Introduction
Single ventricle cardiac defects are one of the most complex heart problems, affecting approximately 5 out of 10,000 newborns and making up 3–4% of all CHD. Reference Liu, Chen and Zühlke1 Outcomes have been greatly and steadily improving since the initiation of palliative attempts four decades ago. Reference Jacobs, Mayer and Pasquali2,Reference Karamlou, Diggs and Ungerleider3 The hybrid pathway is used as the primary palliative approach in a small number of centres including our own. Reference Yerebakan, Valeske and Elmontaser4–Reference Carrillo, Texter and Phelps7 The hybrid approach was developed to shift operative risk from the neonatal period to infancy by delaying complex arch and great vessel reconstruction until the second stage, which then combines reversal of Hybrid stage 1 with conventional stages 1 and 2. Reference Galantowicz8 Despite the complexity of the comprehensive stage 2 operation, early extubation defined as extubation in the operating room or ≤ 6 hours post-operatively has been the goal at our institution.
Failure to extubate following paediatric cardiac surgery has been associated with increased surgical mortality and increased intensive care and hospital length of stay. Reference Alghamdi, Singh and Hamilton9–Reference Gupta, Rettiganti and Gossett14 Physiologic dead space fraction is an easily calculated measure of ventilation in intubated patients, which has been correlated with failure to extubate as well as overall morbidity and mortality in paediatric cardiac patients. Reference Shakti, McElhinney and Gauvreau15–Reference Sayed, Hagen and Rajamanickam19 We hypothesised that physiologic dead space fraction has prognostic value following comprehensive stage 2 for the identification of patients at risk for prolonged intubation, complex post-operative course, and mortality. To our knowledge, this is the first report of the use of physiologic dead space fraction in single ventricle patients palliated with a hybrid strategy.
Methods
This is a retrospective study performed at a quaternary, free-standing children’s hospital. All data were collected from electronic and paper chart review. Institutional Review Board protocol #00002733 approved the study titled “Increased physiologic dead space fraction is associated with mortality after Comprehensive Stage 2 Operation” on 8/25/2022. Need for parental consent was waived. All research activity was performed in accordance with the ethical standards of the IRB and the Helsinki Declaration of 1975.
Consecutive single ventricle cardiac disease patients who underwent the comprehensive stage 2 palliation between January 2002 and December 2021 were enrolled. We included all anatomic variants of single ventricle cardiac defect, all concomitant genetic disorders, patients who necessitated early or urgent comprehensive stage 2, as well as those who were placed on extracorporeal membrane oxygenation post-operatively until the time of cannulation.
Patient characteristics included gender, year of comprehensive stage 2 operation, weight, and age at the time of operation, cardiac anatomy diagnosis, presence of non-cardiac congenital malformations, genetic syndrome, interstage interventions such as for retrograde aortic arch obstruction, early, or urgent operation. Operative data included cardiopulmonary bypass, cross-clamp, and deep hypothermic circulatory arrest times in minutes. Length of stay was calculated as the difference between date of admission and date of discharge. Length of ventilation was measured in hours. Patients having an intraoperative completion angiogram with or without intervention were noted. End tidal carbon dioxide (EtCO2) was measured by carbon dioxide sensor placed between the endotracheal tube and the ventilator circuit and analysed via AVEA ventilator (Viasys Healthcare, Conshohocken, PA) or Philips monitoring platform (Philips Medical Systems, Andover, MA) and collected upon cardiothoracic ICU arrival and at 4 AM daily with the morning partial pressure of carbon dioxide from arterial blood gas (PaCO2), pulse oximetry saturation, lactate, and Vasoactive-Inotropic Score. Reference Belletti, Lerose and Zangrillo20 Physiologic dead space fraction was calculated by the formula: (PaCO2–EtCO2)/PaCO2. Any negative results of this calculation were equalled to 0 for the purposes of analysis given the physiologic impossibility of obtaining a negative value. Decision regarding patient management, including readiness for extubation, were the prerogative of the treating anesthesiologist or ICU attending. Patients were separated into three groups: early extubation defined as extubation in the OR or ≤ 6 hours post-operatively; standard extubation between 6 and 72 hours post-operatively; and delayed extubation after 72 hours. Patients who were extubated in the OR but failed within 2 hours of return to the cardiothoracic ICU were assigned to groups based on the timing of their next extubation attempt. Urgent/emergent comprehensive stage 2 (CS2) for this study is defined as progression to comprehensive stage 2 due to decompensation prior to scheduled procedure requiring urgent or emergent surgery. The primary outcome of the study was correlation of physiologic dead space fraction with mortality. Secondary outcome was the correlation of physiologic dead space fraction with a composite outcome of extracorporeal membrane oxygenation, cardiac arrest, new seizure, central nervous system stroke, or bleed. Furthermore, we investigated the correlation between physiologic dead space fraction and ICU and hospital length of stay.
Demographic, anatomic, and intraoperative characteristics, as well as outcomes for the overall cohort of patients and across the three categories, were described using the sample median and interquartile range for continuous variables, and frequency and percentage for categorical variables. The Kruskal–Wallis and Wilcoxon Rank Sum tests were utilised to detect differences between groups for continuous variables, while Fisher’s exact test was used to compare categorical variables. To evaluate the unadjusted discrimination ability of physiologic dead space fraction on mortality, we constructed ROC curves and used Youden’s J statistic to identify the optimal physiologic dead space fraction cut-point value.
To evaluate the relationship between total hospital length of stay and the exposures of interest, Fine-Gray model for competing risks was used with the event of interest being discharge from the hospital and the competing event being death. Utilising this dataset, we constructed graphs of the cumulative incidence functions by grouping physiologic dead space fraction into two discrete categories based on the previously calculated Youden’s J statistic. Logistic regression models were constructed to evaluate the unadjusted (univariable) and adjusted (multivariable) relationship between physiologic dead space fraction and, separately, hospital length of stay, the composite outcome, and mortality. The models were constructed using complete case observations as the missing data was assumed to be missing completely at random, among patients still intubated at each time point. Logistic regression models were limited by the number of patients and outcome events at each time point. Due to the limited number of patients who remained intubated by post-operative day 3, this data were not able to be modelled in multivariate analysis. The model for physiologic dead space fraction versus mortality could only support univariate analysis. For the physiologic dead space fraction versus hospital length of stay and versus composite outcome analyses, we included cardiopulmonary bypass time and lactate at cardiothoracic ICU arrival as confounders in the model.
Results
Cohort characteristics are presented in Table 1. 180 patients underwent comprehensive stage 2 at a median age of 165 days (IQR, 149–199 days) and median weight of 6.2 kg (IQR, 5.59–7.00 kg). Based on their time to extubation, 76/180 (42%) patients underwent early extubation, 59/180 (33%) patients underwent standard extubation, and 45/180 (25%) patients underwent delayed extubation. Compared to the early extubation group, patients who underwent delayed extubation were significantly younger (156 days vs. 178 days, p 0.006), had lower weight (6.03 kg vs. 6.4 kg, p 0.039), had a higher proportion of early comprehensive stage 2 (20% vs. 3.9%, p 0.014), deep hypothermic cardiac arrest utilisation (16% vs. 3.9%, p 0.039), and longer cardiopulmonary bypass times (269 vs. 245 mins, p 0.067). A total of 67/180 (37%) patients were extubated in OR.
Table 1. Demographic details and characteristics of the study cohort
Values are presented as count (%) or median (IQR).
AA = aortic atresia; AS = aortic stenosis; CS2 = comprehensive stage 2; IQR = interquartile range; MA = mitral atresia; MS = mitral stenosis.
For the entire cohort, median length of intubation was 17 hours (IQR 0–111 hours), with a median ICU Length of stay of 5 days (IQR 3–11 days), and median hospital length of stay of 11 days (IQR 8–22 days). Outcomes by extubation group are presented in Table 2. There was no difference in re-intubation rates between patients extubated in the OR compared to those extubated in the CTICU (21.4% vs. 19.4%, p 0.75). However, there was a statistically significant increase in re-intubation necessity for the delayed extubation group compared to early extubation and standard extubation (37.8% vs. 17.1% vs. 11.9%, p 0.013 and 0.004, respectively). Median time to re-intubation was 3.34 days (IQR 0.95–12.11 days). Notably, the delayed extubation group suffered a significantly higher mortality rate as compared to the early extubation and standard extubation groups (33.33% vs. 2.6% vs. 6.8%, p < 0.0001 for both) as well as higher rates of cardiac arrest, stroke, and need for post-operative catheter and surgical interventions. Physiologic dead space fraction exhibited differences between the delayed extubation and standard extubation groups upon arrival in the cardiothoracic ICU (0.28 vs. 0.19, p 0.042), as well as on post-operative day 1 (0.31 vs. 0.21, p < 0.001) and post-operative day 2 (0.31 vs. 0.21, p 0.069). However, this disparity in median values was not seen on post-operative day 3.
Table 2. Outcomes based on time to extubation
Values are presented as count (%) or median [IQR].
Re-intubation for tube exchanges, procedures, OR take-back for chest closure or ECMO were not counted towards the complication count.
AVDSf = physiologic dead space fraction; CT = cartdiothoracic; DE = Delayed Extubation; ECMO = extracorporeal membrane oxygenation; EE = Early Extubation; ICU = intensive care unit; iNO= inhaled nitric oxide; POD = post-operative day,SE = Standard Extubation.
Comparing survivors to non-survivors, those who suffered mortality were more likely to be pre-intubated (20% vs. 2.5%, p 0.006) and have longer cardiopulmonary bypass times (317 min vs. 253 min, p 0.022). Physiologic dead space fraction exhibited a consistently higher magnitude in non-survivors compared to survivors. During univariate analysis of physiologic dead space fraction in relation to mortality, a significant correlation was found on post-operative days 1 and 3. In particular, for a 0.1 unit increase physiologic dead space fraction on post-operative day 1, the odds of a patient expiring increase by a factor of 2.26 (95% CI 1.41–3.97, p < 0.001). For the same increase in physiologic dead space fraction on post-operative day 3, the expected odds of mortality increase by a factor of 3.79 (95% CI 1.65–11.7, p 0.01). Physiologic dead space fraction on post-operative days 1 and 3 both have adequate discriminatory abilities when used to identify patients who expire (AUC of 0.78 and 0.84, respectively) as shown in Figure 1. We found physiologic dead space fraction of 0.3 to be the discriminatory point by Youden’s J statistic. Figure 2 is a visual representation of the cumulative incidence function outcomes obtained from the competing risk model dichotomised by normal (<0.3) and abnormal (≥0.3) physiologic dead space fraction values. It is evident that among patients with abnormal dead space fractions, the likelihood of mortality at any given time is significantly higher compared to patients with normal dead space fractions.
Figure 1. ROC curves of AVDSf versus mortality. AVDSf has adequate discriminatory power on POD 1 and POD 3 to identify patients who expire. Only complete cases were used in this analysis. AVDSf = physiologic dead space fraction; AUC = area under curve; POD = post-operative day; ROC = receiver operating characteristic.
Figure 2. Cumulative incidence functions of mortality in normal versus abnormal AVDSf. Among patients with elevated AVDSf (≥0.3), the probability of mortality at a given time is higher than the probability of mortality among patients with normal (<0.3) AVDSf. Only complete cases were used in this analysis. AVDSf = physiologic dead space fraction.
Supplemental Tables 3 and 4 present cohort comparisons by extubation group and by survival, respectively. Supplemental Table 5 presents the outcomes of risk analysis, encompassing univariate mortality analysis as well as multivariate analysis of composite outcomes and hospital discharge. Supplemental Figure 1 demonstrates physiologic dead space fraction in survivors and non-survivors.
The multivariate analysis comparing physiologic dead space fraction with hospital discharge revealed a statistically significant relationship which increased in magnitude with each time point. In particular for a 0.1 unit increase in physiologic dead space fraction on post-operative day 1, the odds of discharge decreased by a factor of 0.79 (95% CI 0.67–0.93, p 0.01) and by a factor of 0.69 (95% CI 0.52–0.91, p 0.01) on post-operative day 2. The analysis of physiologic dead space fraction with the composite outcome of extracorporeal membrane oxygenation, cardiac arrest, new seizure, stroke, or bleed did not yield significant results at any of the examined time points.
Discussion
This study aimed to explore the effectiveness of physiologic dead space fraction in identifying patients with the highest vulnerability to mortality and morbidity after undergoing comprehensive stage 2. The analysis revealed physiologic dead space fraction to be predictive of need for prolonged mechanical ventilation and of increased mortality. Furthermore, physiologic dead space fraction was found to correlate with longer hospital length of stay. We did not find a correlation between physiologic dead space fraction and the composite outcome of extracorporeal membrane oxygenation, cardiac arrest, new seizure, stroke, or bleed.
The analysis of physiologic dead space fraction versus mortality revealed a significant disparity between survivors and non-survivors, which progressively widened among the subset of patients who remained intubated at each time point. These findings are similar to recent analyses in Glenn and Fontan populations where physiologic dead space fraction was found to correlate with composite outcomes of surgical or catheter-based intervention, death, or transplant Reference Cigarroa, van den Bosch and Tang16 and surgical or catheter re-intervention, extracorporeal membrane oxygenation, prolonged ventilation, prolonged hospital length of stay, or death, Reference Shostak, Schiller and Merzbach18 respectively. We found a physiologic dead space fraction value of 0.3 to be associated with an increased risk of mortality in patients following comprehensive stage 2, comparable to previously identified discriminatory values of 0.2816 and 0.2918 in other palliated single ventricle populations. Furthermore, in our study, the magnitude of the risk indicated by the discriminatory physiologic dead space fraction value ≥0.3 escalated over time following the operation. Consequently, the longer a patient remains intubated during the acute post-operative period, the greater the significance of physiologic dead space fraction as a predictive marker for mortality.
Post-operative failure to extubate is a significant and worrisome clinical finding. Previous literature has shown single ventricle infants who were unable to be extubated following Norwood palliation to be over five times more likely to suffer mortality during their ICU stay (19.4% vs. 3.5%; p = 0.03) and hospital stay (30.4% vs. 6.1%; p < 0.001). Reference Scodellaro, McKenzie and d’Udekem10 Likewise in our study, delayed extubation was significantly associated with heightened in-hospital mortality compared to standard extubation and early extubation (31.1% vs. 6.8% vs. 2.6%) as well as cardiac arrest, stroke, and need for catheter and surgical intervention. Physiologic dead space fraction has long been utilised in the assessment of readiness for extubation in many clinical settings and has been shown to correlate with the duration of mechanical ventilation and length of hospital stay following congenital heart surgery. Reference Shakti, McElhinney and Gauvreau15,Reference Sayed, Hagen and Rajamanickam19,Reference Ong, Stuart-Killion and Daniel21 In our analysis, physiologic dead space fraction differed significantly between groups at cardiothoracic ICU arrival and post-operative day 1. The discriminatory power diminished with later time points, likely attributable to the fact that the majority of patients in the early extubation and standard extubation groups were liberated from mechanical ventilation, leaving only those who were unable to be extubated. This observation further reinforces the correlation between physiologic dead space fraction and readiness for extubation, as individuals who were unable to be extubated from the early extubation and standard extubation groups exhibited physiologic dead space fraction values comparable to those in the delayed extubation group.
Our study encompassed two decades, during which time many quality improvement initiatives have been undertaken. For example, a standardised post-operative management protocol which included prescribed use of completion angiography and post-operative anticoagulation was implemented in March 2010 given the incidence of pulmonary artery thrombosis seen in our earlier experience. Reference Galantowicz and Yates6 Other initiatives include use of left pulmonary artery stenting during comprehensive stage 2 Reference Carrillo, Best and Hersey22 and implementation of a Proactive Mitigation to Decrease Serious Adverse Events (PROMISE) Reference Cosgrove, Gauntt and Carrillo23 programme to decrease the incidence of post-procedure cardiac arrest. Our institutional philosophy has been to aggressively work toward extubation as early as clinically feasible, including extubation in the OR for all our patients. Despite this dynamic stance, we did not see a difference in re-intubation rates between patients who underwent early versus standard extubation. Others have published similar results. Reference Alghamdi, Singh and Hamilton9,Reference Ovroutski, Kramer and Nordmeyer11,Reference Tirotta, Alcos and Lagueruela12,Reference Joshi, Aggarwal and Agarwal24,Reference Thompson and Wakeham25
For quite some time, the assessment of physiologic dead space fraction has been regarded as a significant indicator of both pulmonary blood flow and cardiac output. In the post-operative single ventricle cardiac defect population, an increased physiologic dead space fraction most commonly reflects an anatomic pulmonary artery flow disruption, pulmonary embolism, or decrease in cardiac output. Reference Brown and Schwartz26 Our study has shown the utility of physiologic dead space fraction in differentiating which of the patients who remain intubated are most likely to suffer a complex post-operative course. In our institution, physiologic dead space fraction is routinely used as part of a comprehensive patient assessment. In patients who have hypoxia without an alternative diagnosis, or who fail to extubate by 72 hours, our centre pursues aggressive diagnostic testing to assure that pulmonary blood flow is unobstructed via transthoracic echocardiography, cardiac catheterisation, or cross-sectional imaging. We believe it is prudent to include physiologic dead space fraction as part of a comprehensive post-operative assessment to direct diagnostic efforts towards those patients at the highest risk of complications.
It is important to exercise caution when interpreting our findings, considering the limitations associated with our methodology. Firstly, given our sample size, the results should be interpreted as associations and not necessarily causal relationships. Conversely, statistical significance may not align with clinical relevance; in particular, some tests may not yield small p-values but clinically interesting differences may still be present. Secondly, our study is based on a retrospective chart review conducted at a single centre, which may introduce biases and limit generalizability. Thirdly, in order to achieve a larger sample size, our cohort spans a 20-year period, leading to a potential era effect. Moreover, not all data could be transferred due to the transition to electronic charting, resulting in the exclusion of some of our earliest patients from physiologic dead space fraction models. Fourthly, due to the nature of chart review, discrepancies in timing between EtCO2 and PaCO2 values may exist, potentially introducing errors in the calculated physiologic dead space fraction values. Furthermore, specific causes of increased dead space fraction, such as differential impacts of cardiac output versus pulmonary blood flow, were not examined in this study and exploring these underlying mechanisms remains an important avenue for future research. Lastly, the absence of standardised guidelines for post-operative management may contribute to variations in practitioner preferences, which could impact the observed outcomes.
Herein, based on the results of this study, physiologic dead space fraction can serve as an indicator of heightened morbidity and mortality risk following comprehensive stage 2. Its predictive value escalates as time progresses following the operation. Calculating physiologic dead space fraction in patients who remain intubated after complex procedures could be crucial in identifying those at the highest risk of complications and potentially direct efforts for additional diagnostic and treatment resources in efforts to improve survival and limit morbidity.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S104795112402674X.
Acknowledgements
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Financial support
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Competing interests
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Ethical standard
Institutional Review Board protocol #00002733 approved the study titled “Increased physiologic dead space fraction is associated with mortality after Comprehensive Stage 2 Operation” on 25 August 2022. Need for parental consent was waived. All research activity was performed in accordance with the ethical standards of the IRB and the Helsinki Declaration of 1975.
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