Investigation Results Associated with Complications
Univariate analysis of the preoperative ECHO data (description of right ventricle function; right ventricle z-score; estimation of mPAP and right ventricle systolic pressure) was not significant except for left ventricle restriction attributable to right ventricle encroachment, which was associated with an increase in intraoperative complications (OR = 4.76; 95% CI = 1.68–13.88; P = 0.0034) and severe (major + death) complications (OR = 6.62; 95% CI = 1.75–25; P = 0.0053) when present. Electrocardiogram diagnosis of right ventricle strain or RVH was not significant (P = 0.07); PVRi and baseline mPAP from catheterization data were also not significant (P = 0.52).
Procedural Factors Associated with Complications
There was no association between complications and airway type (P = 0.39), anesthetic drugs used (all P > 0.09), anesthesiologist with cardiac anesthesia subspecialization (P = 0.29), or location of procedures (P = 0.71). Specifically, cardiac catheterization versus all other procedure sites was not significant for complications.
We performed multiple logistic regression from risk factors identified in the univariate analysis (age as a categorical variable, actual procedure duration, right ventricle restriction of left ventricle filling, degree of PHT, and home oxygen therapy).
The best multiple logistic regression models for intraoperative and severe complications include age (as categorical data) and severity of PHT (Tables 7 and 8) (all P ≤ 0.03). Stratified for disease severity, children <5 months of age were more likely to experience severe complications compared with children >2 years of age (OR = 6.15; 95% CI = 1.23–30.7; P = 0.03) and more likely to have intraoperative complications (OR = 6.05; 95% CI = 1.4–26.08; P = 0.02). Children 6 to 24 months of age were more likely than children >2 years of age to experience intraoperative complications (OR = 6.4; 95% CI = 1.8–22.6; P = 0.004) but not severe complications (OR = 2.1; 95% CI = 0.4–10.8; P = 0.39). Children, regardless of age, with lower-severity disease had fewer complications. Comparing subsystemic PHT with suprasystemic PHT, intraoperative (OR = 0.09; 95% CI = 0.03–0.3; P = 0.0002) and severe complications were less frequent (OR = 0.13; 95% CI = 0.03–0.6; P = 0.0098). Comparing systemic with suprasystemic, severe complications were not significantly different (OR = 0.26; 95% CI = 0.041–1.6; P = 0.15). However, intraoperative complications were significantly different (OR = 0.18; 95% CI = 0.04–0.78; P = 0.02). As actual procedure duration of all cases increased, there was an increase in complication rate (adjusted for disease severity) (OR = 1.54; 95% CI = 1.18–1.9; P = 0.0012) (Fig. 1). After excluding all cardiac catheterization cases, actual procedure duration remained a predictor for intraoperative complications (P = 0.028). However, analyzing the average mean duration of surgical procedures revealed that there was no difference in complications rates.
We have identified that age stratified for disease severity and confirmed the degree of PHT as risk factors for complications. Using similar definitions to previous studies, we describe a minor complication rate of 3.9% of procedures and major complication rate of 3.2% of procedures, which is unchanged since the introduction of disease-modifying treatments (P = 0.45).1 There was no significant difference between minor (χ2 = 0.45, 95% CI = 0.02–0.07) and major (χ2 = 0.63, 95% CI = 0.01–0.06) complication rates between groups of patients who were treated or untreated with new disease-modifying drugs.1
Registry data have demonstrated that age (not stratified for disease severity) is an independent risk factor for anesthesia complications.6 Younger children with PHT experience more complications. Increasing actual procedure duration was associated with increased complications in all 3 severity groups but was most pronounced in the suprasystemic population. We analyzed a smaller data set (108 procedures) excluding cardiac catheterization cases to remove the possible confounding of medication order in PHT protocol studies (the majority of catheterization cases in this data set) causing complications. Nebulized prostacyclin (a potent vasodilator) is administered to a small proportion of patients in PHT studies at the end of the procedure and can result in hemodynamic instability. Actual procedure duration remained significant on univariate analysis (P = 0.028), excluding all cardiac catheterization cases. Carmosino et al.1 reported case duration of >133 minutes as significant in a univariate analysis. However, prolonged case duration may be attributable to the incurrence of complications. In lieu of scheduled duration data, we analyzed the average mean duration of procedures during which there were ≥3 similar procedures. There was no increase in complications.
Additional risk factors for major complications identified by univariate analysis in this study were ECHO evidence of left ventricle restriction by right ventricle encroachment. The resultant limitation to left ventricle filling decreases stroke volume and cardiac output, compromising coronary perfusion. This is likely a confounder for severity of PHT and thus was removed from multiple regression models. Home oxygen use was significant for intraoperative and severe complications when stratified for disease severity in univariate and one multivariate analysis. We elected to use the model describing age and severity of disease in view of the limitations in model building with relatively few events because these risk factors are more generalizable.
Important nonpredictive risk factors include “decompression” lesions, such as atrial septal defect, which were thought to be protective in situations of extreme right ventricle afterload. Right atrial blood can flow right to left through this decompression lesion and preserve left ventricle filling. This theoretical benefit was not demonstrated as significant in our data.
We assessed intraoperative complications (19/284 [7%]) and severe complications (major [9 events] or death [3 events]) to guide resource preparation and surgical decision making. Despite the increase in perioperative risk for these patients, the actual numbers of complications precluded development of multiple regression models to develop a perioperative risk score. With only 10 major complications in our data set, multiple regression model building is difficult. Significant risk factors from univariate analysis need to be interpreted with caution but may provide guidance to clinicians and allow comparisons to similar studies.1,2
We compared proportions of subsystemic, systemic, and suprasystemic PHT to assess disease severity between our study and a previous study.2 Taylor et al.2 described a mean PVRi of 17.5 (SD = 14.7) in those without major complications and a range of PVRis (8–43) in those with major complications. Our mean PVRi was 11.8; those with intraoperative complications had mean PVRi = 14.01 (SD = 12.8) and severe complications PVRi = 17.62 (SD = 12.38). From our data, suprasystemic PHT had an intraoperative complication rate of 28% and severe complications in 16%, confirming increased risk in this group.
Untreated primary PHT has a median survival of 10 months.7 A meta-analysis demonstrated 43% reduction in mortality in patients randomized to active treatment compared with controls (21 randomized controlled trials) and a high mortality rate (1.1% per month).4 Some of these studies included children and adults in enrollment but did not report the number of children enrolled nor analyze outcomes for children separately.8–16 The lowest age limit for these studies was 8 years.14 Pediatric data assessing survival are limited but have been demonstrated for epoprostenol.17,18 We assessed individual and combination treatments versus no treatment to ascertain whether there was any change in complication rates. There was a suggestion of reduced complication rates with treatment, but no combination reached statistical significance. The proportional difference in complication rates in treated and untreated groups may be relevant to clinicians if not attributable to a type 1 error.
As with previous studies in this field, the retrospective data collection and lack of control group are limitations. We identified risk factors for complications from our clinical impressions and previous publications1,2 to test their validity in this era of treated PHT. Many of the predictors were not statistically significant. The small number of actual events limited assessment of possible confounders and the strength of multivariate regression models. To the best of our knowledge, this data set is the largest series of pediatric patients with PHT undergoing anesthesia and the only data set since the introduction of new disease-modifying drugs, which has demonstrated survival benefits. Reported anesthesia morbidity/mortality in this population is high compared with other conditions but not sufficiently high enough to answer questions about modification of anesthesia risk from single-center data. Multicenter collaboration will be required to answer the question whether the anesthesia morbidity and mortality for this population have been modified by new treatments or in the current era.
We describe anesthesia morbidity and mortality in pediatric patients with PHT in the current era to guide clinical practice. We have identified age and disease severity as risk factors for complications on multiple logistic regression and home oxygen, procedure duration, and ECHO presence of restricted left ventricle filling as significant in univariate analysis. Severity of PHT is confirmed as predictive of complications.
The authors thank Dr. Helen Holtby for editing the manuscript.
Name: Katherine Taylor, BMed (Hons), BA, FANZCA.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Katherine Taylor has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Dagmar Moulton, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Dagmar Moulton has seen the original study data and approved the final manuscript.
Name: Xiu Yan Zhao, MSc (Biostatistics).
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Xiu Yan Zhao has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Peter Laussen, MBBS, FCICM.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Peter Laussen has seen some of the original study data, reviewed the analysis some of the data, and approved the final manuscript.
This manuscript was handled by: Peter J. Davis, MD.
1. Carmosino MJ, Friesen RH, Doran A, Ivy DD. Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization. Anesth Analg. 2007;104:521–7
2. Taylor CJ, Derrick G, McEwan A, Haworth SG, Sury MR. Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension. Br J Anaesth. 2007;98:657–61
3. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Circulation. 2012;125:113–22
4. Galie N, Manes A, Negor L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394–403
5. Odegard KC, Bergersen L, Thiagarajan R, Clark L, Shukla A, Wypij D, Laussen PC. The frequency of cardiac arrests in patients with congenital heart disease undergoing cardiac catheterization. Anesth Analg. 2014;118:175–82
6. Morray JP, Geiduschek JM, Ramamoorthy C, Haberkern CM, Hackel A, Caplan RA, Domino KB, Posner K, Cheney FW. Anesthesia-related cardiac arrest in children: initial findings of the Pediatric Perioperative Cardiac Arrest (POCA) Registry. Anesthesiology. 2000;93:6–14
7. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197–208
8. Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J. 2006;151:851.e1–5
9. Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg MBosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. . Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48–54
10. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–63
11. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, Naeije R, Galie NSTRIDE-2 Study Group. . Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47:2049–56
12. Matok I, Leibovitch L, Vardi A, Adam M, Rubinshtein M, Barzilay Z, Paret G. Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock. Pediatr Crit Care Med. 2004;5:116–8
13. Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353–9
14. Galiè N, Humbert M, Vachiéry JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau GArterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group. . Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–502
15. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LRSTRIDE-1 Study Group. . Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441–7
16. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol. 2004;43:1149–53
17. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660–5
© 2015 International Anesthesia Research Society
18. Lammers AE, Hislop AA, Flynn Y, Haworth SG. Epoprostenol treatment in children with severe pulmonary hypertension. Heart. 2007;93:739–43