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We set out to determine whether patients with tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral arteries (TOF/PA/MAPCA) are at risk for elevated dead space ventilation fraction (VD/VT), and whether this is associated with prolonged mechanical ventilation. We hypothesized that elevated VD/VT (>20%) in the first 24 hours after unifocalization surgery is associated with increased risk for prolonged mechanical ventilation (>7 days).All patients with TOF/PA/MAPCA undergoing unifocalization surgery between January 2003 and December 2015 were included in this study. Average VD/VT was calculated over the first 24 hours after surgery. Demographic and surgical data were collected. Outcome data included duration of mechanical ventilation. Patients were separated into 2 groups: elevated VD/VT and normal DVSF. Groups were compared using the Student t test, Wilcoxon rank-sum test, and χ2 test. Univariable and multivariable regression analyses were performed with VD/VT as a continuous variable to test for association.Of the 265 included patients, 127 (48%) had an elevated VD/VT. The 2 groups did not differ significantly in any demographic characteristic. Patients with an elevated VD/VT had longer cardiopulmonary bypass times (P = .03), were more likely to have delayed sternal closure, and more likely to have prolonged respiratory failure (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P = .007). The percent VD/VT was associated with duration of mechanical ventilation in univariable (P < .001) and multivariable (P < .001) regression analyses when controlled for age, weight and bypass time.Elevated postoperative VD/VT is associated with prolonged mechanical ventilation in patients with TOF/PA/MAPCA following unifocalization. Elevated postoperative VD/VT may be an early indicator of patients who will require prolonged duration of mechanical ventilation, allowing optimization of medical management to promote better outcomes.