopressin in neonates following the Norwood procedure. Cardiol Young . 2011;21(5). doi:10.1017/S1047951111000370 Farias JS, Villarreal EG, Flores S, et al. Effects of Vasopressin Infusion After Pediatric Cardiac Surgery: A Meta-analysis. Pediatr Cardiol . 2021;42(2):225-233. doi:10.1007/s00246-020-02496-8 Loomba RS, Culichia C, Schulz K, et al. Acute Effects of Vasopressin Arginine Infusion in Children with Congenital Heart Disease: Higher Blood Pressure Does Not Equal Improved Systemic Oxygen Delivery. Pediatr Cardiol . 2021;42(8):1792-1798. doi:10.1007/s00246-021-02667-1 Bronicki RA, Acosta S, Savorgnan F, et al. The acute influence of vasopressin on hemodynamic status and tissue oxygenation following the Norwood procedure. JTCVS Open . 2022;9:217-224. doi:10.1016/j.xjon.2022.01.008 Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. Journal of Thoracic and Cardiovascular Surgery . 2002;123(1). doi:10.1067/mtc.2002.119064 Davidson J, Tong S, Hancock H, Hauck A, Da Cruz E, Kaufman J. Prospective validation of the vasoactive-inotropic score and correlation to short-term outcomes in neonates and infants after cardiothoracic surgery. Intensive Care Med . 2012;38(7). doi:10.1007/s00134-012-2544-x Alten JA, Borasino S, Toms R, Law MA, Moellinger A, Dabal RJ. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. Pediatric Critical Care Medicine . 2012;13(3). doi:10.1097/PCC.0b013e31822f1753 Indrambarya T, Boyd JH, Wang Y, McConechy M, Walley KR. Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice. Crit Care . 2009;13(3). doi:10.1186/cc7930 Iliopoulos I, Flores S, Pratap JN, Cooper DS, Cassedy A, Nelson DP. Arginine-vasopressin therapy in hypotensive neonates and infants after cardiac surgery: Response is unrelated to baseline ventricular function. Cardiol Young . 2017;27(6). doi:10.1017/S104795111600189X Karki KB, Towbin JA, Harrell C, et al. Concurrent Use of Calcium Chloride and Arginine Vasopressin Infusions in Pediatric Patients with Acute Cardiocirculatory Failure. Pediatr Cardiol . 2019;40(5):1046-1056. doi:10.1007/s00246-019-02114-2 Friesenecker B, Tsai AG, Dünser MW, et al. Oxygen distribution in microcirculation after arginine vasopressin-induced arteriolar vasoconstriction. Am J Physiol Heart Circ Physiol . 2004;287(4 56-4). doi:10.1152/ajpheart.00283.2004 Liard JF. Reduced oxygen consumption induced by vasopressin in dogs depends on systemic administration. Clin Sci . 1991;81(6). doi:10.1042/cs0810751 Liard JF. Vasopressin-induced changes in cardiac vagal tone and oxygen consumption in dogs. Am J Physiol Regul Integr Comp Physiol . 1994;266(3 35-3). doi:10.1152/ajpregu.1994.266.3.r838 Iliopoulos I, Cooper DS, Reagor JA, et al. Absolute Versus Relative Near-Infrared Spectroscopy in Pediatric Cardiac Patients∗. Pediatric Critical Care Medicine . 2023;24(3). doi:10.1097/PCC.0000000000003118 Ghanayem NS, Wernovsky G, Hoffman GM. Near-infrared spectroscopy as a hemodynamic monitor in critical illness. Pediatric Critical Care Medicine . 2011;12(4 SUPPL.). doi:10.1097/PCC.0b013e318221173a Additional Declarations No competing interests reported. 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09:31:04","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18279,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/87c2ba07d0160ead17c0937b.docx"},{"id":92842668,"identity":"4fd0dbc7-9b49-44f7-9a5b-ca95eb5795fc","added_by":"auto","created_at":"2025-10-06 09:15:04","extension":"json","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":8641,"visible":true,"origin":"","legend":"","description":"","filename":"b564058c10ea4b20ae290741e54ff192.json","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/c0ab3eb894f7a6010c700895.json"},{"id":92842676,"identity":"d3cad3fb-0495-4547-bd9d-91de2efb2b63","added_by":"auto","created_at":"2025-10-06 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09:23:04","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77286,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/d7fa29192790a54a98a594b7.html"},{"id":92842671,"identity":"329d0aa8-0704-4d21-b158-c9e4e782c263","added_by":"auto","created_at":"2025-10-06 09:15:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1534209,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/da385dd65249f49d6fa82aa9.jpg"},{"id":92845627,"identity":"b99862cc-1d93-4ac1-8bf0-91cb7743af30","added_by":"auto","created_at":"2025-10-06 09:31:04","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1137093,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/f37fc577d439254e8f28294f.jpg"},{"id":92842674,"identity":"ef0b1581-31ad-4162-aade-899e177c8f0a","added_by":"auto","created_at":"2025-10-06 09:15:04","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1084314,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/bba9fb8b4e2e3e32fc830c2d.jpg"},{"id":92976477,"identity":"81a1c150-3016-4662-89e0-12bed071b1af","added_by":"auto","created_at":"2025-10-07 18:16:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4255277,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7653444/v1/d8a90eb2-c915-4c12-b041-b53b0b5f7cb6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eHemodynamic Effects of Arginine-Vasopressin After Pediatric Cardiac Surgery\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eArginine-vasopressin is an endogenous peptide hormone; however, in clinical practice it is administered in synthetic form to treat hypotension in many groups of critically ill patients, including pediatric cardiac populations. A subset of children develops vasodilatory shock with preserved cardiac function after cardiopulmonary bypass and respond well to exogenous administration of intravenous arginine-vasopressin. It has been suggested that these patients have absolute or relative vasopressin deficiency and exhibit a favorable hemodynamic response to low-dose vasopressin (that will not otherwise cause vasoconstriction in healthy subjects), indicating a replacement effect of vasopressin. However, treatment of hypotension after cardiac surgery frequently requires escalation to higher doses of vasopressin that may instigate vasoconstriction with unknown effects on cardiac output, oxygen consumption, and tissue oxygen balance.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eChildren undergoing corrective cardiac surgery with cardiopulmonary bypass and surgical complexity defined as RACHS-1 score\u0026thinsp;\u0026ge;\u0026thinsp;3 or tetralogy of Fallot repair from April 2016 until July 2018 were eligible. Surgical complexity was defined based on RACHS-1 category and intraoperative hemodynamic predictors of vasopressor requirement. Patients undergoing palliative operations or treated with arginine-vasopressin within 24h prior to surgery were excluded. Patients receiving steroids within the last 30 days, etomidate within the last 3 days, or with known endocrine abnormalities were excluded to avoid hypothalamic-adrenal axis confounding.\u003c/p\u003e\u003cp\u003ePatients that received arginine-vasopressin (Vasostrict, Par Pharmaceutical Inc., Spring Valley, New York, United States of America) within the first 48h after cardiac surgery (treated group) were compared with patients who did not (non-treated group). The non-treated group consisted of patients who either did not develop postoperative hypotension or were treated with alternative vasopressors chosen according to the clinical judgement of the care team. Otherwise, operative and anesthetic management were according to standard of care per the respective clinical team. All patients received intraoperative methylprednisolone 30mg/kg (max 500mg) in the cardiopulmonary bypass pump prime as per standard clinical practice. Clinical and inotropic management (choice of vasopressors, timing, dose of initiation and dose escalation) was at discretion of the clinical team. All patients received the standard of care as per current institutional practice regardless of study participation. Enrolled patients were studied for 48h after completion of cardiopulmonary bypass. Clinical and demographic characteristics, hemodynamic data (heart rate, blood pressure, urine output, central venous pressure, fluid balance) and markers of oxygenation and end organ perfusion (oxygen saturation, near infrared spectroscopy, arteriovenous difference of oxygen, blood lactate) were obtained. All data were extracted by trained research personnel and recorded on standardized study specific case report forms. Data were anonymized and manually entered in web-based secure REDCap database, created specifically for this study. Prior to analysis, data were reviewed for missingness and plausibility.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eVariable definitions\u003c/h2\u003e\u003cp\u003eArteriovenous difference of oxygen was defined as the difference between the systemic oxygen saturation (by pulse oximetry) and the average of cerebral and somatic near infrared spectroscopy. Cerebral and renal oxygen extraction ratio was calculated based on systemic oxygen saturation and cerebral and renal near infrared spectroscopy: systemic saturation \u0026ndash; cerebral (or renal) near infrared spectroscopy / cerebral (or renal) infrared spectroscopy. Near infrared spectroscopy was continuously monitored with an INVOS 5100C (Medtronic, Minneapolis, MN) monitor. The vasoactive inotropic score was modified to exclude arginine-vasopressin: 100 \u0026times; epinephrine dose (mcg/kg/min)\u0026thinsp;+\u0026thinsp;100 \u0026times; norepinephrine dose (mcg/kg/min) 10 \u0026times; milrinone dose (mcg/kg/min).\u003csup\u003e12\u003c/sup\u003e Dopamine and dobutamine were not used based on institutional practice.\u003c/p\u003e\u003cp\u003e The study received approval by the Institutional Review Board of Cincinnati Children\u0026rsquo;s Hospital Medical Center (ID:1891\u0026ndash;2014). Parental informed consent and assent from patients older than 11 years of age was obtained prior to study enrollment.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eData analysis\u003c/h2\u003e\u003cp\u003eA time series regression analysis was performed to model the relationships between cerebral oxygen extraction ratio and the set of independent variables. Each predictor was included in a linear regression model with cerebral oxygen extraction ratio as the outcome variable. Data were preprocessed to include only those time points where cerebral oxygen extraction ratio was measured, and corresponding predictor values were aligned according to the time of measurement. Missing values in medication doses were imputed using the median values calculated from available data.\u003c/p\u003e\u003cp\u003eThe regression model was built using Ordinary Least Squares regression to estimate the coefficients for each predictor while controlling for all other variables in the model. Statistical significance was assessed at a p-value of less than 0.05.\u003c/p\u003e\u003cp\u003eThe model's fit was evaluated using R-squared and Adjusted R-squared values to ascertain the proportion of variance in cerebral oxygen extraction ratio explained by the predictors. The F-statistic was used to determine the overall significance of the regression model. Diagnostic checks were performed to assess potential multicollinearity among predictors, using variance inflation factors and condition numbers.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe enrolled 49 patients in this study. Median age was 8 months (interquartile range 5 to 59 months) and weight 11.0 kg (interquartile range 7.2 to 26.3 kg). For the arginine-vasopressin treated patients, most frequent cardiac operations were tetralogy of Fallot repair (n\u0026thinsp;=\u0026thinsp;9), atrioventricular septal defect repair (n\u0026thinsp;=\u0026thinsp;4) and double outlet right ventricle repair (n\u0026thinsp;=\u0026thinsp;2). For the non-arginine-vasopressin group, most frequent cardiac operations were atrioventricular septal defect repair (n\u0026thinsp;=\u0026thinsp;5), tetralogy of Fallot repair (n\u0026thinsp;=\u0026thinsp;4), and Ross operation (n\u0026thinsp;=\u0026thinsp;3). Complete list of operations performed in both group is provided in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Arginine-vasopressin therapy was used within 48h after surgery for 23 patients. Twenty-six patients did not receive arginine-vasopressin after surgery and there were used as a comparison group. Baseline comparison of clinical and operative characteristics of both groups is demonstrated in in Table\u0026nbsp;2.\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\u003eCardiac operations\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eArginine-vasopressin group (n\u0026thinsp;=\u0026thinsp;23)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eNo arginine vasopressin group (n\u0026thinsp;=\u0026thinsp;26)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTetralogy of Fallot repair (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAtrioventricular septal defect repair (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAtrioventricular septal defect repair (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTetralogy of Fallot repair (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDouble outlet right ventricle repair (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRoss operation (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAortic arch reconstruction/ interrupted aortic arch repair (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRight ventricular to pulmonary artery conduit replacement (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTruncus arteriosus repair (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDouble outlet right ventricle repair (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArterial switch operation (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDouble switch operation (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDouble switch operation (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMitral valve surgery (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMitral valve repair (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAortic root replacement (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRepair of anomalous coronary artery (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAortic valve repair (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRight ventricular to pulmonary artery conduit replacement (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal anomalous pulmonary venous return repair (n\u0026thinsp;=\u0026thinsp;1)\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\u003eAortic coarctation repair (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable .\u003c/strong\u003e \u003cstrong\u003eGeneral characteristics of arginine-vasopressin treated vs. non treated patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eVariable\u003cstrong\u003e[i]\u003c/strong\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eVasopressin\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e(n=23)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNo vasopressin (n=26)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003eFemale gender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e12 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e13 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e0.48 (0.50 to 0.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e4.30 (0.50 to 10.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e6.9 (5.1 to 8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e14.9 (5.4 to 28.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003eCPB[ii] time (min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e165 (137.5 to 212.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e176 (126 to 205)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.851\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003eCross clamp time (min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e123 (88.5 to 171)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e106 (87 to 154)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 204px;\"\u003e\n \u003cp\u003eDHCA (min)[iii]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e4 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e2 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.550\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e[i] Variables presented as count/frequencies or median/interquartile range\u003c/p\u003e\n\u003cp\u003e[ii] CPB=Cardiopulmonary bypass\u003c/p\u003e\n\u003cp\u003e[iii] DHCA= Deep hypothermic circulatory arrest\u003c/p\u003e\u003cp\u003eIn the vasopressin group, the median dose at CICU admission was 0.2 milliunits//kg/min, peaked at 1 and 2 hours at approximately 0.7 milliunits/kg/min, and then decreased to 0.1 milliunits/kg/min at 48 hours.\u003c/p\u003e\u003cp\u003eThe time-series regression conducted to model systolic blood pressure resulted in an R-squared of 0.842, indicating that 84.2% of the variability in systolic blood pressure was explained by the model. The p-value for the model was \u0026lt;\u0026thinsp;0.001, indicating that the model was statistically significant. Systolic blood pressure was associated with age, weight, and vasopressin dose [constant\u0026thinsp;=\u0026thinsp;50.865 (p\u0026thinsp;=\u0026thinsp;0.000) and coefficients\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.518 (p\u0026thinsp;=\u0026thinsp;0.000), 0.072 (p\u0026thinsp;=\u0026thinsp;0.005) and 0.231 (p\u0026thinsp;=\u0026thinsp;0.031) respectively]. The mean systolic blood pressure trends in both groups are depicted in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eThe time-series regression conducted to model cerebral oxygen extraction ratio resulted in an R-squared of 0.628, indicating that 62.8% of the variability in systolic blood pressure was explained by the model. The p-value for the model was \u0026lt;\u0026thinsp;0.254, indicating that the model was not statistically significant. Cerebral oxygen extraction ratio was associated with vasopressin dose [constant\u0026thinsp;=\u0026thinsp;29.141 (p\u0026thinsp;=\u0026thinsp;0.086) with coefficient\u0026thinsp;=\u0026thinsp;13.867 (p\u0026thinsp;=\u0026thinsp;0.043)]. The cerebral oxygen extraction ratio in both groups is depicted in Fig.\u0026nbsp;2.\u003c/p\u003e\u003cp\u003eThe time-series regression conducted to model renal oxygen extraction ratio resulted in an R-squared of 0.932, indicating that 93.2% of the variability in systolic blood pressure was explained by the model. The p-value for the model was 0.00421, indicating that the model was statistically significant. Renal oxygen extraction ratio was associated with age, vasopressin dose and time [constant\u0026thinsp;=\u0026thinsp;27.970 (p\u0026thinsp;=\u0026thinsp;0.016) with coefficient\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.0305 (p\u0026thinsp;=\u0026thinsp;0.034), 21.609 (p\u0026thinsp;=\u0026thinsp;0.002) and 0.438 (p\u0026thinsp;=\u0026thinsp;0.015) respectively]. The cerebral oxygen extraction ratio in both groups is depicted in Fig.\u0026nbsp;3.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study demonstrated that arginine-vasopressin therapy is associated with improved systolic blood pressure but unfavorable changes in oxygen balance of important end organs such as the brain and kidneys. Both cerebral and renal oxygen extraction increased, suggesting that oxygen delivery or oxygen consumption in these end organs changed in an undesirable direction. Additionally, we confirmed associations of age and weight with systolic blood pressure. Interestingly, no statistical differences were observed in systolic or diastolic blood pressure, urine output, or blood lactate between hypotensive patients treated with vasopressin and the non-treated group, indicating that arginine-vasopressin successfully restored clinical hemodynamics.\u003c/p\u003e\u003cp\u003ePeripheral vasodilation in the setting of preserved ventricular function, or mixed circulatory compromise with a significant vasodilatory component, has been well documented in postoperative pediatric cardiac population.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Several factors associated with cardiopulmonary bypass such as hypothermia and inflammatory response can cause vasodilation and, in this setting, arginine-vasopressin therapy at doses necessary to restore vascular tone (but avoid excessive vasoconstriction) is a reasonable option that is supported by significant published evidence. A recent meta-analysis of studies in the pediatric cardiac population indicated that arginine-vasopressin improved systolic and diastolic blood pressure and was associated with lower heart rate.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The neonatal subset benefited further from a significant decrease in catecholamine score and fluid balance. \u003csup\u003e8,13\u003c/sup\u003e Traditional therapies such as administration of volume expanders and catecholamines are associated with significant morbidity and adverse outcomes such as volume overload, arrhythmias and increase in global and myocardial oxygen consumption. Arginine-vasopressin therapy has emerged in the recent years as a reasonable alternative that will likely obviate some of the undesired effects of catecholamines. Indeed, a recent multicenter registry study indicated that vasopressin was the only vasoactive agent with increased use in recent years.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Our study corroborates the existing literature with regards of the positive effect on systolic blood pressure, urine output and clinical hemodynamics.\u003c/p\u003e\u003cp\u003eWe found that despite augmentation of blood pressure arginine-vasopressin was associated with unfavorable change in end organ oxygen balance. The finding of increased oxygen extraction in both brain and kidneys is problematic. There is physiologic concern that excessive vasoconstriction caused by arginine -vasopressin can potentially have deleterious effects in cardiac output, oxygen delivery and oxygen balance despite restoring blood pressure and clinical hemodynamic parameters. This is a more important consideration for patients with impaired ventricular function. Furthermore, animal experiments indicate that arginine-vasopressin can decrease cardiac output with mechanisms unrelated to loading conditions and increase mortality in an ischemia-reperfusion model in mice, a finding that might be relevant for the population of children after cardiopulmonary bypass.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Prior clinical studies have yielded conflicting results. In a single center retrospective report, clinical response to arginine-vasopressin was unrelated to baseline ventricular function.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Similarly, clinical reports advocate for use of arginine-vasopressin as a \u0026ldquo;cleaner inotrope\u0026rdquo; in pediatric patients with heart failure to avoid the side effects and morbidity associated with catecholamine use. \u003csup\u003e16\u003c/sup\u003e On the other hand, studies evaluating end organ perfusion and oxygen balance have also demonstrated similar findings to our study. In a small cohort of 20 children after congenital heart surgery, arginine-vasopressin was not associated with any improvement in organ perfusion.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Moreover, a single center study evaluating the effect of arginine-vasopressin in clinical and oximetric parameters in neonates following stage 1 palliation indicated that improvement in blood pressure was accompanied with an increase in cerebral and renal oxygen extraction for the subset of patients with Sano modification.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e It was presumed that the increase in systemic vascular resistance induced by arginine-vasopressin resulted in increased pulmonary blood flow and systemic steal. Our study population consisted of only biventricular patients without residual shunts, therefore a change in Qp;Qp ratio cannot be the explanation for our findings. Our study was not designed to offer a mechanistic explanation for the change in oxygen balance. It plausible that the increase in systemic vascular resistance has resulted in a decrease cardiac output and oxygen transport but our data cannot support this speculation. Data on the effect of arginine-vasopressin on oxygen consumption are very limited. Nonetheless, animal experiments have suggested that arteriolar vasoconstriction induced by clinical doses of arginine-vasopressin might increase vessel wall oxygen consumption.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Contrarily, animal data exist that suggest a decrease in oxygen consumption associated with arginine-vasopressin.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Given the uncertainty of the specific actions of vasopressin in the microcirculation and the effect on tissue oxygen balance, clinical vigilance is warranted. In the clinical use of arginine-vasopressin avoidance of high doses that can instigate excessive vasoconstriction and monitoring of global and regional tissue oxygen balance is justified.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOur study has several limitations. Firstly, it is a small single center observational study, and its findings might not be generalizable. The design was observational; therefore, the clinical management was not protocolized and decisions on vasoactive management were entirely at the discretion of the clinical team. However, our institutional practice dictates that epinephrine is kept at low inotropic doses and vasopressin is the vasopressor of choice for hypotensive patients. Therefore, the non- arginine-vasopressin group consisted of non-hypotensive patients (only 2 patients were treated with norepinephrine in this group), and it is not a true control group. However, we observed similar slope of progress for all clinical hemodynamics (heart rate, blood pressure, blood lactate) for both groups reasonably supporting the conclusion that arginine-vasopressin restored clinical hemodynamics in the hypotensive patients. Another significant limitation is that oxygen balance data are derived from near infrared spectroscopy which is an imperfect monitor and is characterized by wide limits of agreement with measured central venous saturations.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Despite its limitations near infrared spectroscopy has become the standard of care in postoperative management of pediatric cardiac patients and it is the only available monitor of continuous real time oximetric data of regional circulations. \u003csup\u003e21\u003c/sup\u003eFinally, our cohort was a convenience cohort, and we missed potentially eligible patients during the study period.\u003c/p\u003e\u003cp\u003eSummarizing, arginine-vasopressin therapy is associated with favorable effects in blood pressure and restores clinical hemodynamics in hypotensive postoperative pediatric cardiac patients with biventricular circulation. In addition, it is associated with an increase in cerebral and renal oxygen extraction, necessitating oxygen balance monitoring with its clinical use. Further studies in multicenter cohorts are required to confirm validity and generalizability of these findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eFinancial Support\u003c/h2\u003e\u003cp\u003eThis research received no financial support.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eConflicts of Interest\u003c/h2\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthical Standards\u003c/h2\u003e\u003cp\u003e All study procedures complied with the ethical standards of the Helsinki Declaration and has been approved by Institutional Research Board of Cincinnati Children\u0026rsquo;s Medical Center.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll the authors helped with design and completion of the study. In addition all authors participated in the writing of the main manuscript, preparing figures and tables. All authors reviewed the final document.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003e The authors acknowledge the staff of the Heart Institute Research Core at Cincinnati Children\u0026rsquo;s Hospital Medical Center for the regulatory, data management and statistical support provided.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLoomba RS, Flores S. Use of vasoactive agents in postoperative pediatric cardiac patients: Insights from a national database. \u003cem\u003eCongenit Heart Dis\u003c/em\u003e. 2019;14(6):1176-1184. doi:10.1111/chd.12837\u003c/li\u003e\n\u003cli\u003eLechner E, Hofer A, Mair R, Moosbauer W, Sames-Dolzer E, Tulzer G. Arginine-vasopressin in neonates with vasodilatory shock after cardiopulmonary bypass. \u003cem\u003eEur J Pediatr\u003c/em\u003e. 2007;166(12). doi:10.1007/s00431-006-0400-0\u003c/li\u003e\n\u003cli\u003eRosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. \u003cem\u003eCirculation\u003c/em\u003e. 1999;100(19 SUPPL.). doi:10.1161/01.cir.100.suppl_2.ii-182\u003c/li\u003e\n\u003cli\u003eMastropietro CW, Davalos MC, Seshadri S, Walters HL, Delius RE. Clinical response to arginine vasopressin therapy after paediatric cardiac surgery. \u003cem\u003eCardiol Young\u003c/em\u003e. 2013;23(3). doi:10.1017/S1047951112000996\u003c/li\u003e\n\u003cli\u003eMastropietro CW, Rossi NF, Clark JA, et al. 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Acute Effects of Vasopressin Arginine Infusion in Children with Congenital Heart Disease: Higher Blood Pressure Does Not Equal Improved Systemic Oxygen Delivery. \u003cem\u003ePediatr Cardiol\u003c/em\u003e. 2021;42(8):1792-1798. doi:10.1007/s00246-021-02667-1\u003c/li\u003e\n\u003cli\u003eBronicki RA, Acosta S, Savorgnan F, et al. The acute influence of vasopressin on hemodynamic status and tissue oxygenation following the Norwood procedure. \u003cem\u003eJTCVS Open\u003c/em\u003e. 2022;9:217-224. doi:10.1016/j.xjon.2022.01.008\u003c/li\u003e\n\u003cli\u003eJenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. \u003cem\u003eJournal of Thoracic and Cardiovascular Surgery\u003c/em\u003e. 2002;123(1). doi:10.1067/mtc.2002.119064\u003c/li\u003e\n\u003cli\u003eDavidson J, Tong S, Hancock H, Hauck A, Da Cruz E, Kaufman J. Prospective validation of the vasoactive-inotropic score and correlation to short-term outcomes in neonates and infants after cardiothoracic surgery. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 2012;38(7). doi:10.1007/s00134-012-2544-x\u003c/li\u003e\n\u003cli\u003eAlten JA, Borasino S, Toms R, Law MA, Moellinger A, Dabal RJ. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. \u003cem\u003ePediatric Critical Care Medicine\u003c/em\u003e. 2012;13(3). doi:10.1097/PCC.0b013e31822f1753\u003c/li\u003e\n\u003cli\u003eIndrambarya T, Boyd JH, Wang Y, McConechy M, Walley KR. Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice. \u003cem\u003eCrit Care\u003c/em\u003e. 2009;13(3). doi:10.1186/cc7930\u003c/li\u003e\n\u003cli\u003eIliopoulos I, Flores S, Pratap JN, Cooper DS, Cassedy A, Nelson DP. Arginine-vasopressin therapy in hypotensive neonates and infants after cardiac surgery: Response is unrelated to baseline ventricular function. \u003cem\u003eCardiol Young\u003c/em\u003e. 2017;27(6). doi:10.1017/S104795111600189X\u003c/li\u003e\n\u003cli\u003eKarki KB, Towbin JA, Harrell C, et al. Concurrent Use of Calcium Chloride and Arginine Vasopressin Infusions in Pediatric Patients with Acute Cardiocirculatory Failure. \u003cem\u003ePediatr Cardiol\u003c/em\u003e. 2019;40(5):1046-1056. doi:10.1007/s00246-019-02114-2\u003c/li\u003e\n\u003cli\u003eFriesenecker B, Tsai AG, D\u0026uuml;nser MW, et al. Oxygen distribution in microcirculation after arginine vasopressin-induced arteriolar vasoconstriction. \u003cem\u003eAm J Physiol Heart Circ Physiol\u003c/em\u003e. 2004;287(4 56-4). doi:10.1152/ajpheart.00283.2004\u003c/li\u003e\n\u003cli\u003eLiard JF. Reduced oxygen consumption induced by vasopressin in dogs depends on systemic administration. \u003cem\u003eClin Sci\u003c/em\u003e. 1991;81(6). doi:10.1042/cs0810751\u003c/li\u003e\n\u003cli\u003eLiard JF. Vasopressin-induced changes in cardiac vagal tone and oxygen consumption in dogs. \u003cem\u003eAm J Physiol Regul Integr Comp Physiol\u003c/em\u003e. 1994;266(3 35-3). doi:10.1152/ajpregu.1994.266.3.r838\u003c/li\u003e\n\u003cli\u003eIliopoulos I, Cooper DS, Reagor JA, et al. Absolute Versus Relative Near-Infrared Spectroscopy in Pediatric Cardiac Patients\u0026lowast;. \u003cem\u003ePediatric Critical Care Medicine\u003c/em\u003e. 2023;24(3). doi:10.1097/PCC.0000000000003118\u003c/li\u003e\n\u003cli\u003eGhanayem NS, Wernovsky G, Hoffman GM. Near-infrared spectroscopy as a hemodynamic monitor in critical illness. \u003cem\u003ePediatric Critical Care Medicine\u003c/em\u003e. 2011;12(4 SUPPL.). doi:10.1097/PCC.0b013e318221173a\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Arginine-vasopressin, pediatric cardiac surgery, postoperative cardiac care, congenital heart disease","lastPublishedDoi":"10.21203/rs.3.rs-7653444/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7653444/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Arginine-vasopressin is widely used for treatment of vasodilatory and mixed shock after pediatric cardiac surgery. Although a favorable effect on blood pressure has been documented, data on organ perfusion and tissue oxygen balance remain limited.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: We prospectively evaluated an observational cohort of 49 children after reparative cardiac surgery. Median age was 8 months (interquartile range 5 to 59 months) and weight 11.0 kg (interquartile range 7.2 to 26.3 kg). Patients who received arginine-vasopressin (n=23) for hypotension were compared with patients of similar surgical complexity who did not (n=26), using regression analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: Vasopressin dose was independently associated with an increase in systolic blood pressure (p\u0026lt;0.01), an increase in cerebral oxygen extraction (p=0.04), and an increase in renal oxygen extraction (p\u0026lt;0.01). No statistical difference was observed between treated and non-treated patients in diastolic blood pressure, blood lactate, or urine output.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions: Arginine-vasopressin therapy restores blood pressure in hypotensive children after cardiac surgery but may have unfavorable effects on tissue oxygenation.\u003c/p\u003e","manuscriptTitle":"Hemodynamic Effects of Arginine-Vasopressin After Pediatric Cardiac Surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-06 09:14:59","doi":"10.21203/rs.3.rs-7653444/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":"022490de-46ec-42c4-9f08-c8a5d5b91e64","owner":[],"postedDate":"October 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-07T18:08:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-06 09:14:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7653444","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7653444","identity":"rs-7653444","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}