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A complicated Glenn procedure: risk factors and association with adverse long-term neurodevelopmental and functional outcomes

Published online by Cambridge University Press:  24 August 2022

Gurpreet K. Khaira*
Affiliation:
Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Division of Pediatric Critical Care, Stollery Children’s Hospital, Edmonton, Alberta, Canada
Ari R. Joffe
Affiliation:
Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Division of Pediatric Critical Care, Stollery Children’s Hospital, Edmonton, Alberta, Canada
Gonzalo G. Guerra
Affiliation:
Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Division of Pediatric Critical Care, Stollery Children’s Hospital, Edmonton, Alberta, Canada Pediatric Cardiac Intensive Care Unit, Stollery Children’s Hospital, Edmonton, Alberta, Canada
Brittany A. Matenchuk
Affiliation:
Department of Obstetrics & Gynecology, University of Alberta, Edmonton, Alberta
Irina Dinu
Affiliation:
School of Public Health, University of Alberta, Edmonton, Alberta, Canada
Gwen Bond
Affiliation:
Complex Pediatric Therapies Follow-Up Program, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada
M. Alaklabi
Affiliation:
Division of Pediatric Cardiovascular Surgery, Stollery Children’s Hospital, Edmonton, Alberta, Canada
Charlene M.T. Robertson
Affiliation:
Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Complex Pediatric Therapies Follow-Up Program, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada
V. Ben Sivarajan
Affiliation:
Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Division of Pediatric Critical Care, Stollery Children’s Hospital, Edmonton, Alberta, Canada Pediatric Cardiac Intensive Care Unit, Stollery Children’s Hospital, Edmonton, Alberta, Canada
*
Author for correspondence: Gurpreet K. Khaira, FRCPC, 4-537 Edmonton Clinic Health Academy, 11405 112 Street, Edmonton, Alberta T6G 1C9, Canada. Tel: +1 780 918 4452. E-mail: [email protected]
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Abstract

Objectives:

To determine potentially modifiable risk factors for a complicated Glenn procedure (cGP) and whether a cGP predicted adverse neurodevelopmental and functional outcomes. A cGP was defined as post-operative death, heart transplant, extracorporeal life support, Glenn takedown, or prolonged ventilation.

Methods:

All 169 patients having a Glenn procedure from 2012 to 2017 were included. Neurodevelopmental assessments were performed at age 2 years in consenting survivors (n = 156/159 survivors). The Bayley Scales of Infant and Toddler Development-3rd Edition (Bayley-III) and the Adaptive Behavior Assessment System-2nd Edition (ABAS-II) were administered. Adaptive functional outcomes were determined by the General Adaptive Composite (GAC) score from the ABAS-II. Predictors of outcomes were determined using univariate and multiple variable linear or Cox regressions.

Results:

Of patients who had a Glenn procedure, 10/169 (6%) died by 2 years of age and 27/169 (16%) had a cGP. Variables statistically significantly associated with a cGP were the inotrope score on post-operative day 1 (HR 1.04, 95%CI 1.01, 1.06; p = 0.010) and use of inhaled nitric oxide post-operatively (HR 7.31, 95%CI 3.19, 16.76; p < 0.001). A cGP was independently statistically significantly associated with adverse Bayley-III Cognitive (ES −10.60, 95%CI −17.09, −4.11; p = 0.002) and Language (ES −11.43, 95%CI −19.25, −3.60; p = 0.004) scores and adverse GAC score (ES −14.89, 95%CI −22.86, −6.92; p < 0.001).

Conclusions:

Higher inotrope score and inhaled nitric oxide used post-operatively were associated with a cGP. A cGP was independently associated with adverse 2-year neurodevelopmental and functional outcomes. Whether early recognition and intervention for risk of a cGP can prevent adverse outcomes warrants study.

Type
Original Article
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2022. Published by Cambridge University Press

The bidirectional cavopulmonary shunt (the Glenn procedure) is the second of three-staged surgical procedures that have been utilised for palliating children with single ventricular anatomy and other complex CHDs. Reference Hopkins, Armstrong, Serwer, Peterson and Oldham1Reference Petrucci, Khoury, Manning and Eghtesady5 Used prior to the total cavopulmonary connection (the Fontan procedure), the Glenn procedure has improved overall outcomes in these children. Reference Masuda, Kado and Shiokawa6,Reference Bridges, Jonas and Mayer7 While the mortality and failure rate for this interstage procedure is low, Reference Carlo, Carbery and Heinle8Reference Alsoufi, Manlhiot and Awan13 there exists enough mortality and morbidity that risk factors should be delineated.

Previous researchers have identified possible risk factors associated with Glenn failure: ventricular dysfunction, atrioventricular valvular regurgitation (AVVR), elevated mean pulmonary artery pressure, elevated transpulmonary gradient, and heterotaxy. Reference Carlo, Carbery and Heinle8Reference Alejos, Williams and Jarmakani15 This existing literature is limited by the lack of systematic long-term follow-up and assessment of potential risk factors for late adverse outcomes. Through the Western Canadian Complex Pediatric Therapies Follow-up Program (CPTFP) registry, we have a high rate of long-term follow-up (to age 2 years to determine detailed neurodevelopmental and functional outcomes) in survivors. Reference Robertson, Sauve and Joffe16 We aimed to report the experience of the CPTFP with the Glenn procedure done in infants with single ventricles during a recent surgical era. We hypothesised that there would be potentially modifiable risk factors for a complicated post-Glenn course. We also hypothesised that a complicated post-Glenn course would be an independent predictor of adverse neurodevelopmental and functional outcomes at age 2 years. The results were anticipated to inform timely intervention for patients to prevent a complicated Glenn course and thus lead to better decision-making to reduce morbidity and mortality.

Materials and methods

Study design

This was a prospective inception-cohort study that included all consecutive patients having the Glenn procedure at the Stollery Children’s Hospital (Edmonton, Alberta, Canada) from January 2012 to December 2017. The Stollery Children’s Hospital is a Western Canadian referral centre for complex paediatric cardiac surgery for multiple tertiary referral sites. Patients were identified at the time of complex cardiac surgery at which point consent was obtained and they were recruited for inclusion into the CPFTP registry. This study was approved by our university research ethics board (Pro00001030). Previously agreed upon demographic, pre-operative, intra-operative, and post-operative variables were collected prospectively. Reference Robertson, Sauve and Joffe16 Pre-operative anatomy and haemodynamic assessments were conducted using pre-operative echocardiogram and either pre-operative catheterisation or cardiac MRI. Use of catheterisation versus cardiac MRI was largely dependent on the referral centre. Long-term follow-up was performed at 2 years of age at one of the tertiary sites of origin. Follow-up at age 2 years was used to allow enough time for recovery after the Glenn procedure (and at least 6 months after any surgical procedure), but before the Fontan procedure. The follow-up study and database have been approved by each respective institutional health research ethics board.

Variables and definitions

Variables previously agreed upon had been collected prospectively in the CPTFP Registry (eTables 1 and 2). Additional pre-specified variables were collected by retrospective chart review: need for Glenn take down, cardiac catheterisation or cardiac MRI data (whichever was performed and allowed determination of ratio of pulmonary to systemic blood flow [Qp/Qs], presence of pulmonary artery [PA] or vein [PV] obstruction, or presence of restrictive atrial septal defect), pre-Glenn echocardiogram (ECHO) data (to assess for presence of at least moderate AVVR or at least moderate systemic ventricular dysfunction), presence of significant residual lesions on post-Glenn ECHO (defined as at least moderate ventricular dysfunction, at least moderate AVVR, decompressing collateral vessel(s), or residual anatomic obstruction [of PA, PV, or aortic arch]). Each finding was recorded as on the cardiac catheterisation, MRI, and ECHO report.

We defined a complicated Glenn Procedure (cGP) as any one of i) death by age 2 years, ii) cardiac transplant by age 2 years, iii) need for extracorporeal life support (ECLS, i.e., extracorporeal membrane oxygenation [ECMO] or ventricular assist device) during the Glenn hospitalisation, iv) need for Glenn take down during the hospitalisation, or v) prolonged mechanical ventilation after the Glenn procedure (defined as ≥90th percentile of post-operative ventilation duration in the cohort). There is no consistent definition of a cGP in the literature; the components used were decided by consensus of the authors to reflect what we believe clinicians and parents would want to know regarding an in-hospital complicated course (i.e., Glenn takedown, prolonged ventilation days, death, ECLS, transplant) and 2-year severe complications (i.e., death, transplant).

Certified paediatric psychologists obtained the results of the Adaptive Behavior Assessment System, 2nd Edition (ABAS-II) in the patient’s respective referral institutions. Adaptive functional outcomes were determined by the General Adaptive Composite (GAC) score from the ABAS-II. The GAC has a normative population mean of 100 and standard deviation (SD) of 15; higher scores indicate better performance, a score <85 is 1 SD below the mean (expected in 15.9% of the normative population), and a score <70 is 2 SD below the mean (expected in 2.27% of the normative population). Reference Harrison and Oakland17

Certified paediatric psychologists and psychometrists administered the Bayley Scales of Infant and Toddler Development-3rd Edition (Bayley-III) in their respective referral institutions. Corrected age was used up to 2 years as recommended. The Cognitive Scale includes non-verbal activities involving memory, problem solving, and manipulation of the physical world. The Language Scale includes Receptive and Expressive Communication subtests. The Motor Scale includes a Fine Motor (e.g., visual–motor integration, visual–spatial, and motor control skills in the hands) and Gross Motor (e.g., large body movements, mobility, and complex movements) subtests. The population norm score on these scales is 100, with SD 15. 18

Statistical analysis

We described variables and outcomes using proportions (percentages) for categorical variables and mean (SD) or median [interquartile range, IQR] for continuous variables.

The primary outcome was prediction of a cGP. Cox regression for univariate associations was performed for all predictor variables in eTables 1 and 2. A multiple Cox regression model was done including all variables with p-value <0.05 on univariate analysis, and after screening for multicollinearity. Associations are presented as Hazard Ratios (HR) with 95% confidence intervals (CI) and two-sided p-values. The potential predictor variables for a cGP were determined a priori. These included demographic, pre-operative, intra-operative, and day 1 post-operative (i.e., on day of operation) variables, and certain post-operative variables that occurred in at least 5% of patients, specifically the use of iNO and residual anatomic cardiac abnormalities (see eTables 1 and 2). Inotrope score post-operative day 1 and iNO use post-operatively were variables included that aimed to reflect clinician therapy in response to deteriorating patient condition.

We considered that clinicians and parents would want to know if survival after a cGP may be associated with adverse neurodevelopmental and functional outcomes. The secondary outcome was thus whether a cGP was an independent predictor of adverse neurodevelopmental and functional outcomes. Linear regression for univariate associations was performed for all predictor variables in eTables 1 and 2. All univariate variables with a p-value approaching significance at p ≤ 0.1 for association with the outcome were evaluated, after screening for multicollinearity, in a multiple variable linear regression model for each outcome. A priori we determined that two variables would be forced into each of these models, regardless of their univariate association: socioeconomic status (determined by the Blishen Index Reference Blishen, Carroll and Moore19 ) and cGP. Results are presented as effect sizes (ES) with 95% CI. A p-value <0.05 was used to determine statistical significance in the multivariable models.

We present results of univariate regressions that have a p-value ≤0.10, and of multiple variable regressions that have a p-value ≤0.05 or that were pre-specified to be forced into the regressions. Coefficients (effect sizes) and Hazard Ratios that have higher p-values are not presented because, given low prior probabilities in this exploratory research, their posterior probability of being a true association would be very low and likely misleading. Reference Nostedt and Joffe20

Some analyses were done post-hoc (i.e., not pre-specified) after obtaining our results for primary and secondary outcomes and are therefore exploratory. These explored associations of some variables, based on the above multiple regression results, potentially suggest what was driving the findings. These are described in the supplemental methods.

Results

Description of the cohort

During the 6-year study period, 171 patients had a Glenn procedure. Patients whose charts were not available were excluded (n = 2). Demographic, anatomic, haemodynamic, and acute-care variables are shown in eTables 1 and 2. Variables significantly associated with the outcome are provided in Table 1.

Table 1. Descriptive variables of significance for two-year outcome in 169 children having the Glenn procedure.

CPR: cardiopulmonary resuscitation; DHCA: deep hypothermic circulatory arrest; ECMO: extracorporeal membrane oxygenation; PA: pulmonary artery.

Overall, pre-op catheterisations occurred in 93 (55%) patients, pre-operative cardiac MRI in 77 (46%), both MRI and catheterisation in 12 (7%), Computed Tomography (CT) chest with angiography and catheterisation in 1 (0.6%), and none (of catheterisation, cardiac MRI or CT) in 11 (6.5%). Also, 92 (54.4%) were male, 77 (46%) underwent a Norwood/Sano as their initial procedure, the median age at Glenn was 6.4 [2.8, 10] months, the median days of ventilation was 1 [0, 2] days, and the median length of hospital stay was 10 [7, 18] days. Four patients (2%) died within 30 days of the Glenn procedure (three of whom died during the Glenn procedure hospitalisation).

The outcomes in survivors are shown in eTable 3. Growth was within normal range, but 22% required the use of a G-tube. Survivors experienced several re-hospitalisations (mean 2, SD 3) and remained on pulmonary and cardiac medications (mean 2, SD 1.5) at 2 years of age.

Complicated Glenn procedure

Of the 169 patients, 27 (16%) met criteria for a cGP (Table 2). The reasons for being classified as a cGP are given in Table 2. The Kaplan–Meier curve for survival without meeting the definition of a cGP is shown in Figure 1.

Figure 1. Kaplan-Meier Survival curve for survival without meeting the definition of a complicated Glenn Procedure. This curve shows the probability over time of survival without having a complicated Glenn procedure; at 2 years of age this probability was 84%.

Table 2. Description of components of the complicated Glenn procedure composite outcome.

None had use of ventricular assist device used post-operative Glenn. Of Glenn takedowns, 0 had transplant or death; of ECMO post-operative Glenn, 1 had transplant, and 3 died.

cGP: complicated Glenn procedure; ECMO: extracorporeal membrane oxygenation; VA: veno-arterial.

Demographic, anatomic, and haemodynamic variables were compared between cGP and non-cGP patients. Results of univariate (for all variables from eTables 1 and 2 having a p-value ≤ 0.05) and multiple variable Cox regression are shown in Table 3. The inotrope score on post-operative day 1 (HR 1.04 (1.01, 1.06) p = 0.010) and use of iNO post-operatively (HR 7.31 (3.19, 16.76) p < 0.001) were associated with cGP. Post-hoc exploratory analyses for associations with the use of iNO and day 1 inotrope score are in the supplemental results and shown in eTable 4. Post-hoc exploratory analyses for association of highest CVP and a surrogate for transpulmonary gradient are in the supplemental results.

Table 3. Predictors on univariate and multiple-variable Cox regressions of a Complicated Glenn Procedure in 169 children.

Variables not statistically significant on univariate analysis included: maximum CVP d1-5; fluid balance d1; at least moderate AVVR on ECHO pre-operatively; PA obstruction or restrictive atrial septal defect on catheterization or MRI pre-operatively; residual at least moderate AVVR on ECHO post-operatively.

Variables statistically significant on univariate, but not included due to too few patients having the finding (<5% of cohort): two transfusions d1 (2.4%), positive blood culture sepsis (4.1%), CPR post-operatively (2.4%), dialysis post-operatively (2.4%), re-CPB during Glenn operation (4.7%), pre-operative ECHO at least moderate ventricular dysfunction (4.7%), residual PV obstruction on post-operative ECHO (2.4%), and re-opening of sternum post-operatively (4.1%). The lowest Qp:Qs pre-operatively was only available in 85 (60%) of non-cGP 1.02 (0.65) and 14 (52%) cGP 1.42 (2.07) for a univariate HR 1.45 (1.00, 2.09) p = 0.049.

cGP: complicated Glenn Procedure; CPB: cardiopulmonary bypass; ECHO: echocardiogram; ECMO: extra-corporeal membrane oxygenation; iNO: inhaled nitric oxide.

a Inotrope score calculated as: (100)(epinephrine + norepinephrine) + (dopamine + dobutamine) + (10)(milrinone), with each of the vasoactive agents dose in mcg/kg/min. Reference Martin, Jonker and Joffe30

b Additional procedures: aortic arch repair 13, ventriculo-arterial valve repair/replacement 11, atrio-ventricular valve repair/replacement 12, pulmonary artery plasty 45, atrial septectomy 21, pulmonary artery band removal 7, DKS 10, pulmonary band 2.

Neurodevelopmental and functional outcomes

Of the 159 patients who survived to 2 years, 3 refused follow-up, leaving 156 (98%) having full neurodevelopmental outcome assessments. Follow-up was done at a mean of 22.9 (SD 4.6) and median of 22 (IQR 20–24) months of age, in all cases prior to the Fontan operation. Neurodevelopmental and functional outcomes were within population norms, though shifted to the left. A delay in these scores (i.e., score < 70 is > 2SD below the population norms) occurred in 10–20% of survivors, higher than the expected 2.27% of the normative population (eTable 3).

The results of univariate (for all variables having a p-value approaching statistical significance, p ≤ 0.10) and multiple variable linear regression for each Bayley-III outcome are shown in Tables 4 and 5. A cGP was statistically significantly independently associated with adverse Bayley-III Cognitive (ES −10.60, 95% CI −17.09, −4.11; p = 0.002) and Language (ES −11.43, 95% CI −19.25, −3.60; p = 0.004) scores, but not with the Motor score. Other variables independently associated with better outcomes on at least two of the Bayley-III scores included higher socioeconomic status, fewer ventilator days at neonatal operation, use of deep hypothermic circulatory arrest (DHCA) at the Glenn procedure, and PA obstruction present prior to the Glenn operation.

Table 4. Univariate linear regressions for Bayley-III Scores in 156 children surviving to 2 years of age after having the Glenn procedure.

Of 169 patients included, 10 died by age 2 years, and 3 refused follow-up, giving 156 for these outcomes.

CPR: cardiopulmonary resuscitation; DHCA: deep hypothermic circulatory arrest; ECHO: echocardiogram; ECMO: extracorporeal membrane oxygenation; PA: pulmonary artery; PICU: pediatric ICU.

Table 5. Multiple variable linear regressions for Bayley-III Scores in 156 children surviving to 2 years of age after having the Glenn procedure.

Of 169 patients included, 10 died by age 2 years, and 3 refused follow-up, giving 156 for these outcomes. Note that day 1 lowest haemoglobin after Glenn and day 1 lowest PaO2 after Glenn had low correlation of r = 0.10. In multiple variable linear regressions including only the n = 122 who had neonatal operation, ventilator days at neonatal operation was independently associated with Cognitive composite score (Coefficient −0.39 (95% CI −0.66, −0.12) p = 0.005) and Motor composite score (Coefficient −0.58 (−0.92, −0.24) p = 0.001), and CPR at time of neonatal operation was independently associated with Cognitive composite score (Coefficient −7.35 (−13.54, −1.17) p = 0.020).

CPR: cardiopulmonary resuscitation; DHCA: deep hypothermic circulatory arrest; ECHO: echocardiogram; PA: pulmonary artery.

The results of univariate (for all variables having a p-value ≤ 0.10) and multiple variable linear regression for the GAC score are shown in Table 6. A cGP was statistically significantly independently associated with adverse GAC score (ES −14.89, 95% CI −22.86, −6.92; p < 0.001). Other variables independently associated with adverse GAC score included longer ventilator days at the neonatal operation, cardiopulmonary resuscitation at the time of neonatal operation and having a chromosomal abnormality.

Table 6. Univariate and multiple variable linear regression for general adaptive composite score in 156 children surviving to 2 years of age after having the Glenn procedure.

Of 169 patients included, 10 died by age 2 years, and 3 refused follow-up, giving 156 for these outcomes. In multiple variable linear regressions including only n = 122 who had neonatal operation, ventilator days at neonatal operation was independently associated with GAC (Coefficient −0.43 (−0.80, −0.06) p = 0.022), and CPR at time of neonatal operation was independently associated with GAC (coefficient −8.81 (−17.18, −0.44) p = 0.039).

CPR: cardiopulmonary resuscitation; ECHO: echocardiogram.

Discussion

We report the outcomes of 169 patients having a Glenn procedure at a Western Canadian referral centre for complex paediatric cardiac surgery over a recent 6-year period. The main findings of this study are highlighted. First, 27 (16%) patients met our definition of a cGP, including 10 (6%) who died by age 2 years. Second, higher inotrope score on the first post-operative day of the Glenn procedure and the use of iNO post-operatively were identified as independent risk factors for a cGP. Whether these predictors are modifiable requires future study. Third, a cGP was an independent predictor of adverse Bayley-III outcomes on cognitive and language scores and GAC outcome, with ES that were close to 1 SD of the population norms. In addition to the variables peri and post the Stage-1 surgery that impact long-term outcomes, Reference Ohye, Sleeper and Mahony21 these findings emphasise that events at the time of the Glenn procedure have the potential to impact these long-term outcomes as well. Indeed, the 14-month neurodevelopmental outcomes from the single ventricle reconstruction trial were deemed to be more dependent on the innate patient factors and patient morbidities in the first year than the specific Stage-1 operative strategies. Reference Newberger, Sleeper and Bellinger22 We describe here unrecognised morbidities and risk factors during the Glenn procedure that may contribute to these findings noted in the single ventricle reconstruction trial.

The early mortality after the Glenn procedure (defined as death <30 days after the Glenn procedure, rate of 2%) and rates of cGP (16%) in this study are comparable to those reported by other investigators. Reference Petrucci, Khoury, Manning and Eghtesady5Reference Scheurer, Hill and Vasuki9,Reference Kogon, Plattner, Leong, Simsic, Kirshbom and Kanter11 In contrast to previous studies, some risk factors, including pre-operative ventricular dysfunction and AVVR, were not statistically significantly associated with a cGP outcome - potentially explainable by different definitions for a complicated post-Glenn course. Reference Reddy, McElhinney, Moore, Haas and Hanley4Reference Kogon, Plattner, Leong, Simsic, Kirshbom and Kanter11 These risk factors were previously identified in populations with predominantly Hypoplastic Left Heart Syndrome (accounting for only 32.5% of the diagnoses in our population). In our population, 46% had a Norwood-Sano procedure as their first operation. Our institutional preference for the Norwood/Sano procedure (as opposed to the classical Norwood procedure) may mitigate some of these risks, as we previously reported a survival and neurodevelopmental benefit at age 2 years during the Sano era versus the modified BT shunt era at our institution, Reference Atallah, Dinu and Joffe23 which we acknowledge may differ from the experience of other centers. Reference Ohye, Sleeper and Mahony21

On univariate analysis, some variables that may be associated with these previously identified risk factors were associated with a cGP (Table 3), including severity of illness on the first post-operative day, existence of collateral vessels, and moderate to severe ventricular dysfunction on echocardiogram post-operatively. However, most of these variables were not independent predictors; only higher inotrope score on the first post-operative day and use of iNO post-operatively were statistically significantly associated with a cGP. Of note, higher inotrope score could relate to post-operative ventricular dysfunction. Also, identification of use of iNO has not been previously identified as a risk factor. Reference Carlo, Carbery and Heinle8Reference Alejos, Williams and Jarmakani15

We do not have a protocol for starting nor weaning iNO. Inhaled nitric oxide was likely used by clinicians to manage refractory hypoxemia or low cardiac output; potentially to reduce elevated pulmonary vascular resistance and thus improve effective pulmonary blood flow. Many have reported a reduction in central venous pressure (i.e., Glenn pressure) and hence the transpulmonary pressure gradient with use of iNO in patients immediately after the Glenn procedure. Reference Agarwal, Churchwell and Doyle24Reference Georgiev, Latcheva, Pilossoff, Lazarov and Mitev26 However, these physiological changes may not consistently translate to an improvement in systemic oxygenation - especially in patients with residual anatomic obstruction. Reference Adatia, Atz and Wessel27 The use of this therapy in the post-operative period may therefore indicate a failing circulation that, in the absence of other investigations and/or interventions, may confer risk for a cGP and the attendant neurodevelopment sequelae. This explanation is consistent with our finding of statistically significant associations between the use of iNO and post-operative day 1 and 2–5 lactates and PaO2, day 2–5 inotrope score, and number of transfusions on post-operative day 1. Similarly, the association of higher post-operative inotrope score with cGP likely reflects higher doses of vasoactive medications being used when there is a failing circulation resulting in hypoxia and low cardiac output. Again, this is consistent with our finding of statistically significant associations between day 1 inotrope score and post-operative day 1 and day 2–5 lactates and PaO2. Overall, we believe that the need for iNO post-operatively and/or higher inotropes should trigger important clinical decisions, including cardiac catheterisation, looking for potentially treatable residual lesions; this requires further study.

As far as we are aware, this is the first study to find a strong association between a cGP and adverse long-term neurodevelopmental and functional outcomes. The CPTFP achieved longitudinal follow-up to 2 years of age in 156/159 (98%) of survivors after a Glenn procedure. We were able to show that a cGP was a statistically significant independent predictor of adverse neurodevelopmental and functional outcomes as determined by the Bayley-III and GAC scores, with effect size being clinically significant (between ½ to 1 SD of the population norms of the scores). Only the motor score on Bayley-III was not statistically significantly associated with a cGP. These findings of adverse neurodevelopmental and functional outcomes may reflect the effects of hypoxia and low cardiac output that are components of the definition of a cGP: requiring heart transplant, extra-corporeal life support, Glenn take-down, or prolonged ventilation to achieve survival.

After multivariable logistic regression, DHCA used during the Glenn procedure was independently associated with higher Bayley-III Cognitive and Language scores. After multivariable logistic regression, the presence of pre-Glenn PA obstruction was unexpectedly independently associated with higher cognitive and motor scores on the Bayley-III. As we explored many relationships, it is possible that these associations with neurodevelopmental outcomes were false positives. In addition, the p-values for these findings can be considered only suggestive, and confirmation in future studies is required. Further discussion of these associations can be found in the supplemental discussion.

This study has limitations. First, this was a single centre study and may reflect local practice patterns and surgical techniques resulting in limited generalisability. Even so, during the period of this study, we had 4 paediatric cardiac surgeons operating and 11 cardiac intensivists; clinical practice was at their discretion. A second limitation is that some of the variables were collected retrospectively resulting in a risk of information bias. The retrospectively collected variables were objective measurements reported in the medical charts from cardiac catheterisation, echocardiogram, and MRI, potentially mitigating this limitation. In addition, we did not include some variables that may have improved prediction, including pulmonary artery pressures and detailed anatomic abnormalities (e.g., aortic atresia). A previous study by our group found no difference in Bayley-III scores at age 2 years between patients with HLHS and non-HLHS having a Norwood-Sano operation. Reference Martin, Jonker and Joffe30

This was an observational study and cannot prove cause and effect, and there may be unmeasured variables that confound the results. The findings should therefore be considered hypothesis generating and warrant confirmation, particularly the suggestion that inotrope score and use of iNO may be modifiable. Finally, a cGP is a composite outcome, and each component is not necessarily mutually exclusive (e.g., prolonged ventilation may occur in those requiring ECMO) nor temporally related. It is possible that some variables would predict one component and not another. Further, it is possible that certain components of the definition for a cGP (e.g., need for ECLS, transplantation, prolonged ventilation) may be independent risk factors for poor neurodevelopmental outcomes. Given the sample size, we did not explore these possibilities because we would likely obtain spurious findings due to multiple testing.

Strengths of this study include the large cohort, the prospective collection of most variables, and the very high rate of completed long-term follow-up. Further, we include variables across time, and were able to show that some variables associated with neurodevelopmental outcome reflect illness severity during the first surgery (i.e., ventilator days and need for cardiopulmonary resuscitation), chromosomal or syndromic diagnosis, and socioeconomic status of the parents, while others reflect severity of illness during the Glenn procedure. This emphasises that patients have exposure to many different risks over time and a focus on all potentially modifiable variables (e.g., improving social determinants of health) has the potential to improve long-term outcomes.

Conclusion

In 169 single ventricle patients having a Glenn procedure from a large Canadian cohort, higher inotrope score and iNO use post-operatively were independently statistically significantly associated with a cGP. Further study is required to explain the relationship of iNO use with cGP. In addition, a cGP was associated with adverse neurodevelopmental and functional outcomes at 2 years of age and should be added to the list of risk factors that increase the need for surveillance for adverse neurodevelopment. Reference Wernovsky and Licht31 Whether earlier identification of patients at risk for a cGP can allow interventions, such as early post-operative cardiac catheterisation, that prevent long-term morbidity and mortality warrants further study.

Supplementary material

To view supplementary material for this article, please visit https://doi.org/10.1017/S104795112200261X

Financial support

The Western Canadian Complex Pediatric Therapies Follow-up Program has been supported over the years by contributions from the following: Alberta Health, Stollery Children’s Hospital, Women and Children’s Health Research Institute, referral-site follow-up clinics (Saskatoon and Regina SK, Winnipeg MB, Calgary AB, Vancouver BC), and the Glenrose Rehabilitation Hospital Research Trust, with ongoing funding by the Glenrose Rehabilitation Hospital. These funding agencies had no role in the design and conduct of the study; collection, analysis, or interpretation of the data; preparation, writing, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Conflicts of interest

None.

HREB Number for CPFTP Registry

Pro00001030 (Approved yearly, last October 19, 2020). This number comes from our local research ethics board.

Consent statement

Patients were identified at the time of complex cardiac surgery at which point consent was obtained and they were recruited for inclusion into the Western Canadian Complex Pediatric Therapies Follow-up Program (CPFTP) registry.

References

Hopkins, RA, Armstrong, BE, Serwer, GA, Peterson, RJ, Oldham, HN Jr. Physiologic rationale for a bidirectional cavopulmonary shunt. J Thorac Cardiovasc Surg. 1985; 90: 391398.10.1016/S0022-5223(19)38595-2CrossRefGoogle ScholarPubMed
Jaquiss, R, Ghanayem, N, Hoffman, G, et al. Early cavopulmonary anastomosis in very young infants after the Norwood procedure: impact on oxygenation, resource utilization, and mortality. J Thorac Cardiovasc Surg. 2004; 127: 982989.10.1016/j.jtcvs.2003.10.035CrossRefGoogle ScholarPubMed
McElhinney, DB, Reddy, VM, Moore, P, Hanley, FL. Bidirectional cavopulmonary shunt in patients with anomalies of systemic and pulmonary venous drainage. Ann Thorac Surg 1997; 63: 16761684.10.1016/S0003-4975(97)00364-0CrossRefGoogle ScholarPubMed
Reddy, VM, McElhinney, DB, Moore, P, Haas, GS, Hanley, FL. Outcomes after bidirectional cavopulmonary shunt in infants less than 6 months old. JACC. 1997; 29: 13651370.10.1016/S0735-1097(97)00068-5CrossRefGoogle ScholarPubMed
Petrucci, O, Khoury, PR, Manning, PB, Eghtesady, P. Outcomes of bidirectional Glenn procedure in patients less than 3 months of age. J Thorac Cardiovasc Surg 2010; 139: 562568.10.1016/j.jtcvs.2009.08.025CrossRefGoogle ScholarPubMed
Masuda, M, Kado, H, Shiokawa, Y, et al. Clinical results of the staged Fontan procedure in high-risk patients. Ann Thorac Surg 1998; 65: 17211725.10.1016/S0003-4975(98)00264-1CrossRefGoogle ScholarPubMed
Bridges, ND, Jonas, RA, Mayer, JE, et al. Bidirectional cavopulmonary anastomosis as interim palliation for high-risk Fontan candidates: early results. Circulation 1990; 82: IV170-IV-176.Google ScholarPubMed
Carlo, WF, Carbery, KE, Heinle, JS, et al. Interstage attrition between bidirectional Glenn and Fontan palliation in children with hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 2011; 142: 511516.10.1016/j.jtcvs.2011.01.030CrossRefGoogle ScholarPubMed
Scheurer, MA, Hill, EG, Vasuki, N, et al. Survival after bidirectional cavopulmonary anastomosis: analysis of preoperative risk factors. J Thorac Cardiovasc Surg 2007; 134: 8289.10.1016/j.jtcvs.2007.02.017CrossRefGoogle ScholarPubMed
Tanoue, Y, Kado, H, Boku, N, et al. Three hundred and thirty-three experiences with the bidirectional Glenn Procedure in a single institution. Interac Cardiovasc Thorac Surg. 2007; 6: 97101.10.1510/icvts.2006.138560CrossRefGoogle Scholar
Kogon, BE, Plattner, C, Leong, T, Simsic, J, Kirshbom, PM, Kanter, KR. The bidirectional Glenn operation: a risk factor analysis for morbidity and mortality. J Thorac Cardivasc Surg. 2008; 136: 12371242.10.1016/j.jtcvs.2008.05.017CrossRefGoogle ScholarPubMed
Friedman, KG, Salvin, JW, Wypij, D, et al. Risk factors for failed staged palliation after bidirectional Glenn in infants who have undergone stage one palliation. Eur J Cardiothor Surg 2011; 40: 10001006.Google ScholarPubMed
Alsoufi, B, Manlhiot, C, Awan, A, et al. Current outcomes of the Glenn bidirectional cavopulmonary connection for single ventricle palliation. Eur J Cardiothorac Surg. 2012; 42: 4249.10.1093/ejcts/ezr280CrossRefGoogle ScholarPubMed
Ota, N, Ikai, A, Hirose, K, Sakamoto, K. Retrospective analysis of stage I Norwood procedures with tricuspid valve insufficiency in the past 5 years. Interact Cardiovasc Thorac Surg 2007; 6: 121123.10.1510/icvts.2006.142596CrossRefGoogle Scholar
Alejos, JC, Williams, RG, Jarmakani, JM, et al. Factors influencing survival in patients undergoing the bidirectional Glenn anastomosis. Am J Cardiol 1995; 75: 10481050.10.1016/S0002-9149(99)80722-XCrossRefGoogle ScholarPubMed
Robertson, CMT, Sauve, RS, Joffe, AR, et al. The registry and follow-up of complex pediatric therapies program of western Canada: a mechanism for service, audit and research after life-saving therapies for young children. Cardiol Res Pract 2011; 2011: 965740.10.4061/2011/965740CrossRefGoogle Scholar
Harrison, PL, Oakland, T. Manual for the Adaptive Behavior Assessment System. 2nd edn. The Psychological Corporation, San Antonio, TX, 2003.Google Scholar
Bayley Scales of Infant and Toddler Development, 3rd edn. Psych Corp, Harcourt Assessment Inc, 2006.10.1037/t14978-000CrossRefGoogle Scholar
Blishen, BR, Carroll, WK, Moore, C. The 1981 socioeconomic index for occupations in Canada. Can Rev Soc Anthrop. 1987; 24: 465488.10.1111/j.1755-618X.1987.tb00639.xCrossRefGoogle Scholar
Nostedt, S, Joffe, AR. Reverse Bayesian implications of p-value reported in critical care randomized trials. J Intensive Care Med 2022; 37: 954964. DOI 10.1177/08850666211053793.10.1177/08850666211053793CrossRefGoogle ScholarPubMed
Ohye, RG, Sleeper, LA, Mahony, L, et al. Comparison of shunt types in the Norwood procedure for single ventricle lesions. N Engl J Med 2010; 362: 19801992.10.1056/NEJMoa0912461CrossRefGoogle ScholarPubMed
Newberger, JW, Sleeper, LA, Bellinger, DC, et al. Early developmental outcome in children with Hypoplastic Left Heart Syndrome and related anomalies. Circulation 2012; 125: 20812091.10.1161/CIRCULATIONAHA.111.064113CrossRefGoogle Scholar
Atallah, J, Dinu, IA, Joffe, AR, et al. Two-year survival and mental and psychomotor outcomes after the Norwood procedure. Circulation. 2008; 118: 14101418.10.1161/CIRCULATIONAHA.107.741579CrossRefGoogle ScholarPubMed
Agarwal, HS, Churchwell, KB, Doyle, TP, et al. Inhaled nitric oxide use in bidirectional Glenn anastomosis for elevated Glenn Pressures. Ann Thorac Surg 2006; 81: 14291435.10.1016/j.athoracsur.2005.11.004CrossRefGoogle ScholarPubMed
Gamillscheg, A, Zobel, G, Urlesberger, B, et al. Inhaled nitric oxide in patients with critical pulmonary perfusion after Fontan-type procedures and bidirectional Glenn anastomosis. J Thorac Cardiovasc Surg 1997; 113: 435442.10.1016/S0022-5223(97)70355-6CrossRefGoogle ScholarPubMed
Georgiev, SG, Latcheva, AZ, Pilossoff, VB, Lazarov, SD, Mitev, PD. Inhaled nitric oxide for elevated cavopulmonary pressure and hypoxemia after cavopulmonary operations. World J Pediatr Congenit Heart Surg 2012; 3: 226231.10.1177/2150135111424294CrossRefGoogle ScholarPubMed
Adatia, I, Atz, AM, Wessel, DL. Inhaled nitric oxide does not improve systemic oxygenation after bidirectional superior cavopulmonary anastomosis. J Thorac Cardiovasc Surg 2005; 129: 217219.10.1016/j.jtcvs.2004.04.024CrossRefGoogle Scholar
MacIver, RH, Stewart, RD, Backer, CL, Mavroudis, C. Results with continuous cardiopulmonary bypass for the bidirectional cavopulmonary anastomosis. Cardiol Young 2008; 18: 147152.10.1017/S104795110800200XCrossRefGoogle ScholarPubMed
Das, D, Dutta, N, Chowdhuri, KR. Total circulatory arrest as a support modality in congenital heart surgery: review and current evidence. Indian J Thorac Cardiovasc Surg 2020, DOI 10.1007/s12055-020-00930-3.Google ScholarPubMed
Martin, BJ, Jonker, IDV, Joffe, AR, et al. Hypoplastic left heart syndrome is not associated with worse clinical or neurodevelopmental outcomes than other cardiac pathologies after the Norwood-Sano operation. Pediatr Cardiol 2017; 38: 922931.10.1007/s00246-017-1598-5CrossRefGoogle ScholarPubMed
Wernovsky, G, Licht, DJ. Neurodevelopmental outcomes in children with congenital heart disease – what can we impact? Pediatr Crit Care Med 2016; 17: S232S242.10.1097/PCC.0000000000000800CrossRefGoogle ScholarPubMed
Gaies, MG, Jeffries, HE, Niebler, RA, et al. Vasoactive-inotropic score is associated with outcome after infant cardiac surgery: an analysis from the pediatric cardiac critical care consortium and virtual PICU system registries. Pediatr Crit Care Med 2014 July; 15: 529537.10.1097/PCC.0000000000000153CrossRefGoogle ScholarPubMed
Gaies, MG, Gurney, JG, Yen, AH, et al. Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatr Crit Care Med 2010; 11: 234238.10.1097/PCC.0b013e3181b806fcCrossRefGoogle ScholarPubMed
Figure 0

Table 1. Descriptive variables of significance for two-year outcome in 169 children having the Glenn procedure.

Figure 1

Figure 1. Kaplan-Meier Survival curve for survival without meeting the definition of a complicated Glenn Procedure. This curve shows the probability over time of survival without having a complicated Glenn procedure; at 2 years of age this probability was 84%.

Figure 2

Table 2. Description of components of the complicated Glenn procedure composite outcome.

Figure 3

Table 3. Predictors on univariate and multiple-variable Cox regressions of a Complicated Glenn Procedure in 169 children.

Figure 4

Table 4. Univariate linear regressions for Bayley-III Scores in 156 children surviving to 2 years of age after having the Glenn procedure.

Figure 5

Table 5. Multiple variable linear regressions for Bayley-III Scores in 156 children surviving to 2 years of age after having the Glenn procedure.

Figure 6

Table 6. Univariate and multiple variable linear regression for general adaptive composite score in 156 children surviving to 2 years of age after having the Glenn procedure.

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