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Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension)
International Journal of Cardiology 203 (2016) 325–330
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Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension) M. Beghetti a,⁎,1, I. Schulze-Neick b,1, R.M.F. Berger c,1, D.D. Ivy d,1, D. Bonnet e,1, R.G. Weintraub f,1, T. Saji g,1, D. Yung h,1, G.B. Mallory i,1, R. Geiger j,1, J.T. Berger k,1, R.J. Barst l,1, T. Humpl m,1, for the, TOPP investigators TOPP Registry investigators (not listed in the author's list) by country alphabetical order: S. Mattos n, Z.C. Jing o, Z.Y. Han o, L. Sondergaard p, T. Jensen p, M. Levy ag, S. Mebus q, Ch. Apitz r, A. Szatmari s, L. Ablonczy s, O. Milanesi t, V. Favero t, T. Pulido u, P. De La Garza u, J.M. Douwes af, H. Brun v, L. Moll w, K. Michalak w, W. Kawalec x, M. Zuk x, M. Fasnacht Boillat y, R. Olgunturk z, S. Serdar Kula z, A. Dursun aa, R.W. Day ab, E. Austin ac, D.J. Moore ac, A.M. Atz ad, J.A. Feinstein ae, n
Royal Portuguese Hospital, Maternal-Fetal Cardiac Unit, Recife, Brazil Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China p Rigshospitalet, University of Copenhagen, Heart Center, Copenhagen, Denmark q German Heart Centre, Munich, Germany r Universitätsklinikum Giessen, Giessen, Germany s Hungarian Institute of Cardiology, Pediatric Cardiac Center, Budapest, Hungary t Universita di Padova, Dipartimento di Pediatria, Padova, Italy u National Heart Institute, Mexico City, Mexico v Rikshospitalet, Section for Pediatric Cardiology, Oslo, Norway w Polish Mothers Hospital Research Institute, Lodz, Poland x Children's Memorial Health Institute, Department of Cardiology, Warsaw, Poland y Universitäts-Kinderklinik, Zurich, Switzerland z Gazi Universitesi Tip Fakultesi, Pediyatrik Kardiyoloji ABD, Ankara, Turkey aa Hacettepe University Ihsan Dogramaci, Tip Fak, Pediyatrik Kardiyoloji, Ankara, Turkey ab University of Utah, University of Health Care, Division of Pediatric Cardiology, Salt Lake City, USA ac Vanderbilt Children's Hospital, Division of Cardiology, Nashville, USA ad Medical University of South Carolina, Charleston, USA ae Stanford University Medical Center Packard Children's Hospital, Palo Alto, USA af Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Netherlands ag M3C-Paediatric Cardiology, Université Paris Descartes, Necker Enfants Malades, AP-HP, Paris, France o
a
Pediatric Cardiology, Department of the Child and Adolescents, Hôpital des Enfants, University of Geneva, Switzerland Cardiac Unit, Great Ormond Street Hospital for Children, London, UK c Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Netherlands d Pediatrics, University of Colorado School of Medicine, Aurora, USA e M3C-Paediatric Cardiology, Université Paris Descartes, Necker Enfants Malades, AP-HP, Paris, France f Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Australia g Toho University Medical Center Omori Hospital, Tokyo, Japan h Seattle Children's Hospital, University of Washington School of Medicine, Seattle, USA i Texas Children's Hospital, Baylor College of Medicine, Houston, USA j Innsbruck Medical University, Pediatric Cardiology, Innsbruck, Austria k Children's National Medical Center, Pediatric Critical Care and Cardiology, WA, USA l Pediatrics, Columbia University, New York, USA m Cardiology and Critical Care, University of Toronto, Toronto, ON, Canada b
⁎ Corresponding author at: Pediatric Cardiology Unit, Children's Hospital, University Hospital of Geneva, 6 rue Willy Donzé 1211 Geneva 14, Switzerland. E-mail address: [email protected] (M. Beghetti). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2015.10.087 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
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M. Beghetti et al. / International Journal of Cardiology 203 (2016) 325–330
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Article history: Received 5 May 2015 Received in revised form 4 September 2015 Accepted 12 October 2015 Available online 23 October 2015 Keywords: Catheterisation Heart defects Congenital Hypertension Pulmonary Paediatrics
a b s t r a c t Background: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. Methods and results: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg and pulmonary vascular resistance index [PVRI] of N 3 WU × m2). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p = 0.04) and with higher functional class (p = 0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m2; 95% confidence interval 3.4–4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m2, 95% confidence interval 15.6–17.76). However, 24% of the patients had a CI of b2.5 L/min/m2 at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p b 0.001). Conclusion: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary hypertension (PH) remains an important cause of mortality and morbidity [1]. It is characterised by a progressive increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) that ultimately leads to right ventricular dysfunction and death. The definition of pulmonary arterial hypertension (PAH) is based on haemodynamics using the same criteria for children as for adult patients [1,2]. Non-invasive tests are useful for screening suspected PH but haemodynamic assessment with invasive heart catheterisation (HC) remains the gold standard to confirm diagnosis and to assess disease severity [2–4]. Haemodynamics (PVR and right atrial pressure) are recognised as risk factors at baseline and important for therapeutic decisions [1, 5–7]. The recent statement of the AHA on the indications for HC in paediatrics recommends HC to assess PVR and reversibility of PH in patients with congenital heart disease (CHD) or idiopathic PAH (iPAH) when accurate assessment of PVR is needed to make therapeutic decisions [8]. The majority of children with PH enrolled in current registries have iPAH or CHD–PAH, underscoring the need to perform HC at diagnosis in this population [9,10]. Multi-centre studies have been published describing the complication rate of HC in paediatrics but no large studies have focused on a pure population of PH [11,12]. Controversial opinions challenge the use of invasive haemodynamics and are mainly focused on the potential risks of HC [1]. With increasing treatment options, accurate characterisation of the disease is needed to provide optimal care as, until now, targeted therapies have not shown efficacy in other forms of PH than PAH [2]. The haemodynamic profile for the PH population enrolled in TOPP as well as HC-related complications of 908 diagnostic and follow-up HCs performed are reported.
2. Methods The Registry was designed as a multi-centre, prospective observational cohort study at 31 centres in 19 countries. Patients underwent clinical assessment and received treatment and follow-up according to the sole judgement of their local physician and were not on TOPP-related specific diagnostic and therapeutic protocols. Enrolment began in January 2008. All eligible patients with complete HC data available on 27th February 2012 were included in the analysis. The study was designed and supervised by an Executive Board (EB). Data management and analyses were performed by contract organisations working with the EB. The protocol was approved by the relevant Institutional Review Boards and/or Ethics Committees; the study complies with the Declaration of Helsinki; and informed consent has been obtained from all patients and/or their legal guardians. Consecutive patients between 3 months and 18 years of age at the time of diagnosis with PH confirmed by HC were eligible for enrolment in the TOPP Registry. Both newly
diagnosed (incident, within 3 months of enrolment in the registry) patients and previously diagnosed (prevalent, more than 3 months prior to enrolment) patients were eligible. Patients were eligible if they had PH belonging to Venice Groups 1, 3, 4, or 5 according to the Venice 2003 clinical classification [13], as this was the actual classification at the time of registry design. The diagnosis of “PH-confirmed” required HC confirmation (defined as mPAP ≥ 25 mm Hg, PVRI ≥ 3 WU × m 2 , and PCWP ≤ 12 mm Hg). The EB reviewed all cardiac catheterisation data sets and recalculated PVRI and cardiac output by the Fick method using a single assumed oxygen consumption table [14] or the recorded cardiac output as measured by thermodilution (if performed and physiology permitted). Following this review, patients not fulfilling the above-mentioned definition of PH were excluded from the analysis of the haemodynamic parameters. Patients for whom a diagnostic HC could not be performed because of clinical reasons, could be included based on a confirmatory echocardiography and/or histopathology as they may have a follow-up HC. Overall data on general anaesthesia (GA) and conscious sedation to perform HC was collected but information on specific drugs was not collected. Acute vasodilatory response testing (AVRT) was recorded, where the interpretation of a positive or absent response to AVRT was left with the local physician following the rules of a non-interventional registry. Predefined HC-related complications were recorded but were not adjudicated by the EB. For the purpose of this analysis all diagnostic and follow-up HCs were pooled together. 2.1. Statistical analysis A statistical analysis plan was written to specify the initial descriptive analysis, and was completed prior to data finalisation. After team review of the descriptive results, evaluation of specific hypotheses (ANOVA) was executed. No formal sample size calculation was performed, and hence the sample was not powered a priori for specific comparisons. The analysis population for haemodynamic parameters was the PH-confirmed cohort, which included only patients who met all enrolment criteria, but all patients were analysed for HC complications. Continuous data was summarised using descriptive statistics (mean, SD, 95% confidence interval, median, min/max and 25th and 75th percentiles) and 95% confidence intervals where relevant. Age was grouped for descriptive summaries (3–24 months, 2–6 years, 7–11 years and 12–18 years). Categorical data was summarised using counts and percentages. Unless stated otherwise, the denominator for percentages was the total number of patients with non-missing data for each variable analysed. All eCRFs were individually reviewed and assessed by EB members. Post-review values were used in the analyses, unless there was insufficient data for review in which case the original eCRF data was used. The association between key haemodynamic parameters and age at diagnosis (years), aetiology and NYHA functional class (FC) was investigated using an ANCOVA model including all 3 variables. Cardiac index (CI), PVRI and PVRI/ SVRI were log-transformed to improve the assumption of normality. In order to investigate the potential risk factors for HC complications at diagnosis, logistic regression analyses were performed. The risk factors investigated were age at diagnosis (years), NYHA FC (trend over classes I–IV), aetiology and sedation method, with all variables retained in the final model. All analyses were performed using SAS statistical software package (version 8.2 or higher).
3. Results At the data cut on February 2012, 568 patients were enrolled and 480 fulfilled the inclusion criteria, i.e., are patients for whom PH has
M. Beghetti et al. / International Journal of Cardiology 203 (2016) 325–330 Table 1 Demographics. Age at diagnosis (mean (SD) min–max) Female Weight (mean (SD) min–max) Height (mean (SD) min–max) Caucasian (includes Hispanics) Asian Black Other/unknown ethnicity Idiopathic/familial PH Congenital heart disease Other associated PAH Chronic lung disease Group 4 and 5 (Venice)
7.3 y (5.3) 59% 27.2 kg (19.6) 118 cm (33.8) 327 105 15 33 243 161 23 48 5
0–17 (284) 2.4–117 49–186 (68%) (22%) (3%) (7%) (57%) (38%) (4%) (10%) (1%)
been confirmed after EB review of haemodynamic data either by HC (472 patients) or by approved ECHO or histology review by the EB (8 patients). These 8 patients are included for the follow-up HC analysis of complications. Patients' demographics are presented in Table 1. Children presented with severe PH (mPAP: 57.8 ± 18.8 mm Hg,) and elevated PVRI (16.6 ± 11.6 WU × m2). The CI averaged at 3.7 ± 3.7 L/min/m2; however 113 (24%) presented with a CI of b 2.5 L/min/m2, 8% had a right atrial pressure of N 12 mm Hg and 4% had both a CI b2.5 L/min/m2 and a right atrial pressure of N12 mm Hg. Haemodynamics by age groups, aetiology and FC are presented in Tables 2, 3 and 4. Analysis of the haemodynamic profile at diagnosis by age (Table 2) showed a progressive increase in mPAP (p = 0.003), SAP, SVRI and PVRI (all p b 0.001) and a decrease in CI (p b 0.001) and PAP/SAP (p = 0.006) with increase in age after adjusting for aetiology and FC. Table 3 illustrates the haemodynamic profile for different aetiologies and suggests that in patients with PH related to lung diseases a less severe haemodynamic presentation with a lower mPAP, PVRI and a higher CI seems to prevail. The association with aetiology was statistically significant for mPAP, PAP/SAP and PVRI (all p b 0.001) after adjusting for age at diagnosis and FC. There was an association of haemodynamics with FC (Table 4): mPAP (p = 0.005) and PAP/SAP (p = 0.02) increased in relation to higher FC after adjusting for age at diagnosis and aetiology. This association was similar when performing the correlation for the isolated group of iPAH (mPAP: p = 0.025, PAP/SAP: p = 0.017). AVRT was performed in 92% (500/544) of the patients with 34% (185) considered by the local investigator as responders.
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Reported complications observed within 24 h of HC are shown in Table 5. In order to establish a comprehensive set of HC complications, a total of 908 HC (554 diagnostic and 354 follow-up [in 235 patients]), were analysed. 154 patients had 1 follow-up HC, 51 had 2, 21 had 3, 6 had 4 and 2 had 5 follow-up HCs. Death related to diagnostic HC was reported in 5 patients (0.9% of patients and 0.6% of all HCs). Adverse events occurred in 54 (5.9%) of all HCs of which 37 occurred at diagnostic HC. No significant differences were observed between diagnostic (37/554: 6.7%, 5 deaths) and follow-up HCs (17/354: 4.8%, no death) even if slightly lower for the follow-up procedures. The ages of patients who died were 3, 4, 14, 24 months and 15 years; 4 patients had iPAH and 1 was PAH after repair of a ventricular septal defect. FC IV was recorded for 2 patients and III in 3 patients. The reasons for death were cardiac arrest post-HC and complications of extracorporeal membrane oxygenation (ECMO), death at induction of anaesthesia, severe bleeding during HC procedure, progressive heart failure after HC and brain lesions following cardiac arrest during HC. Diagnostic HC was performed under GA in 291 (53%) and under conscious sedation in 257 (47%); no data were available for 6 patients. GA and FC were found to be significant predictors of complications at diagnosis, with complications more likely to occur with GA (26/291 versus 11/257) (p = 0.04) and with higher FC (p = 0.02). GA was most frequently used in b2 years of age. 4. Discussion Important clinical features specific to paediatric PH have been previously identified by TOPP [9]. The analysis of the haemodynamic profile of TOPP patients presented here shows that 88/568 (18%) of patients had to be excluded from the confirmed PH group because of incomplete or inadequate HC data. This illustrates the complexity of haemodynamic evaluation in the paediatric population, characterised by heterogeneous aetiologies such as CHD. It further emphasises the need of meticulous haemodynamic measurement methodologies, in particular because the complication rate of the HC is not insignificant in children. The most frequent reason for incomplete or inadequate HC data was missing data for PVRI calculation, and inappropriate use of thermodilution to estimate cardiac output in the presence of significant intracardiac shunting. The haemodynamic profile at diagnosis in children differs from the one reported in adults [15]. Despite high PAP and high PVRI, children in general have better CI and lower RA pressures, suggesting that right ventricular function remains preserved. However, 24% presented with
Table 2 Haemodynamics at diagnosis by age groups (PH-confirmed population).
No. patients with HC (n) RA pressure (mm Hg) Mean PAP (mm Hg) Mean SAP (mm Hg) Cardiac index (L/min/m2) PAP/SAP PVRI (wood units ∗ m2) SVRI (wood units ∗ m2) PVRI/SVRI
All patients (N = 480)
N3 months to b24 months (N = 92)
2–6 years (N = 145)
7–11 years (N = 109)
12–18 years (N = 134)
472 7.1 (3.77) 0–25 57.8 (18.80) 25–143 68.0 (14.41) 37–113 3.7 (3.74) 1–75 0.9 (0.27) 0.3–2.4 16.6 (11.62) 3–96 20.4 (10.82) 1–89 0.9 (0.60) 0.2–8.3
89 6.5 (3.03) 1–16 49.3 (15.97) 26–88 58.4 (12.84) 37–93 4.1 (2.65) 1–21 0.9 (0.25) 0.3–1.5 12.7 (12.49) 3–89 16.9 (12.29) 3–89 0.8 (0.45) 0.2–3.0
144 7.1 (3.75) 0–21 59.0 (19.00) 25–126 65.1 (13.10) 38–113 4.4 (6.20) 1–75 0.9 (0.30) 0.4–2.4 14.9 (8.33) 3–49 17.0 (8.12) 1–58 1.0 (0.85) 0.2–8.3
106 7.3 (4.21) 0–20 57.0 (17.21) 26–97 69.0 (11.51) 43–103 3.5 (1.46) 1–10 0.8 (0.24) 0.4–1.6 16.3 (11.00) 3–64 20.5 (8.49) 5–60 0.8 (0.36) 0.2–2.4
133 7.2 (3.84) 0–25 62.9 (19.69) 26–143 76.8 (13.82) 40–112 2.9 (0.97) 1–7 0.8 (0.27) 0.3–1.9 21.4 (13.03) 4–96 26.4 (11.54) 9–85 0.8 (0.48) 0.2–4.3
Data are mean (SD) and range unless stated otherwise. RA: right atrial, PAP: pulmonary arterial pressure, SAP: systemic arterial pressure, PVRI: indexed pulmonary vascular resistance; SVRI: indexed systemic vascular resistance.
0.75 (0.328) 0.58–1.33 0.70 (0.341) 0.26–1.74
22 7.8 (3.14) 4–15 49.4 (15.10) 27–78 70.7 (17.83) 40–110 3.30 (1.054) 1.00–5.00 0.73 (0.265) 0.4–1.4 14.25 (8.153) 4.68–31.80 23.10 (17.293) 8.96–85.00 20.43 (10.817) 0.60–88.91
0.87 (0.603) 0.16–8.27
SVRI (wood units ∗ m2)
PVRI/SVRI
PVRI (wood units ∗ m2)
PAP/SAP
SAP (mm Hg) Cardiac index (L/min/m2)
Data are mean (SD) and range unless stated otherwise. RA: right atrial, PAP: pulmonary arterial pressure, SAP: systemic arterial pressure, PVRI: indexed pulmonary vascular resistance; SVRI: indexed systemic vascular resistance. ⁎ Negative values of 95% confidence interval lower limit are rounded to zero as limit of valid range.
0.79 (0.318) 0.24–1.98 0.89 (0.605) 0.21–8.27
20.88 (10.765) 0.60–88.91
20.35 (9.788) 4.67–59.12 0.91 (0.641) 0.17–4.34
20.35 (9.397) 5.45–54.02 0.96 (0.747) 0.17–4.34
19.82 (10.264) 4.67–59.12
2 6.0 (1.41) 5–7 54.5 (12.02) 46–63 68.0 (15.56) 57–79 2.04 (0.588) 1.63–2.46 0.80 (0.007) 0.8–0.8 24.04 (13.852) 14.25–33.84 32.73 (16.354) 21.17–44.30 0.72 (0.064) 0.67–0.76 49 8.1 (3.80) 0–20 55.9 (21.04) 27–143 67.4 (12.55) 48–106 3.81 (2.254) 1.13–11.84 0.83 (0.265) 0.4–1.9 16.11 (12.533) 3.34–62.53 108 6.4 (3.87) 0–25 63.4 (18.37) 26–126 68.4 (15.82) 37–112 3.57 (1.633) 1.37–11.19 0.94 (0.233) 0.4–2.4 17.50 (13.631) 3.20–96.11 159 6.9 (3.89) 0–25 61.0 (19.41) 26–143 68.1 (14.79) 37–112 3.62 (1.846) 1.13–11.84 0.90 (0.247) 0.4–2.4 17.15 (13.259) 3.20–96.11 238 7.1 (3.92) 0–21 59.4 (18.10) 25–106 68.7 (13.47) 39–113 3.69 (4.806) 0.92–75.00 0.88 (0.278) 0.3–1.9 17.72 (11.128) 3.33–88.69
48 6.8 (2.81) 2–14 43.1 (14.45) 26–81 61.5 (14.23) 38–95 4.41 (3.119) 1.50–20.93 0.72 (0.236) 0.3–1.2 10.04 (6.872) 3.31–37.06 16.13 (8.726) 3.20–38.77 0.73 (0.559) 0.16–3.95 472 7.1 (3.77) 0–25 57.8 (18.80) 25–143 68.0 (14.41) 37–113 3.71 (3.744) 0.92–75.00 0.86 (0.269) 0.3–2.4 16.60 (11.620) 3.20–96.11 No. patients with HC (N) RA pressure (mm Hg) PAP (mm Hg)
APAH excluding APAH–CHD (N = 23) Never had shunt (N = 2)⁎ Repaired shunt (N = 50) Shunt (unrepaired/partial repair) (N = 109) All CHD (N = 161) iPAH/FPAH (N = 243) Group 3 PH (N = 48) All patients (N = 480)
Table 3 Haemodynamics at diagnosis by aetiologies (PH-confirmed population).
5 7.8 (3.56) 3–13 59.4 (11.59) 48–77 80.2 (15.80) 59–102 3.09 (1.359) 1.53–4.47 0.78 (0.296) 0.6–1.3 19.16 (8.532) 10.43–31.42 28.51 (15.696) 12.57–49.75
M. Beghetti et al. / International Journal of Cardiology 203 (2016) 325–330 Groups 4 and 5 (N = 5)
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low CI, and 4% together with high RA pressure (N 12 mm Hg). This difference between adults and children was previously described in a registry (REVEAL) including adults and children but in a smaller population [10]. A gradual worsening of haemodynamic values was observed with increased age, e.g., adolescents over 12 years of age presented with a lower CI. This may disclose a different presentation of the disease with age. A further difference in haemodynamics was seen in patients with PH related to lung diseases. They present with a better haemodynamic profile than iPAH or CHD (lower mPAP and PVRI). This finding is consistent with studies in adults with PH related to lung disease, which also have a lower mPAP if compared with patients with iPAH [16,17]. Patients with PH related to lung diseases are of particular interest and may be underreported and are currently not well investigated. It is possible that patients in this group less frequently undergo haemodynamic assessment, but this information is still considered of utmost importance particularly if treatment with PAH specific drugs is considered. HC may also display unrecognised problems such as anomalies of pulmonary veins or other cardiovascular abnormalities such as aortopulmonary collaterals [18,19]. A total of 908 HCs (diagnostic and follow-up procedures) were analysed, demonstrating an incidence of complications of 5.9% including 5 deaths (0.6%) (Table 5). Taylor et al. reported a higher rate of 6% cardiac arrest or death in a series of 75 consecutive HC in children with PH [20]. In this single-centre study all patients were catheterised under GA which may raise the question whether GA is associated with and may be a risk factor for complications as suggested previously [20]. Another study disclosed a 5% rate for major complications with a 1.4% mortality rate [21]. Data from the MAGIC Registry suggests a similar rate of adverse events (3.9%) as TOPP with no procedural deaths in 217 paediatric patients [22]. The risk for adverse events was primarily related to patients with “supra-systemic” mPAP. Zuckerman et al. reported a complication rate of 5.7% and a mortality rate of 0.2% in a population of children and adults with PH [23]. A recent single-centre report of 97 HCs in 75 children with PH reported a similar rate (6.2%) of complications [6,24]. Comparing the above-mentioned paediatric and adult data, it seems that the rate of complications is higher in children: Hoeper et al. reported only 1.1% complications in 7218 adult HCs, with similar complications to those reported in our registry [25]. This may reflect lower risk in adults. Within the Congenital Cardiac Catheterization Outcome Project (C3PO) complications varied between 10% and 20% in a cohort of children undergoing diagnostic or interventional HC, with high severity events (including death) of 2–5%. The group at higher risk was undergoing interventional HC. Lower age and haemodynamic vulnerability were significant risk factors [11,12]. The complication rate in our study, for a pure population with PH, is lower than the general rate considering that our group can be considered as a high-risk group with haemodynamic vulnerability. GA was also reported to be a risk factor of HC complication in a different large series of paediatric PH HCs [23]. The risk of GA was recently confirmed also in a group of patients already treated with targeted therapies [26]. Younger age was seen to be a risk factor by Zuckerman et al.; however, in our registry when adjusted for age only GA remained significant taking into account that most very young patients were done under GA [23]. The challenge remains to perform HC safely in a very young child but avoiding hypoxia and agitation without the use of GA. GA and a higher FC at time of HC seem to be the most important risk factors for mortality and morbidity. We believe that HC should remain the gold standard for diagnosis and should be performed in all suitable patients. The identification of GA as a risk factor for complications and death requires a thorough evaluation of pre- and post-anaesthetic care of paediatric patients with pulmonary hypertension, which has been reviewed recently [27]. The literature on this subject still shows discrepancies due to the retrospective design, the limited number of patients
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Table 4 Haemodynamics at diagnosis by functional class (PH-confirmed population).
No. patients with HC (n) RA pressure (mm Hg) Mean pulmonary arterial pressure (mm Hg) Systemic arterial pressure (mm Hg) Cardiac index (L/min/m2) PAP/SAP PVRI (wood units ∗ m2) SVRI (wood units ∗ m2) PVRI/SVRI
All patients (N = 480)
Class I (N = 62)
Class II (N = 227)
Class III (N = 158)
Class IV (N = 33)
472 7.1 (3.77) 0–25 57.8 (18.80) 25–143 68.0 (14.41) 37–113 3.7 (3.74) 1–75 0.9 (0.27) 0.3–2.4 16.6 (11.62) 3–96 20.4 (10.82) 1–89 0.9 (0.60) 0.2–8.3
62 6.5 (2.94) 0–14 49.1 (15.74) 25–83 63.9 (13.86) 38–103 3.7 (1.54) 1–12 0.8 (0.21) 0.4–1.3 13.1 (11.61) 3–89 18.5 (11.61) 5–89 0.7 (0.26) 0.2–1.3
226 7.0 (3.90) 0–25 57.8 (19.66) 25–143 68.2 (14.59) 38–112 3.6 (1.61) 1–11 0.9 (0.28) 0.4–1.9 16.9 (12.48) 3–96 20.2 (10.55) 5–85 0.9 (0.58) 0.2–4.3
155 7.1 (3.43) 1–17 60.7 (17.36) 26–126 68.9 (14.17) 37–112 4.0 (6.14) 1–75 0.9 (0.27) 0.3–2.4 17.1 (9.85) 3–49 21.2 (10.51) 1–59 0.9 (0.75) 0.2–8.3
29 8.9 (5.43) 0–21 61.3 (20.49) 27–103 70.4 (14.71) 44–113 3.4 (1.48) 1–8 0.9 (0.30) 0.4–1.6 19.0 (12.54) 4–56 22.5 (12.45) 6–59 0.9 (0.32) 0.3–1.7
Data are mean (SD) and range unless stated otherwise. RA: right atrial, PAP: mean pulmonary arterial pressure, SAP: mean systemic arterial pressure, PVRI: indexed pulmonary vascular resistance. SVRI: indexed systemic vascular resistance.
and procedures, and different aetiologies [6,23,24,27–29]. These procedures should include an experienced anaesthetic team with availability of inhaled vasodilators such as nitric oxide to treat pulmonary hypertensive crisis and mechanical support (ECMO) should the patient present with cardiac arrest [6,23,28,29]. Further a “balanced” approach to general anaesthesia and analgesia minimises the lowering of systemic vascular resistance, increase in pulmonary vascular resistance and depression of myocardial function. Limitation of inhaled gas and avoidance of bolus infusion of most medication is essential. A knowledge of all potential haemodynamic effects of the anaesthetic agents is mandatory to avoid complications [29]. There is no ideal anaesthetic agent but a team approach seems mandatory. Finally the post-anaesthetic management is essential as complications may appear following recovery of anaesthesia, as seen in most of the deaths reported in our study. Respiratory depression, and airway obstruction stimulate pulmonary hypertensive crises, through hypoventilation and hypoxia. Most patients should be admitted to an ICU or step down unit for post-procedure observation and should be discharged when the effects of anaesthesia and sedatives are worn off or no longer needed. Based on these considerations, the authors feel that HC procedures, especially in young and sicker infants with PH should be carried out in centres with extensive expertise in performing the procedure. Based on our findings, a recommendation may be derived that patients in FC IV should be first treated aggressively (double or triple combination therapy) to achieve stabilisation before proceeding to the invasive haemodynamic assessment. This is supported by
Bobhate et al. in a recent single-centre study including 75 patients with PH [6]. Furthermore, in the current study, the initial HC before initiation of therapy was associated with a slightly greater risk than a follow-up catheterisation on PH-targeted medications, although this did not reach statistical significance. However, it is confirmed by recent reports supporting that the follow-up HC may provide important information to adapt the therapeutic strategy [6,30]. In about 30% of the studied children, local physicians considered the response to AVRT “positive”, but criteria or test protocols to define positive a response are lacking, and interpretation differed between sites. The appropriate criteria for acute responders in children with PAH are currently debated [31]. It is unclear whether the response criteria, defined and modified by Barst specifically for children [32], or the criteria defined by Sitbon for adults [33], are most valuable in children with PAH. This needs to be clarified and requires further work in this population. 5. Limitations The TOPP Registry is a prospective observational registry with associated limitations. Inclusion criteria for the registry and for the current study included invasive haemodynamic data confirming the diagnosis PH. Although this has resulted in a well-described disease status in the patients in the cohort, this might have introduced a selection bias with severe patients
Table 5 Complications at heart catheterisation.
Relevant complications (total) Hypotension requiring intervention Inotropic support required Pulmonary hypertensive crisis Unexpected ICU admission after procedure Other Cardiac arrest Arrhythmia requiring intervention Death Pulmonary haemorrhage Cardiac perforation Pericardial effusion Stroke
Patients (n = 555)
All catheterisations (n = 908)
Diagnostic catheterisations (n = 554)
Follow-up catheterisations (n = 354)
51 (9.2%) 20 (3.6%) 16 (2.9%) 14 (2.5%) 12 (2.2%) 12 (2.2%) 10 (1.8%) 8 (1.4%) 5 (0.9%) 2 (0.4%) 1 (0.2%) 1 (0.2%) 1 (0.2%)
54 (5.9%) 20 (2.2%) 16 (1.8%) 14 (1.5%) 12 (1.3%) 12 (1.3%) 10 (1.1%) 8 (0.9%) 5 (0.6%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 1 (0.1%)
37 (6.7%) 17 (3.1%) 14 (2.5%) 10 (1.8%) 7 (1.3%) 5 (0.9%) 5 (0.9%) 4 (0.7%) 2 (0.6%) 1 (0.2%) 0 0 0
17 (4.8%) 3 (0.8%) 2 (0.6%) 4 (1.1%) 5 (1.4%) 7 (2%) 5 (1.4%) 4 (1.1%) 3 (0.8%) 1 (0.3%) 1 (0.3%) 1 (0.3%) 1 (0.3%)
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not enrolled because HC has been considered too high risk for some of these patients. In theory, this may also have led to underreporting of complications of death during the procedure prohibiting the collection of haemodynamic data, leading to non-inclusion. Further, there was no predefined protocol used for performing HC in the TOPP Registry. This could induce differences in data between centres. For instance, AVRT was performed using different protocols and different response criteria in the various centres, limiting the value of the reported prevalence of acute responders in this cohort. The decision to include referral centres only for paediatric PH for recruitment in this registry may also have induced some bias with more severe patients referred to these expert centres (increasing the risk of complications). It is also possible that HC performed in patients not referred to expert centres present a higher risk of complications during invasive procedures. Nevertheless, these data reflect current era “real-life” practice in centres treating children with PH worldwide and underscore the importance of standardised invasive haemodynamic assessment in this population. The significance of the data is derived from the largest sample size of HC data in paediatric PH patients reported so far and the data reveal unique haemodynamic presentation of PH in paediatrics.
[5]
[6] [7]
[8]
[9] [10]
[11] [12]
[13]
6. Conclusion
[14]
In this large sample size of invasive haemodynamics in paediatric PH, it becomes evident that most of the children with PH present with preserved CI and normal RA pressure even in the presence of severe PH. Nevertheless, 24% presented with a CI of b 2.5 L/min × m2. There is an apparent increase in mPAP and PVRI with age reaching similar values as in adults. A correlation between mPAP with FC is apparent. The use of GA was associated with higher risk of complications. In addition, complications related to HC showed a higher incidence compared with current adult data but lower than in interventional paediatric HC, with patients with FC IV being at higher risk. As the complication rate is not negligible, we recommend performing HC in expert centres.
[15]
Funding
[21]
The TOPP Registry is supported by a funding from Actelion Pharmaceuticals Ltd. Actelion does not participate in the management of the Registry, nor does it have access to the database, the individual sites and patient data. All Registry-related decisions lie solely with the Executive Board of the Association for Pediatric Pulmonary Hypertension.
[22]
[16]
[17]
[18]
[19] [20]
[23]
[24]
Conflict of interest [25]
No disclosures are reported in association to the content of this manuscript. Acknowledgements We thank Katherine Hutchinson, Jeremy Wheeler and Emily Wood, Quanticate UK, for statistical analysis and Rita Locher, Project Manager, for continuous organisational support. This manuscript was written by the investigators. References [1] D.D. Ivy, S.H. Abman, R.J. Barst, et al., Pediatric pulmonary hypertension, J. Am. Coll. Cardiol. 62 (2013) D117–D126. [2] N. Galie, M.M. Hoeper, M. Humbert, et al., Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT), Eur. Heart J. 30 (2009) 2493–2537. [3] M. Beghetti, R.M. Berger, I. Schulze-Neick, et al., Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice, Eur. Respir. J. 42 (2013) 689–700. [4] V.V. McLaughlin, S.L. Archer, D.B. Badesch, et al., ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology
[26]
[27]
[28] [29]
[30]
[31]
[32]
[33]
Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association, J. Am. Coll. Cardiol. 53 (2009) 1573–1619. W.M. Zijlstra, J.M. Douwes, E.B. Rosenzweig, et al., Survival differences in pediatric pulmonary arterial hypertension: clues to a better understanding of outcome and optimal treatment strategies, J. Am. Coll. Cardiol. 63 (2014) 2159–2169. P. Bobhate, L. Guo, S. Jain, et al., Cardiac catheterization in children with pulmonary hypertensive vascular disease, Pediatr. Cardiol. 36 (2015) 873–879. D.D. Ivy, E.B. Rosenzweig, J.C. Lemarie, M. Brand, D. Rosenberg, R.J. Barst, Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings, Am. J. Cardiol. 106 (2010) 1332–1338. T.F. Feltes, E. Bacha, R.H. Beekman III, et al., Indications for cardiac catheterization and intervention in pediatric cardiac disease: a scientific statement from the American Heart Association, Circulation 123 (2011) 2607–2652. R.M. Berger, M. Beghetti, T. Humpl, et al., Clinical features of paediatric pulmonary hypertension: a registry study, Lancet 379 (2012) 537–546. R.J. Barst, M.D. McGoon, C.G. Elliott, A.J. Foreman, D.P. Miller, D.D. Ivy, Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management, Circulation 125 (2012) 113–122. L. Bergersen, K. Gauvreau, A. Marshall, et al., Procedure-type risk categories for pediatric and congenital cardiac catheterization, Circ. Cardiovasc. Interv. 4 (2011) 188–194. L. Bergersen, A. Marshall, K. Gauvreau, et al., Adverse event rates in congenital cardiac catheterization — a multi-center experience, Catheter. Cardiovasc. Interv. 75 (2010) 389–400. G. Simonneau, N. Galie, L.J. Rubin, et al., Clinical classification of pulmonary hypertension, J. Am. Coll. Cardiol. 43 (2004) 5s–12s. C.G. LaFarge, O.S. Miettinen, The estimation of oxygen consumption, Cardiovasc. Res. 4 (1970) 23–30. M. Humbert, O. Sitbon, A. Chaouat, et al., Pulmonary arterial hypertension in France: results from a national registry, Am. J. Respir. Crit. Care Med. 173 (2006) 1023–1030. J. Hurdman, R. Condliffe, C.A. Elliot, et al., ASPIRE Registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre, Eur. Respir. J. 39 (2012) 945–955. M.M. Hoeper, S. Andreas, A. Bastian, et al., Pulmonary hypertension due to chronic lung disease: updated recommendations of the Cologne Consensus Conference 2011, Int. J. Cardiol. 154 (Suppl. 1) (2011) S45–S53. M.J. del Cerro, A. Sabate Rotes, A. Carton, et al., Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes, Pediatr. Pulmonol. 49 (2014) 49–59. T.J. Kulik, L.M. Rhein, M.P. Mullen, Pulmonary arterial hypertension in infants with chronic lung disease: will we ever understand it? J. Pediatr. 157 (2010) 186–190. C.J. Taylor, G. Derrick, A. McEwan, S.G. Haworth, M.R. Sury, Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension, Br. J. Anaesth. 98 (2007) 657–661. G.D. Williams, H. Maan, C. Ramamoorthy, et al., Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine, Paediatr. Anaesth. 20 (2010) 28–37. K.D. Hill, D.S. Lim, A.D. Everett, D.D. Ivy, J.D. Moore, Assessment of pulmonary hypertension in the pediatric catheterization laboratory: current insights from the Magic Registry, Catheter. Cardiovasc. Interv. 76 (2010) 865–873. W.A. Zuckerman, M.E. Turner, J. Kerstein, et al., Safety of cardiac catheterization at a center specializing in the care of patients with pulmonary arterial hypertension, Pulm. Circ. 3 (2013) 831–839. M.J. Carmosino, R.H. Friesen, A. Doran, D.D. Ivy, Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization, Anesth. Analg. 104 (2007) 521–527. M.M. Hoeper, S.H. Lee, R. Voswinckel, et al., Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers, J. Am. Coll. Cardiol. 48 (2006) 2546–2552. K. Taylor, D. Moulton, X.Y. Zhao, P. Laussen, The impact of targeted therapies for pulmonary hypertension on pediatric intraoperative morbidity or mortality, Anesth. Analg. 120 (2015) 420–426. D.F. Chau, M. Gangadharan, L.P. Hartke, M.D. Twite, The post-anesthetic care of pediatric patients with pulmonary hypertension, Seminars in Cardiothoracic and Vascular Anesthesia (2015). http://dx.doi.org/1089253215593179 (E-pub ahead of print). A.C. Shukla, M.C. Almodovar, Anesthesia considerations for children with pulmonary hypertension, Pediatr. Crit. Care Med. 11 (2010) S70–S73. M.D. Twite, R.H. Friesen, The anesthetic management of children with pulmonary hypertension in the cardiac catheterization laboratory, Anesthesiol. Clin. 32 (2014) 157–173. M.J. Ploegstra, J.M. Douwes, M.T. Roofthooft, W.M. Zijlstra, H.L. Hillege, R.M. Berger, Identification of treatment goals in paediatric pulmonary arterial hypertension, Eur. Respir. J. 44 (2014) 1616–1626. J.M. Douwes, R.L. van Loon, E.S. Hoendermis, et al., Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria, Eur. Heart J. 32 (2011) 3137–3146. R.J. Barst, G. Agnoletti, A. Fraisse, J. Baldassarre, D.L. Wessel, Vasodilator testing with nitric oxide and/or oxygen in pediatric pulmonary hypertension, Pediatr. Cardiol. 31 (2010) 598–606. O. Sitbon, M. Humbert, X. Jais, et al., Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension, Circulation 111 (2005) 3105–3111.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension) M. Beghetti a,⁎,1, I. Schulze-Neick b,1, R.M.F. Berger c,1, D.D. Ivy d,1, D. Bonnet e,1, R.G. Weintraub f,1, T. Saji g,1, D. Yung h,1, G.B. Mallory i,1, R. Geiger j,1, J.T. Berger k,1, R.J. Barst l,1, T. Humpl m,1, for the, TOPP investigators TOPP Registry investigators (not listed in the author's list) by country alphabetical order: S. Mattos n, Z.C. Jing o, Z.Y. Han o, L. Sondergaard p, T. Jensen p, M. Levy ag, S. Mebus q, Ch. Apitz r, A. Szatmari s, L. Ablonczy s, O. Milanesi t, V. Favero t, T. Pulido u, P. De La Garza u, J.M. Douwes af, H. Brun v, L. Moll w, K. Michalak w, W. Kawalec x, M. Zuk x, M. Fasnacht Boillat y, R. Olgunturk z, S. Serdar Kula z, A. Dursun aa, R.W. Day ab, E. Austin ac, D.J. Moore ac, A.M. Atz ad, J.A. Feinstein ae, n
Royal Portuguese Hospital, Maternal-Fetal Cardiac Unit, Recife, Brazil Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China p Rigshospitalet, University of Copenhagen, Heart Center, Copenhagen, Denmark q German Heart Centre, Munich, Germany r Universitätsklinikum Giessen, Giessen, Germany s Hungarian Institute of Cardiology, Pediatric Cardiac Center, Budapest, Hungary t Universita di Padova, Dipartimento di Pediatria, Padova, Italy u National Heart Institute, Mexico City, Mexico v Rikshospitalet, Section for Pediatric Cardiology, Oslo, Norway w Polish Mothers Hospital Research Institute, Lodz, Poland x Children's Memorial Health Institute, Department of Cardiology, Warsaw, Poland y Universitäts-Kinderklinik, Zurich, Switzerland z Gazi Universitesi Tip Fakultesi, Pediyatrik Kardiyoloji ABD, Ankara, Turkey aa Hacettepe University Ihsan Dogramaci, Tip Fak, Pediyatrik Kardiyoloji, Ankara, Turkey ab University of Utah, University of Health Care, Division of Pediatric Cardiology, Salt Lake City, USA ac Vanderbilt Children's Hospital, Division of Cardiology, Nashville, USA ad Medical University of South Carolina, Charleston, USA ae Stanford University Medical Center Packard Children's Hospital, Palo Alto, USA af Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Netherlands ag M3C-Paediatric Cardiology, Université Paris Descartes, Necker Enfants Malades, AP-HP, Paris, France o
a
Pediatric Cardiology, Department of the Child and Adolescents, Hôpital des Enfants, University of Geneva, Switzerland Cardiac Unit, Great Ormond Street Hospital for Children, London, UK c Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Netherlands d Pediatrics, University of Colorado School of Medicine, Aurora, USA e M3C-Paediatric Cardiology, Université Paris Descartes, Necker Enfants Malades, AP-HP, Paris, France f Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Australia g Toho University Medical Center Omori Hospital, Tokyo, Japan h Seattle Children's Hospital, University of Washington School of Medicine, Seattle, USA i Texas Children's Hospital, Baylor College of Medicine, Houston, USA j Innsbruck Medical University, Pediatric Cardiology, Innsbruck, Austria k Children's National Medical Center, Pediatric Critical Care and Cardiology, WA, USA l Pediatrics, Columbia University, New York, USA m Cardiology and Critical Care, University of Toronto, Toronto, ON, Canada b
⁎ Corresponding author at: Pediatric Cardiology Unit, Children's Hospital, University Hospital of Geneva, 6 rue Willy Donzé 1211 Geneva 14, Switzerland. E-mail address: [email protected] (M. Beghetti). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2015.10.087 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
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i n f o
Article history: Received 5 May 2015 Received in revised form 4 September 2015 Accepted 12 October 2015 Available online 23 October 2015 Keywords: Catheterisation Heart defects Congenital Hypertension Pulmonary Paediatrics
a b s t r a c t Background: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. Methods and results: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg and pulmonary vascular resistance index [PVRI] of N 3 WU × m2). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p = 0.04) and with higher functional class (p = 0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m2; 95% confidence interval 3.4–4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m2, 95% confidence interval 15.6–17.76). However, 24% of the patients had a CI of b2.5 L/min/m2 at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p b 0.001). Conclusion: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary hypertension (PH) remains an important cause of mortality and morbidity [1]. It is characterised by a progressive increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) that ultimately leads to right ventricular dysfunction and death. The definition of pulmonary arterial hypertension (PAH) is based on haemodynamics using the same criteria for children as for adult patients [1,2]. Non-invasive tests are useful for screening suspected PH but haemodynamic assessment with invasive heart catheterisation (HC) remains the gold standard to confirm diagnosis and to assess disease severity [2–4]. Haemodynamics (PVR and right atrial pressure) are recognised as risk factors at baseline and important for therapeutic decisions [1, 5–7]. The recent statement of the AHA on the indications for HC in paediatrics recommends HC to assess PVR and reversibility of PH in patients with congenital heart disease (CHD) or idiopathic PAH (iPAH) when accurate assessment of PVR is needed to make therapeutic decisions [8]. The majority of children with PH enrolled in current registries have iPAH or CHD–PAH, underscoring the need to perform HC at diagnosis in this population [9,10]. Multi-centre studies have been published describing the complication rate of HC in paediatrics but no large studies have focused on a pure population of PH [11,12]. Controversial opinions challenge the use of invasive haemodynamics and are mainly focused on the potential risks of HC [1]. With increasing treatment options, accurate characterisation of the disease is needed to provide optimal care as, until now, targeted therapies have not shown efficacy in other forms of PH than PAH [2]. The haemodynamic profile for the PH population enrolled in TOPP as well as HC-related complications of 908 diagnostic and follow-up HCs performed are reported.
2. Methods The Registry was designed as a multi-centre, prospective observational cohort study at 31 centres in 19 countries. Patients underwent clinical assessment and received treatment and follow-up according to the sole judgement of their local physician and were not on TOPP-related specific diagnostic and therapeutic protocols. Enrolment began in January 2008. All eligible patients with complete HC data available on 27th February 2012 were included in the analysis. The study was designed and supervised by an Executive Board (EB). Data management and analyses were performed by contract organisations working with the EB. The protocol was approved by the relevant Institutional Review Boards and/or Ethics Committees; the study complies with the Declaration of Helsinki; and informed consent has been obtained from all patients and/or their legal guardians. Consecutive patients between 3 months and 18 years of age at the time of diagnosis with PH confirmed by HC were eligible for enrolment in the TOPP Registry. Both newly
diagnosed (incident, within 3 months of enrolment in the registry) patients and previously diagnosed (prevalent, more than 3 months prior to enrolment) patients were eligible. Patients were eligible if they had PH belonging to Venice Groups 1, 3, 4, or 5 according to the Venice 2003 clinical classification [13], as this was the actual classification at the time of registry design. The diagnosis of “PH-confirmed” required HC confirmation (defined as mPAP ≥ 25 mm Hg, PVRI ≥ 3 WU × m 2 , and PCWP ≤ 12 mm Hg). The EB reviewed all cardiac catheterisation data sets and recalculated PVRI and cardiac output by the Fick method using a single assumed oxygen consumption table [14] or the recorded cardiac output as measured by thermodilution (if performed and physiology permitted). Following this review, patients not fulfilling the above-mentioned definition of PH were excluded from the analysis of the haemodynamic parameters. Patients for whom a diagnostic HC could not be performed because of clinical reasons, could be included based on a confirmatory echocardiography and/or histopathology as they may have a follow-up HC. Overall data on general anaesthesia (GA) and conscious sedation to perform HC was collected but information on specific drugs was not collected. Acute vasodilatory response testing (AVRT) was recorded, where the interpretation of a positive or absent response to AVRT was left with the local physician following the rules of a non-interventional registry. Predefined HC-related complications were recorded but were not adjudicated by the EB. For the purpose of this analysis all diagnostic and follow-up HCs were pooled together. 2.1. Statistical analysis A statistical analysis plan was written to specify the initial descriptive analysis, and was completed prior to data finalisation. After team review of the descriptive results, evaluation of specific hypotheses (ANOVA) was executed. No formal sample size calculation was performed, and hence the sample was not powered a priori for specific comparisons. The analysis population for haemodynamic parameters was the PH-confirmed cohort, which included only patients who met all enrolment criteria, but all patients were analysed for HC complications. Continuous data was summarised using descriptive statistics (mean, SD, 95% confidence interval, median, min/max and 25th and 75th percentiles) and 95% confidence intervals where relevant. Age was grouped for descriptive summaries (3–24 months, 2–6 years, 7–11 years and 12–18 years). Categorical data was summarised using counts and percentages. Unless stated otherwise, the denominator for percentages was the total number of patients with non-missing data for each variable analysed. All eCRFs were individually reviewed and assessed by EB members. Post-review values were used in the analyses, unless there was insufficient data for review in which case the original eCRF data was used. The association between key haemodynamic parameters and age at diagnosis (years), aetiology and NYHA functional class (FC) was investigated using an ANCOVA model including all 3 variables. Cardiac index (CI), PVRI and PVRI/ SVRI were log-transformed to improve the assumption of normality. In order to investigate the potential risk factors for HC complications at diagnosis, logistic regression analyses were performed. The risk factors investigated were age at diagnosis (years), NYHA FC (trend over classes I–IV), aetiology and sedation method, with all variables retained in the final model. All analyses were performed using SAS statistical software package (version 8.2 or higher).
3. Results At the data cut on February 2012, 568 patients were enrolled and 480 fulfilled the inclusion criteria, i.e., are patients for whom PH has
M. Beghetti et al. / International Journal of Cardiology 203 (2016) 325–330 Table 1 Demographics. Age at diagnosis (mean (SD) min–max) Female Weight (mean (SD) min–max) Height (mean (SD) min–max) Caucasian (includes Hispanics) Asian Black Other/unknown ethnicity Idiopathic/familial PH Congenital heart disease Other associated PAH Chronic lung disease Group 4 and 5 (Venice)
7.3 y (5.3) 59% 27.2 kg (19.6) 118 cm (33.8) 327 105 15 33 243 161 23 48 5
0–17 (284) 2.4–117 49–186 (68%) (22%) (3%) (7%) (57%) (38%) (4%) (10%) (1%)
been confirmed after EB review of haemodynamic data either by HC (472 patients) or by approved ECHO or histology review by the EB (8 patients). These 8 patients are included for the follow-up HC analysis of complications. Patients' demographics are presented in Table 1. Children presented with severe PH (mPAP: 57.8 ± 18.8 mm Hg,) and elevated PVRI (16.6 ± 11.6 WU × m2). The CI averaged at 3.7 ± 3.7 L/min/m2; however 113 (24%) presented with a CI of b 2.5 L/min/m2, 8% had a right atrial pressure of N 12 mm Hg and 4% had both a CI b2.5 L/min/m2 and a right atrial pressure of N12 mm Hg. Haemodynamics by age groups, aetiology and FC are presented in Tables 2, 3 and 4. Analysis of the haemodynamic profile at diagnosis by age (Table 2) showed a progressive increase in mPAP (p = 0.003), SAP, SVRI and PVRI (all p b 0.001) and a decrease in CI (p b 0.001) and PAP/SAP (p = 0.006) with increase in age after adjusting for aetiology and FC. Table 3 illustrates the haemodynamic profile for different aetiologies and suggests that in patients with PH related to lung diseases a less severe haemodynamic presentation with a lower mPAP, PVRI and a higher CI seems to prevail. The association with aetiology was statistically significant for mPAP, PAP/SAP and PVRI (all p b 0.001) after adjusting for age at diagnosis and FC. There was an association of haemodynamics with FC (Table 4): mPAP (p = 0.005) and PAP/SAP (p = 0.02) increased in relation to higher FC after adjusting for age at diagnosis and aetiology. This association was similar when performing the correlation for the isolated group of iPAH (mPAP: p = 0.025, PAP/SAP: p = 0.017). AVRT was performed in 92% (500/544) of the patients with 34% (185) considered by the local investigator as responders.
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Reported complications observed within 24 h of HC are shown in Table 5. In order to establish a comprehensive set of HC complications, a total of 908 HC (554 diagnostic and 354 follow-up [in 235 patients]), were analysed. 154 patients had 1 follow-up HC, 51 had 2, 21 had 3, 6 had 4 and 2 had 5 follow-up HCs. Death related to diagnostic HC was reported in 5 patients (0.9% of patients and 0.6% of all HCs). Adverse events occurred in 54 (5.9%) of all HCs of which 37 occurred at diagnostic HC. No significant differences were observed between diagnostic (37/554: 6.7%, 5 deaths) and follow-up HCs (17/354: 4.8%, no death) even if slightly lower for the follow-up procedures. The ages of patients who died were 3, 4, 14, 24 months and 15 years; 4 patients had iPAH and 1 was PAH after repair of a ventricular septal defect. FC IV was recorded for 2 patients and III in 3 patients. The reasons for death were cardiac arrest post-HC and complications of extracorporeal membrane oxygenation (ECMO), death at induction of anaesthesia, severe bleeding during HC procedure, progressive heart failure after HC and brain lesions following cardiac arrest during HC. Diagnostic HC was performed under GA in 291 (53%) and under conscious sedation in 257 (47%); no data were available for 6 patients. GA and FC were found to be significant predictors of complications at diagnosis, with complications more likely to occur with GA (26/291 versus 11/257) (p = 0.04) and with higher FC (p = 0.02). GA was most frequently used in b2 years of age. 4. Discussion Important clinical features specific to paediatric PH have been previously identified by TOPP [9]. The analysis of the haemodynamic profile of TOPP patients presented here shows that 88/568 (18%) of patients had to be excluded from the confirmed PH group because of incomplete or inadequate HC data. This illustrates the complexity of haemodynamic evaluation in the paediatric population, characterised by heterogeneous aetiologies such as CHD. It further emphasises the need of meticulous haemodynamic measurement methodologies, in particular because the complication rate of the HC is not insignificant in children. The most frequent reason for incomplete or inadequate HC data was missing data for PVRI calculation, and inappropriate use of thermodilution to estimate cardiac output in the presence of significant intracardiac shunting. The haemodynamic profile at diagnosis in children differs from the one reported in adults [15]. Despite high PAP and high PVRI, children in general have better CI and lower RA pressures, suggesting that right ventricular function remains preserved. However, 24% presented with
Table 2 Haemodynamics at diagnosis by age groups (PH-confirmed population).
No. patients with HC (n) RA pressure (mm Hg) Mean PAP (mm Hg) Mean SAP (mm Hg) Cardiac index (L/min/m2) PAP/SAP PVRI (wood units ∗ m2) SVRI (wood units ∗ m2) PVRI/SVRI
All patients (N = 480)
N3 months to b24 months (N = 92)
2–6 years (N = 145)
7–11 years (N = 109)
12–18 years (N = 134)
472 7.1 (3.77) 0–25 57.8 (18.80) 25–143 68.0 (14.41) 37–113 3.7 (3.74) 1–75 0.9 (0.27) 0.3–2.4 16.6 (11.62) 3–96 20.4 (10.82) 1–89 0.9 (0.60) 0.2–8.3
89 6.5 (3.03) 1–16 49.3 (15.97) 26–88 58.4 (12.84) 37–93 4.1 (2.65) 1–21 0.9 (0.25) 0.3–1.5 12.7 (12.49) 3–89 16.9 (12.29) 3–89 0.8 (0.45) 0.2–3.0
144 7.1 (3.75) 0–21 59.0 (19.00) 25–126 65.1 (13.10) 38–113 4.4 (6.20) 1–75 0.9 (0.30) 0.4–2.4 14.9 (8.33) 3–49 17.0 (8.12) 1–58 1.0 (0.85) 0.2–8.3
106 7.3 (4.21) 0–20 57.0 (17.21) 26–97 69.0 (11.51) 43–103 3.5 (1.46) 1–10 0.8 (0.24) 0.4–1.6 16.3 (11.00) 3–64 20.5 (8.49) 5–60 0.8 (0.36) 0.2–2.4
133 7.2 (3.84) 0–25 62.9 (19.69) 26–143 76.8 (13.82) 40–112 2.9 (0.97) 1–7 0.8 (0.27) 0.3–1.9 21.4 (13.03) 4–96 26.4 (11.54) 9–85 0.8 (0.48) 0.2–4.3
Data are mean (SD) and range unless stated otherwise. RA: right atrial, PAP: pulmonary arterial pressure, SAP: systemic arterial pressure, PVRI: indexed pulmonary vascular resistance; SVRI: indexed systemic vascular resistance.
0.75 (0.328) 0.58–1.33 0.70 (0.341) 0.26–1.74
22 7.8 (3.14) 4–15 49.4 (15.10) 27–78 70.7 (17.83) 40–110 3.30 (1.054) 1.00–5.00 0.73 (0.265) 0.4–1.4 14.25 (8.153) 4.68–31.80 23.10 (17.293) 8.96–85.00 20.43 (10.817) 0.60–88.91
0.87 (0.603) 0.16–8.27
SVRI (wood units ∗ m2)
PVRI/SVRI
PVRI (wood units ∗ m2)
PAP/SAP
SAP (mm Hg) Cardiac index (L/min/m2)
Data are mean (SD) and range unless stated otherwise. RA: right atrial, PAP: pulmonary arterial pressure, SAP: systemic arterial pressure, PVRI: indexed pulmonary vascular resistance; SVRI: indexed systemic vascular resistance. ⁎ Negative values of 95% confidence interval lower limit are rounded to zero as limit of valid range.
0.79 (0.318) 0.24–1.98 0.89 (0.605) 0.21–8.27
20.88 (10.765) 0.60–88.91
20.35 (9.788) 4.67–59.12 0.91 (0.641) 0.17–4.34
20.35 (9.397) 5.45–54.02 0.96 (0.747) 0.17–4.34
19.82 (10.264) 4.67–59.12
2 6.0 (1.41) 5–7 54.5 (12.02) 46–63 68.0 (15.56) 57–79 2.04 (0.588) 1.63–2.46 0.80 (0.007) 0.8–0.8 24.04 (13.852) 14.25–33.84 32.73 (16.354) 21.17–44.30 0.72 (0.064) 0.67–0.76 49 8.1 (3.80) 0–20 55.9 (21.04) 27–143 67.4 (12.55) 48–106 3.81 (2.254) 1.13–11.84 0.83 (0.265) 0.4–1.9 16.11 (12.533) 3.34–62.53 108 6.4 (3.87) 0–25 63.4 (18.37) 26–126 68.4 (15.82) 37–112 3.57 (1.633) 1.37–11.19 0.94 (0.233) 0.4–2.4 17.50 (13.631) 3.20–96.11 159 6.9 (3.89) 0–25 61.0 (19.41) 26–143 68.1 (14.79) 37–112 3.62 (1.846) 1.13–11.84 0.90 (0.247) 0.4–2.4 17.15 (13.259) 3.20–96.11 238 7.1 (3.92) 0–21 59.4 (18.10) 25–106 68.7 (13.47) 39–113 3.69 (4.806) 0.92–75.00 0.88 (0.278) 0.3–1.9 17.72 (11.128) 3.33–88.69
48 6.8 (2.81) 2–14 43.1 (14.45) 26–81 61.5 (14.23) 38–95 4.41 (3.119) 1.50–20.93 0.72 (0.236) 0.3–1.2 10.04 (6.872) 3.31–37.06 16.13 (8.726) 3.20–38.77 0.73 (0.559) 0.16–3.95 472 7.1 (3.77) 0–25 57.8 (18.80) 25–143 68.0 (14.41) 37–113 3.71 (3.744) 0.92–75.00 0.86 (0.269) 0.3–2.4 16.60 (11.620) 3.20–96.11 No. patients with HC (N) RA pressure (mm Hg) PAP (mm Hg)
APAH excluding APAH–CHD (N = 23) Never had shunt (N = 2)⁎ Repaired shunt (N = 50) Shunt (unrepaired/partial repair) (N = 109) All CHD (N = 161) iPAH/FPAH (N = 243) Group 3 PH (N = 48) All patients (N = 480)
Table 3 Haemodynamics at diagnosis by aetiologies (PH-confirmed population).
5 7.8 (3.56) 3–13 59.4 (11.59) 48–77 80.2 (15.80) 59–102 3.09 (1.359) 1.53–4.47 0.78 (0.296) 0.6–1.3 19.16 (8.532) 10.43–31.42 28.51 (15.696) 12.57–49.75
M. Beghetti et al. / International Journal of Cardiology 203 (2016) 325–330 Groups 4 and 5 (N = 5)
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low CI, and 4% together with high RA pressure (N 12 mm Hg). This difference between adults and children was previously described in a registry (REVEAL) including adults and children but in a smaller population [10]. A gradual worsening of haemodynamic values was observed with increased age, e.g., adolescents over 12 years of age presented with a lower CI. This may disclose a different presentation of the disease with age. A further difference in haemodynamics was seen in patients with PH related to lung diseases. They present with a better haemodynamic profile than iPAH or CHD (lower mPAP and PVRI). This finding is consistent with studies in adults with PH related to lung disease, which also have a lower mPAP if compared with patients with iPAH [16,17]. Patients with PH related to lung diseases are of particular interest and may be underreported and are currently not well investigated. It is possible that patients in this group less frequently undergo haemodynamic assessment, but this information is still considered of utmost importance particularly if treatment with PAH specific drugs is considered. HC may also display unrecognised problems such as anomalies of pulmonary veins or other cardiovascular abnormalities such as aortopulmonary collaterals [18,19]. A total of 908 HCs (diagnostic and follow-up procedures) were analysed, demonstrating an incidence of complications of 5.9% including 5 deaths (0.6%) (Table 5). Taylor et al. reported a higher rate of 6% cardiac arrest or death in a series of 75 consecutive HC in children with PH [20]. In this single-centre study all patients were catheterised under GA which may raise the question whether GA is associated with and may be a risk factor for complications as suggested previously [20]. Another study disclosed a 5% rate for major complications with a 1.4% mortality rate [21]. Data from the MAGIC Registry suggests a similar rate of adverse events (3.9%) as TOPP with no procedural deaths in 217 paediatric patients [22]. The risk for adverse events was primarily related to patients with “supra-systemic” mPAP. Zuckerman et al. reported a complication rate of 5.7% and a mortality rate of 0.2% in a population of children and adults with PH [23]. A recent single-centre report of 97 HCs in 75 children with PH reported a similar rate (6.2%) of complications [6,24]. Comparing the above-mentioned paediatric and adult data, it seems that the rate of complications is higher in children: Hoeper et al. reported only 1.1% complications in 7218 adult HCs, with similar complications to those reported in our registry [25]. This may reflect lower risk in adults. Within the Congenital Cardiac Catheterization Outcome Project (C3PO) complications varied between 10% and 20% in a cohort of children undergoing diagnostic or interventional HC, with high severity events (including death) of 2–5%. The group at higher risk was undergoing interventional HC. Lower age and haemodynamic vulnerability were significant risk factors [11,12]. The complication rate in our study, for a pure population with PH, is lower than the general rate considering that our group can be considered as a high-risk group with haemodynamic vulnerability. GA was also reported to be a risk factor of HC complication in a different large series of paediatric PH HCs [23]. The risk of GA was recently confirmed also in a group of patients already treated with targeted therapies [26]. Younger age was seen to be a risk factor by Zuckerman et al.; however, in our registry when adjusted for age only GA remained significant taking into account that most very young patients were done under GA [23]. The challenge remains to perform HC safely in a very young child but avoiding hypoxia and agitation without the use of GA. GA and a higher FC at time of HC seem to be the most important risk factors for mortality and morbidity. We believe that HC should remain the gold standard for diagnosis and should be performed in all suitable patients. The identification of GA as a risk factor for complications and death requires a thorough evaluation of pre- and post-anaesthetic care of paediatric patients with pulmonary hypertension, which has been reviewed recently [27]. The literature on this subject still shows discrepancies due to the retrospective design, the limited number of patients
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Table 4 Haemodynamics at diagnosis by functional class (PH-confirmed population).
No. patients with HC (n) RA pressure (mm Hg) Mean pulmonary arterial pressure (mm Hg) Systemic arterial pressure (mm Hg) Cardiac index (L/min/m2) PAP/SAP PVRI (wood units ∗ m2) SVRI (wood units ∗ m2) PVRI/SVRI
All patients (N = 480)
Class I (N = 62)
Class II (N = 227)
Class III (N = 158)
Class IV (N = 33)
472 7.1 (3.77) 0–25 57.8 (18.80) 25–143 68.0 (14.41) 37–113 3.7 (3.74) 1–75 0.9 (0.27) 0.3–2.4 16.6 (11.62) 3–96 20.4 (10.82) 1–89 0.9 (0.60) 0.2–8.3
62 6.5 (2.94) 0–14 49.1 (15.74) 25–83 63.9 (13.86) 38–103 3.7 (1.54) 1–12 0.8 (0.21) 0.4–1.3 13.1 (11.61) 3–89 18.5 (11.61) 5–89 0.7 (0.26) 0.2–1.3
226 7.0 (3.90) 0–25 57.8 (19.66) 25–143 68.2 (14.59) 38–112 3.6 (1.61) 1–11 0.9 (0.28) 0.4–1.9 16.9 (12.48) 3–96 20.2 (10.55) 5–85 0.9 (0.58) 0.2–4.3
155 7.1 (3.43) 1–17 60.7 (17.36) 26–126 68.9 (14.17) 37–112 4.0 (6.14) 1–75 0.9 (0.27) 0.3–2.4 17.1 (9.85) 3–49 21.2 (10.51) 1–59 0.9 (0.75) 0.2–8.3
29 8.9 (5.43) 0–21 61.3 (20.49) 27–103 70.4 (14.71) 44–113 3.4 (1.48) 1–8 0.9 (0.30) 0.4–1.6 19.0 (12.54) 4–56 22.5 (12.45) 6–59 0.9 (0.32) 0.3–1.7
Data are mean (SD) and range unless stated otherwise. RA: right atrial, PAP: mean pulmonary arterial pressure, SAP: mean systemic arterial pressure, PVRI: indexed pulmonary vascular resistance. SVRI: indexed systemic vascular resistance.
and procedures, and different aetiologies [6,23,24,27–29]. These procedures should include an experienced anaesthetic team with availability of inhaled vasodilators such as nitric oxide to treat pulmonary hypertensive crisis and mechanical support (ECMO) should the patient present with cardiac arrest [6,23,28,29]. Further a “balanced” approach to general anaesthesia and analgesia minimises the lowering of systemic vascular resistance, increase in pulmonary vascular resistance and depression of myocardial function. Limitation of inhaled gas and avoidance of bolus infusion of most medication is essential. A knowledge of all potential haemodynamic effects of the anaesthetic agents is mandatory to avoid complications [29]. There is no ideal anaesthetic agent but a team approach seems mandatory. Finally the post-anaesthetic management is essential as complications may appear following recovery of anaesthesia, as seen in most of the deaths reported in our study. Respiratory depression, and airway obstruction stimulate pulmonary hypertensive crises, through hypoventilation and hypoxia. Most patients should be admitted to an ICU or step down unit for post-procedure observation and should be discharged when the effects of anaesthesia and sedatives are worn off or no longer needed. Based on these considerations, the authors feel that HC procedures, especially in young and sicker infants with PH should be carried out in centres with extensive expertise in performing the procedure. Based on our findings, a recommendation may be derived that patients in FC IV should be first treated aggressively (double or triple combination therapy) to achieve stabilisation before proceeding to the invasive haemodynamic assessment. This is supported by
Bobhate et al. in a recent single-centre study including 75 patients with PH [6]. Furthermore, in the current study, the initial HC before initiation of therapy was associated with a slightly greater risk than a follow-up catheterisation on PH-targeted medications, although this did not reach statistical significance. However, it is confirmed by recent reports supporting that the follow-up HC may provide important information to adapt the therapeutic strategy [6,30]. In about 30% of the studied children, local physicians considered the response to AVRT “positive”, but criteria or test protocols to define positive a response are lacking, and interpretation differed between sites. The appropriate criteria for acute responders in children with PAH are currently debated [31]. It is unclear whether the response criteria, defined and modified by Barst specifically for children [32], or the criteria defined by Sitbon for adults [33], are most valuable in children with PAH. This needs to be clarified and requires further work in this population. 5. Limitations The TOPP Registry is a prospective observational registry with associated limitations. Inclusion criteria for the registry and for the current study included invasive haemodynamic data confirming the diagnosis PH. Although this has resulted in a well-described disease status in the patients in the cohort, this might have introduced a selection bias with severe patients
Table 5 Complications at heart catheterisation.
Relevant complications (total) Hypotension requiring intervention Inotropic support required Pulmonary hypertensive crisis Unexpected ICU admission after procedure Other Cardiac arrest Arrhythmia requiring intervention Death Pulmonary haemorrhage Cardiac perforation Pericardial effusion Stroke
Patients (n = 555)
All catheterisations (n = 908)
Diagnostic catheterisations (n = 554)
Follow-up catheterisations (n = 354)
51 (9.2%) 20 (3.6%) 16 (2.9%) 14 (2.5%) 12 (2.2%) 12 (2.2%) 10 (1.8%) 8 (1.4%) 5 (0.9%) 2 (0.4%) 1 (0.2%) 1 (0.2%) 1 (0.2%)
54 (5.9%) 20 (2.2%) 16 (1.8%) 14 (1.5%) 12 (1.3%) 12 (1.3%) 10 (1.1%) 8 (0.9%) 5 (0.6%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 1 (0.1%)
37 (6.7%) 17 (3.1%) 14 (2.5%) 10 (1.8%) 7 (1.3%) 5 (0.9%) 5 (0.9%) 4 (0.7%) 2 (0.6%) 1 (0.2%) 0 0 0
17 (4.8%) 3 (0.8%) 2 (0.6%) 4 (1.1%) 5 (1.4%) 7 (2%) 5 (1.4%) 4 (1.1%) 3 (0.8%) 1 (0.3%) 1 (0.3%) 1 (0.3%) 1 (0.3%)
330
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not enrolled because HC has been considered too high risk for some of these patients. In theory, this may also have led to underreporting of complications of death during the procedure prohibiting the collection of haemodynamic data, leading to non-inclusion. Further, there was no predefined protocol used for performing HC in the TOPP Registry. This could induce differences in data between centres. For instance, AVRT was performed using different protocols and different response criteria in the various centres, limiting the value of the reported prevalence of acute responders in this cohort. The decision to include referral centres only for paediatric PH for recruitment in this registry may also have induced some bias with more severe patients referred to these expert centres (increasing the risk of complications). It is also possible that HC performed in patients not referred to expert centres present a higher risk of complications during invasive procedures. Nevertheless, these data reflect current era “real-life” practice in centres treating children with PH worldwide and underscore the importance of standardised invasive haemodynamic assessment in this population. The significance of the data is derived from the largest sample size of HC data in paediatric PH patients reported so far and the data reveal unique haemodynamic presentation of PH in paediatrics.
[5]
[6] [7]
[8]
[9] [10]
[11] [12]
[13]
6. Conclusion
[14]
In this large sample size of invasive haemodynamics in paediatric PH, it becomes evident that most of the children with PH present with preserved CI and normal RA pressure even in the presence of severe PH. Nevertheless, 24% presented with a CI of b 2.5 L/min × m2. There is an apparent increase in mPAP and PVRI with age reaching similar values as in adults. A correlation between mPAP with FC is apparent. The use of GA was associated with higher risk of complications. In addition, complications related to HC showed a higher incidence compared with current adult data but lower than in interventional paediatric HC, with patients with FC IV being at higher risk. As the complication rate is not negligible, we recommend performing HC in expert centres.
[15]
Funding
[21]
The TOPP Registry is supported by a funding from Actelion Pharmaceuticals Ltd. Actelion does not participate in the management of the Registry, nor does it have access to the database, the individual sites and patient data. All Registry-related decisions lie solely with the Executive Board of the Association for Pediatric Pulmonary Hypertension.
[22]
[16]
[17]
[18]
[19] [20]
[23]
[24]
Conflict of interest [25]
No disclosures are reported in association to the content of this manuscript. Acknowledgements We thank Katherine Hutchinson, Jeremy Wheeler and Emily Wood, Quanticate UK, for statistical analysis and Rita Locher, Project Manager, for continuous organisational support. This manuscript was written by the investigators. References [1] D.D. Ivy, S.H. Abman, R.J. Barst, et al., Pediatric pulmonary hypertension, J. Am. Coll. Cardiol. 62 (2013) D117–D126. [2] N. Galie, M.M. Hoeper, M. Humbert, et al., Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT), Eur. Heart J. 30 (2009) 2493–2537. [3] M. Beghetti, R.M. Berger, I. Schulze-Neick, et al., Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice, Eur. Respir. J. 42 (2013) 689–700. [4] V.V. McLaughlin, S.L. Archer, D.B. Badesch, et al., ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology
[26]
[27]
[28] [29]
[30]
[31]
[32]
[33]
Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association, J. Am. Coll. Cardiol. 53 (2009) 1573–1619. W.M. Zijlstra, J.M. Douwes, E.B. Rosenzweig, et al., Survival differences in pediatric pulmonary arterial hypertension: clues to a better understanding of outcome and optimal treatment strategies, J. Am. Coll. Cardiol. 63 (2014) 2159–2169. P. Bobhate, L. Guo, S. Jain, et al., Cardiac catheterization in children with pulmonary hypertensive vascular disease, Pediatr. Cardiol. 36 (2015) 873–879. D.D. Ivy, E.B. Rosenzweig, J.C. Lemarie, M. Brand, D. Rosenberg, R.J. Barst, Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings, Am. J. Cardiol. 106 (2010) 1332–1338. T.F. Feltes, E. Bacha, R.H. Beekman III, et al., Indications for cardiac catheterization and intervention in pediatric cardiac disease: a scientific statement from the American Heart Association, Circulation 123 (2011) 2607–2652. R.M. Berger, M. Beghetti, T. Humpl, et al., Clinical features of paediatric pulmonary hypertension: a registry study, Lancet 379 (2012) 537–546. R.J. Barst, M.D. McGoon, C.G. Elliott, A.J. Foreman, D.P. Miller, D.D. Ivy, Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management, Circulation 125 (2012) 113–122. L. Bergersen, K. Gauvreau, A. Marshall, et al., Procedure-type risk categories for pediatric and congenital cardiac catheterization, Circ. Cardiovasc. Interv. 4 (2011) 188–194. L. Bergersen, A. Marshall, K. Gauvreau, et al., Adverse event rates in congenital cardiac catheterization — a multi-center experience, Catheter. Cardiovasc. Interv. 75 (2010) 389–400. G. Simonneau, N. Galie, L.J. Rubin, et al., Clinical classification of pulmonary hypertension, J. Am. Coll. Cardiol. 43 (2004) 5s–12s. C.G. LaFarge, O.S. Miettinen, The estimation of oxygen consumption, Cardiovasc. Res. 4 (1970) 23–30. M. Humbert, O. Sitbon, A. Chaouat, et al., Pulmonary arterial hypertension in France: results from a national registry, Am. J. Respir. Crit. Care Med. 173 (2006) 1023–1030. J. Hurdman, R. Condliffe, C.A. Elliot, et al., ASPIRE Registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre, Eur. Respir. J. 39 (2012) 945–955. M.M. Hoeper, S. Andreas, A. Bastian, et al., Pulmonary hypertension due to chronic lung disease: updated recommendations of the Cologne Consensus Conference 2011, Int. J. Cardiol. 154 (Suppl. 1) (2011) S45–S53. M.J. del Cerro, A. Sabate Rotes, A. Carton, et al., Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes, Pediatr. Pulmonol. 49 (2014) 49–59. T.J. Kulik, L.M. Rhein, M.P. Mullen, Pulmonary arterial hypertension in infants with chronic lung disease: will we ever understand it? J. Pediatr. 157 (2010) 186–190. C.J. Taylor, G. Derrick, A. McEwan, S.G. Haworth, M.R. Sury, Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension, Br. J. Anaesth. 98 (2007) 657–661. G.D. Williams, H. Maan, C. Ramamoorthy, et al., Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine, Paediatr. Anaesth. 20 (2010) 28–37. K.D. Hill, D.S. Lim, A.D. Everett, D.D. Ivy, J.D. Moore, Assessment of pulmonary hypertension in the pediatric catheterization laboratory: current insights from the Magic Registry, Catheter. Cardiovasc. Interv. 76 (2010) 865–873. W.A. Zuckerman, M.E. Turner, J. Kerstein, et al., Safety of cardiac catheterization at a center specializing in the care of patients with pulmonary arterial hypertension, Pulm. Circ. 3 (2013) 831–839. M.J. Carmosino, R.H. Friesen, A. Doran, D.D. Ivy, Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization, Anesth. Analg. 104 (2007) 521–527. M.M. Hoeper, S.H. Lee, R. Voswinckel, et al., Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers, J. Am. Coll. Cardiol. 48 (2006) 2546–2552. K. Taylor, D. Moulton, X.Y. Zhao, P. Laussen, The impact of targeted therapies for pulmonary hypertension on pediatric intraoperative morbidity or mortality, Anesth. Analg. 120 (2015) 420–426. D.F. Chau, M. Gangadharan, L.P. Hartke, M.D. Twite, The post-anesthetic care of pediatric patients with pulmonary hypertension, Seminars in Cardiothoracic and Vascular Anesthesia (2015). http://dx.doi.org/1089253215593179 (E-pub ahead of print). A.C. Shukla, M.C. Almodovar, Anesthesia considerations for children with pulmonary hypertension, Pediatr. Crit. Care Med. 11 (2010) S70–S73. M.D. Twite, R.H. Friesen, The anesthetic management of children with pulmonary hypertension in the cardiac catheterization laboratory, Anesthesiol. Clin. 32 (2014) 157–173. M.J. Ploegstra, J.M. Douwes, M.T. Roofthooft, W.M. Zijlstra, H.L. Hillege, R.M. Berger, Identification of treatment goals in paediatric pulmonary arterial hypertension, Eur. Respir. J. 44 (2014) 1616–1626. J.M. Douwes, R.L. van Loon, E.S. Hoendermis, et al., Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria, Eur. Heart J. 32 (2011) 3137–3146. R.J. Barst, G. Agnoletti, A. Fraisse, J. Baldassarre, D.L. Wessel, Vasodilator testing with nitric oxide and/or oxygen in pediatric pulmonary hypertension, Pediatr. Cardiol. 31 (2010) 598–606. O. Sitbon, M. Humbert, X. Jais, et al., Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension, Circulation 111 (2005) 3105–3111.