Since its initial description in 1971, the Fontan procedureReference Fontan and Baudet 1 has undergone significant modifications in patient preparation, surgical technique, and postoperative management, which have reduced both mortality and postoperative hospital stay.Reference Hirsch, Goldberg and Bove 2 – Reference Khairy, Fernandes and Mayer 4
Nevertheless, after the modified Fontan procedure, there is still a significant percentage of patients with a prolonged postoperative length of stay.Reference Hirsch, Goldberg and Bove 2 , Reference Salvin, Scheurer and Laussen 5 One of the risk factors contributing to morbidity after surgery is the elevation of pulmonary vascular resistance.Reference Rogers, Glatz and Ravishankar 3 , Reference Knott-Craig, Danielson, Schaff, Puga, Weaver and Driscoll 6 , Reference Gentles, Mayer and Gauvreau 7 In the early postoperative period, pulmonary vascular resistance is more labile owing to pulmonary endothelial dysfunction after cardiopulmonary bypass. In this condition, even minor pulmonary vascular resistance elevations may lead to serious reduction in pulmonary flow and a low cardiac output syndrome. In this sense, maintenance of a low pulmonary vascular resistance becomes a priority during the immediate postoperative period.
In recent years, growing attention has been paid to the usefulness of pulmonary vasodilators in patients with Fontan circulation.Reference Beghetti 8 – Reference Beghetti and Tissot 10 Nevertheless, to date, there are no studies that have assessed the usefulness of oral sildenafil during the immediate postoperative period after the modified Fontan procedure.
Materials and methods
Patients
Between January, 2010 and March, 2013, 16 patients with univentricular physiology, who had previously undergone a bidirectional Glenn operation, underwent the modified Fontan procedure at our centre.
Demographic, anatomic, haemodynamic, procedural, and postoperative variables were recorded from the medical records (Table 1).
Clinical, haemodynamic, preoperative, and postoperative characteristics of the study cohorts.
AV=atrioventricular, CPB=cardiopulmonary bypass; EDVP=end diastolic ventricular pressure; HLHS=hypoplastic left heart syndrome; mPAP=mean pulmonary artery pressure; PICU=paediatric ICU; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient; WU=Wood units
Data are expressed as n (%), mean±standard deviation or median [interquartile range]
All patients were catheterised in the preceding 6-month period before the Fontan procedure. We collected data on the surgical techniques used, such as extracardiac or lateral tunnel Fontan, surgery with cardiopulmonary bypass, cross-clamping and circulatory arrest, surgical times, and associated procedures. Postoperative Fontan and left atrial pressure were monitored and transpulmonary gradient was calculated. We collected data on the duration of postoperative pleural effusions, mechanical ventilation time, length of stay in the paediatric ICU, and length of hospital stay. We also recorded immediate postoperative complications and mortality.
Study design
The 16 patients of the study – postoperative pulmonary vasodilator group – received oral sildenafil with an average dose of 4.6±1.6 mg/kg/day in three divided doses. Treatment began during the first 24 hours following operation and continued at least until hospital discharge. Treatment cessation was decided by the responsible cardiologist, but always on the base of a stable clinic situation after Fontan surgery and never before the closure of the fenestration, when it had been made. Average treatment duration after surgery was 10 months [interquartile range 7–22]. If the patient remained intubated 12 hours after surgery, he/she also received inhaled nitric oxide until extubation. Of the patients, six received a maximum inhaled nitric oxide dose of 20 ppm during 36 hours [interquartile range 8.5–78]. There were no adverse effects of the medication.
This group was compared with our previously publishedReference Mendoza, Albert and Ruiz 11 historical cohort of 32 patients operated between March, 2000 and December, 2009 (control group).
The local ethics committee approved the study protocol. Informed consent was obtained from the parents of all patients.
Statistical analysis
Continuous variables were expressed as means (standard deviations) or medians [interquartile range]. Categorical variables are shown as frequencies and percentages. Student’s t-test was used for between-group comparisons with normally distributed continuous variables. The Mann–Whitney test was used for variables showing a non-normal distribution. Linear regression was used to analyse correlations between continuous variables. Comparisons between categorical variables were made using the χ2-test or Fisher’s exact test. Data were analysed using SPSS 20.0 (SPSS Inc., Chicago, Illinois, United States).
Results
There were no significant differences in the clinical characteristics or catheterisation data between the postoperative pulmonary vasodilator and control groups. Regarding the surgical variables, in the postoperative pulmonary vasodilator group, there were no patients with lateral tunnel Fontan, and the percentage of patients who underwent surgery without cardiopulmonary bypass was significantly greater than the control group. Regarding postoperative variables, there were no significant differences between the prophylactic vasodilator and control groups (Table 1). No patient in the postoperative pulmonary vasodilator group died.
Discussion
Different studies have shown that the main determinants of cardiac output after the Fontan procedure are: the cavopulmonary connection itself,Reference Sundareswaran, Pekkan and Dasi 12 the size of the pulmonary arteries,Reference Dasi, KrishnankuttyRema and Kitajima 13 and pulmonary vascular resistance.Reference Gewillig, Brown and Eyskens 14
With regard to the cavopulmonary connection, it seems connection geometry,Reference Bove, de Leval, Migliavacca, Guadagni and Dubini 15 conduit size,Reference Itatani, Miyaji and Tomoyasu 16 or connection typeReference Stewart, Pasquali and Jacobs 17 – lateral tunnel versus extracardiac conduit – not only influence haemodynamics but also clinical evolution after the Fontan procedure.
Other studies have found that the area of the pulmonary arteries correlates with cardiac output.Reference Dasi, KrishnankuttyRema and Kitajima 13 Moreover, theoretical models have been calculated for the minimum area of pulmonary arteries compatible with a low-pressure Fontan.Reference Itatani, Miyaji, Nakahata, Ohara, Takamoto and Ishii 18
Nevertheless, most authors support the fact that pulmonary vascular resistance is the major determining factor of cardiac output and clinical evolution in patients with Fontan physiology.Reference Gewillig, Brown and Eyskens 14 Supporting this theory, on the one hand, is the fact that in most series preoperative and postoperative pressures and pulmonary vascular resistance accounted for the main morbidity and mortality risk factors.Reference Salvin, Scheurer and Laussen 5 – Reference Gentles, Mayer and Gauvreau 7 , Reference Mendoza, Albert and Ruiz 11 In a recent study,Reference Rogers, Glatz and Ravishankar 3 the cut-off point that predicted bad postoperative evolution was a mean pulmonary artery pressure of ⩾15 mmHg during catheterisation before surgery. On the other hand, the anatomopathological study on lungs in patients with failed Fontan shows a high rate of alterations in pulmonary vasculatureReference Mitchell, Campbell and Ivy 19 characterised by medial hypertrophy in the preacinar arteriolesReference Yamaki, Ajiki, Haneda, Takanashi, Ban and Takahashi 20 and muscularisation of the intraacinar arteries.Reference Lévy, Danel, Tamisier, Vouhé and Leca 21
During early postoperative period, labile pulmonary vascular resistance may predispose to increase in pulmonary pressures leading to low output and Fontan failure, despite a technically successful procedure. This elevation of pulmonary vascular resistance is due to endothelial dysfunction after the cardiopulmonary bypass mediated by a reduction in the endogenous nitric oxide production of the pulmonary endothelial cells and subsequent local reduction of its vasodilator effect,Reference Törnberg, Angdin, Settergen, Liska, Lundberg and Weitzberg 22 , Reference Lévy, Danel, Laval, Leca, Vouhé and Israël-Biet 23 along with an increase in endothelin levels acting as a pulmonary vasoconstrictor, the levels of which have been correlated with pulmonary vascular resistance in patients during postoperative Fontan.Reference Hiramatsu, Imai and Takanashi 24
Evidence that pulmonary vasculature plays a critical role in univentricular circulation functioning has fostered growing interest in the use of pulmonary vasodilators in Fontan patients.Reference Beghetti 8
Both inhaled nitric oxide and sildenafil are powerful pulmonary vasodilators that have demonstrated their effectiveness in treating pulmonary hypertension in biventricular heart patients.Reference Journois, Baufreton, Mauriat, Pouard, Vouhé and Safran 25 , Reference Barst, Ivy and Gaitan 26
Different studies have proven the usefulness of inhaled nitric oxide during immediate postoperative period after the Fontan procedure in patients with reduced pulmonary perfusion because of high pulmonary vascular resistance. In these studies, inhaled nitric oxide administration reduced the pressure in Fontan, the transpulmonary gradient, and improved oxygenation.Reference Gamillscheg, Zobel and Urlesberger 27 , Reference Goldman, Delius and Deanfield 28 However, it seems that the response is not identical in all patients and is greater in those with oxygen saturation <85%, pulmonary vascular resistance >2 UW·m2, Fontan pressure ⩾15 mmHg, and transpulmonary gradient ⩾8 mmHg.Reference Goldman, Delius and Deanfield 28 – Reference Yoshimura, Yamaguchi and Oka 30 One of the problems associated with the use of inhaled nitric oxide is the rebound effect of pulmonary pressures after suspension. Combined administration with a phosphodiesterase inhibitor such as milrinone not only blocks this rebound but also boosts the pulmonary vasodilator effect of both drugs in postoperative Fontan.Reference Cai, Su and Shi 31
Sildenafil has also demonstrated its effectiveness in reducing Fontan postoperative pressure in patients with O2 saturations ⩽85%, Fontan pressure ⩾16 mmHg, or prolonged pleural effusion ⩾2 weeks,Reference Uhm, Jhang, Park, Seo, Yun and Yung 32 as well as in patients with failed Fontan.Reference Morchi, Ivy, Duster, Claussen, Chan and Kay 33 Isolated cases have been published where sildenafil improved the evolution of serious Fontan complications such as plastic bronchitisReference Haseyama, Satomi, Yasukochi, Matsui, Harada and Uchita 34 or protein-losing enteropathy.Reference Uzun, Wong, Bhole and Stumper 35 Furthermore, different studies have demonstrated that sildenafil improves exercise capacity and cardiac output in patients with Fontan circulation.Reference Goldberg, French, McBride, Marino, Mirarchi and Hanna 36 – Reference Jackson, Butts, Svenson, McQuinn and Atz 38
Our study is the first to assess the usefulness of pulmonary vasodilators administered to non-selected patients after the Fontan procedure. A similar studyReference Harada, Uchita and Sakamoto 9 administered inhaled nitric oxide from the end of the cardiopulmonary bypass until extubation, followed by oral pulmonary vasodilators when digestive tolerance began, with good postoperative results. However, in that study, there was no control group. Beraprost was administered to the majority of patients and sildenafil to only three patients.
The absence of pulmonary vasodilator effects on the postoperative evolution of our Fontan patients may be due to several factors. On the one hand, given the short intubation period, only six patients received nitric oxide. On the other hand, sildenafil administration commenced in the initial hours, in most cases via nasogastric tube. It is highly likely that drug absorption was erratic during the first few days owing to paralytic ileus secondary to the surgery and the low oral intake during the first few postoperative days. Intravenous sildenafil could have been an alternative treatment, but it was not available for us at the beginning of the study.
Fontan surgery was performed at a relatively old age – five and a half years –in our series, what possibly enhanced the appearance of collateral circulation. Other studiesReference Glatz, Rome and Small 39 have related this increased collateral circulation to higher pressures in the Fontan surgery and longer duration of pleural effusions, necessitating drainages for a longer time period, what could explain the higher incidence of infections. This circumstance could have acted as a confounding factor.
As shown by some studies, there is also the possibility that pulmonary vasodilators are only useful in patients with critically reduced pulmonary perfusion after the Fontan procedure.Reference Goldman, Delius and Deanfield 28 – Reference Yoshimura, Yamaguchi and Oka 30
Study limitations
The main limitations of the study are: the small sample size and the fact that the control group is a historical cohort not contemporary with the study group. Nevertheless, both samples are very similar in most of the variables analysed. Similarly, preoperative and postoperative treatment of these patients did not suffer significant variations between both periods.
Conclusion
The systematic administration of pulmonary vasodilators after the Fontan procedure does not improve early postoperative evolution in these patients.
Acknowledgements
None.
Financial Support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflict of interest
None.
Ethical Standards
The study was conducted in accordance with the principles of Good Clinical Practice (ICH, 1996) and the Declaration of Helsinki (WMA, 2008) and has been approved by the local ethics committee.
