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The Impact of Targeted Therapies for Pulmonary Hypertension on Pediatric Intraoperative Morbidity or Mortality

Taylor, Katherine BMed (Hons), BA, FANZCA; Moulton, Dagmar MD; Zhao, Xiu Yan MSc; Laussen, Peter MBBS, FCICM

doi: 10.1213/ANE.0000000000000547
Pediatric Anesthesiology: Research Report

BACKGROUND: Pulmonary hypertension (PHT) is a significant risk factor for major adverse events during anesthesia, with a reported incidence of 5% to 7%, secondary to acute pulmonary hypertensive crises or right ventricular ischemia. Newer therapies for treating PHT have reduced mortality. In this single-center study, we investigated the frequency of major and minor events during anesthesia under the current strategies to manage PHT.

METHODS: We reviewed the records of children with PHT who underwent noncardiopulmonary bypass procedures from 2008 to 2012. Clinically important symptoms, physical signs, and results of investigations present before anesthesia were recorded. The incidence and type of intraoperative complications and death (up to 7 days) were collected.

RESULTS: Data were collected for 122 patients undergoing 284 procedures. Minor (3.9%) and major (3.2%) complication rates were unchanged from previous publications. The etiology of PHT was not significant for complications (P = 0.14). Disease-modifying agents were not associated with reduced complications: 4.1% in treated versus 8.6% untreated (all P > 0.14). Patients receiving home oxygen had more complications (P = 0.02). Multiple logistic regression identified age and degree of PHT as significant predictors of complications (all P ≤ 0.03).

CONCLUSIONS: The risk for adverse events during anesthesia in patients with PHT remains high, despite newer disease-modifying treatments. Risk factors for complications include age and severity of PHT.

From the Department of Anesthesia, Hospital for Sick Children, Toronto, Ontario, Canada.

Accepted for publication September 23, 2014.

Funding: No funding.

The authors declare no conflicts of interest.

This report was previously presented in part at the SPA Las Vegas, 2013, and Pediatric Anesthesia Conference Toronto, 2013.

Reprints will not be available from the authors.

Address correspondence to Katherine Taylor, BMed (Hons), BA, FANZCA, Department of Anesthesia, Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada M5G1X8. Address e-mail to katherine.taylor@sickkids.ca.

Suprasystemic pulmonary hypertension (PHT) has a reported 5% to 7% major anesthesia morbidity secondary to acute pulmonary hypertensive crises or right ventricular (RV) ischemia. These data are based on 2 single-center retrospective reviews of patients from 1999 to 2004, examining 256 procedures in 156 patients and 70 “first anesthetics,” respectively.1,2

In the past 5 years, long-term oral treatments of PHT targeting pulmonary vascular responses have improved symptoms.3 A meta-analysis of adults and children demonstrated a 43% reduction in mortality.4 Consequently, patients are now presenting to anesthesia/surgical services for procedures associated with PHT and other childhood and adolescence illnesses. Previously, all but the most life-threatening surgery would have been canceled in this population because of the anesthesia risk and shortened life expectancy. We sought updated information regarding anesthesia mortality to counsel patients and their families and to assist in managing these noncardiac surgeries.

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METHODS

After research ethics board (REB) approval and waived patient consent (REB 1000033649), we conducted a retrospective review of patients with PHT identified from the central surgical registration database who underwent anesthesia or sedation for noncardiopulmonary bypass procedures from January 2008 to November 2012, a convenience sample of approximately 5 years. The database records all cases for which anesthesia services were requested (including “standby”) in all sites in the hospital.

One of the authors reviewed the medical records of all eligible patients and extracted demographic, clinical, and diagnostic data (Table 1). We recorded clinically important symptoms and physical signs as identified by the anesthesiologist at the time of patient anesthesia assessment.

Table 1

Table 1

Right heart catheterization and 2-dimensional (2D) echocardiographic (ECHO) data were included if performed within 3 years of the index surgical date. The 2D ECHO performed closest to the surgical date was used if there were multiple 2D ECHO scans performed. ECHO indicators of PHT severity included right ventricle function, right ventricle hypertrophy, right ventricle z-score, any restriction of the left ventricle attributable to the size of the right ventricle, estimation of the mean pulmonary artery pressure (mPAP) in mm Hg, and estimation of the right ventricle systolic pressure in mm Hg. Right heart catheterization data including baseline pulmonary vascular resistance (PVRi) in Wood units/m2 and mPAP were recorded. Electrocardiograms were examined for evidence of right heart strain and right ventricle hypertrophy.

The type of surgical procedure, anesthetic management, including induction drugs, and airway technique were included. The incidence and type of complications that occurred intraoperatively as well as death (up to 7 days postoperatively) were also collected. We used the same definition of complications used in previous studies1,2 to allow comparison of data. Major complications were defined as hypotension, hypoxia, or arrhythmia occurring during or within 24 hours of anesthesia that required resuscitation by external cardiac massage, direct current electrical shock, rapid IV fluid bolus >20 mL/kg, inotrope or antiarrhythmic drug administration, unplanned tracheal intubation, or mechanical ventilation. Minor complications were defined as transient self-limiting disturbances in arterial blood pressure, oxygenation, or cardiac rhythm that required either minimal therapy (e.g., oxygen or fluid only) or no treatment at all. Each anesthetic was considered a separate event. In cases of >1 complication or death per procedure, only 1 complication was counted.

To assist practitioners in managing these patients and to guide discussion regarding anesthesia risk, we grouped complications into either intraoperative (major + minor) or severe (major + death within 24 hours). Events were categorized as anesthesia related or not anesthesia related by 1 author not involved in the patients’ clinical care using a definition by Odegard et al.5

Descriptive statistics (means and SD for continuous data and proportions for categorical data) were used to summarize the characteristics of the study population. χ2 goodness of fit was used to compare disease severity, and binomial tests were used to compare complication rates between our sample and previous studies.1,2 χ2 or the Fisher exact test was used for categorical data. Mantel-Haenszel χ2 test and Cochran-Armitage test for trend were used to test the trend of intraoperative and severe complication rates with increasing disease severity. Cochran-Armitage test was used to determine whether complications increased or decreased with disease severity. Disease severity and outcome were considered ordinal variables. Mantel-Haenszel was used to test whether complications differed according to disease severity when adjusted for treatment group. χ2/Fisher exact tests and 2-sample independent t tests were used. Age was analyzed as continuous and categorical data for regression modeling. Collinearity among covariates was assessed. χ2/Fisher exact tests were used for the association between categorical variables, and correlations were used for continuous variables. Variables achieving a univariate analysis significance of <0.20 were entered into the multiple logistic regression model to assess the impact of treatment and disease severity on intraoperative and severe complication rates while adjusting for other covariates. Purposeful model-building strategy was used for multiple logistic regression model building. Final model was chosen based on the lowest Akaike information criterion and significance of covariates (P ≤ 0.05). Prediction plots were used to graphically show the impact of age in years and actual procedure duration in minutes while adjusting for disease severity. We also analyzed average mean surgical procedure duration where ≥3 occurrences of the same procedures occurred in lieu of actual scheduled times. SAS version 9.3 and PROC LOGISTIC were used during the analysis.

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RESULTS

Data were collected for 122 patients undergoing 284 procedures. Patient demographics, etiology and severity of PHT, and incidence of medical therapy are presented in Table 1. A total of 121 of 284 (43%) procedures occurred while the patient was receiving disease-modifying treatments. Surgical procedures and anesthetic details are presented in Table 1.

There were 11 minor (3.9%) and 9 major (3.2%) complications/procedure, with both 1 minor and major complication occurring in 1 procedure, totaling 20 complications (7%), resulting in 19 intraoperative complications and 10 severe complications. There were 3 deaths (1.1% per procedure). Table 2 describes the patients with severe complications or death. The cause of PHT by complications/procedure is described in Table 3. Five of the 9 major complications were classified as related to the procedure or the underlying clinical condition. Three events were possibly related to the anesthesia, and 1 event was thought to be related to the administration of propofol and sevoflurane.

Table 2

Table 2

Table 3

Table 3

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Patient Risk Factors for Complications

Complications occurred in 13 of 136 (9.56%) males undergoing procedures and 6 of 148 (4.05%) females (P = 0.06). Age was significant in determining complications (t = 9.63; P ≤0.0001). No difference in complication rate was evident in patients with trisomy 21 (P = 0.14) or those with a decompression or “pop-off” valve, such as an atrial septal defect (P = 0.055). None of the preoperative symptoms (dizziness, syncope, chest pain, or reduced exercise capacity) was significant (P = 0.708). The presence of other cardiovascular or respiratory comorbidities was not associated with complications. There was no difference in complication rate according to etiology of PHT (P = 0.14). Specifically, comparing idiopathic causes with all other causes was not associated with an increase in intraoperative complications (1 of 44 [2.27%] vs 18 of 240 [7.5%] [P = 0.32] or severe complications 1 of 44 [2.27%] vs 9 of 240 [3.75%]) (P = 1.0). Patients with suprasystemic disease were at greatest risk for complications (Table 4). A univariate analysis comparing suprasystemic with systemic and subsystemic PHT demonstrated increased risk for intraoperative complications (Table 5). suprasystemic compared with subsystemic (odds ratio [OR] = 8.77; 95% confidence interval [CI] = 2.84–27.02; P = 0.0044); suprasystemic compared with systemic (OR = 4.46; 95% CI = 1.17–17.24; P = 0.49). For severe complications (Table 6), suprasystemic patients compared with subsystemic patients were also increased (OR = 8.77; 95% CI = 2.04–37.0; P = 0.0376); suprasystemic to systemic was not significant (OR = 4.56; 95% CI = 0.78–27.0; P = 0.59).

Table 4

Table 4

The incidence of all complications in those treated was 5 of 121 (4.12%) versus not treated 14 of 163 (8.6%) (P = 0.16). Similarly, major complications in treated patients occurred in 2.5% vs 3.7% in those not treated (P = 0.74) and death in 0.8% treated versus 1.2% in those not treated (P = 1.0). Medical treatment with disease-modifying drugs (bosentan, sildenafil, milrinone, calcium channel blockers, nitric oxide, and prostacyclin) in combination or isolation was not associated with reduced complications (all P > 0.14). Treatment adjusted for disease severity did not reduce complications (all P > 0.3). Patients on home oxygen had more intraoperative and severe complications (Tables 5 and 6).

Table 5

Table 5

Table 6

Table 6

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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).

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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.

Table 7

Table 7

Table 8

Table 8

Figure 1

Figure 1

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DISCUSSION

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.

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ACKNOWLEDGMENTS

The authors thank Dr. Helen Holtby for editing the manuscript.

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DISCLOSURES

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.

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