tipology:research-article

numero rivista e pagine: HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2011; 3(2): 123-130
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Efficacy of inhaled iloprost in the management of pulmonary hypertension after cardiopulmonary bypass in infants undergoing congenital heart surgery. A case series of 31 patients

Authors: M. Müller*1, S. Scholz1, H. Maxeiner1, F. Brenck1, K. Valeske2, J. Thul3, H. Akintürk2

1Departments of Anesthesiology and Intensive Care Medicine, University Hospital Giessen and Marburg GmbH, Campus Giessen
2Departments of Cardiac Surgery, University Hospital Giessen and Marburg GmbH, Campus Giessen
3Departments of Paediatric Cardiology Paediatric Heart Center Giessen, University Hospital Giessen and Marburg GmbH, Campus Giessen

Corresponding author: * Corresponding author:
PD Dr. med. Matthias Muller
Department of Anaesthesiology and Intensive Care Medicine,
Pediatric Heart Center Giessen
University Hospital Giessen und Marburg GmbH, Campus Giessen
Rudolf-Buchheim-Str. 7, 35392 Giessen, Germany
E-mail: matthias.f.mueller@chiru.med.uni-giessen.de

ABSTRACT

INTRODUCTION: 

Reactive pulmonary hypertension is frequent in children with high pulmonary flow and pressure. Inhaled iloprost and nitric oxide are the only substances approved as selective pulmonary vasodilators, but data about the effectiveness and safety of inhaled iloprost during cardiac surgery in infants and children are limited.

METHODS: 

We retrospectively analysed the effects of inhaled iloprost after cardiopulmonary bypass weaning on the ratio of mean pulmonary artery to mean arterial pressure. The effectiveness of the inhalation set up was tested in an in vitro study.

RESULTS: 

Thirty-one patients received inhaled iloprost during surgery. The clinically used inhalation set up for inhaled iloprost delivered 20% to 30% (500 to 750 ng * kg-1) of the nebulizer dose and caused a decrease in the ratio of mean pulmonary artery to mean arterial pressure from 0.6±0.2 to 0.4±0.1 and 0.4±0.1 (30 and 60 minutes after)p <0.05. In eleven (35%) patients norepinephrine infusion was started.

CONCLUSION: 

Our data suggest that a single dose of inhaled iloprost significantly decreases the ratio of mean pulmonary artery to mean arterial pressure for at least 60 min. Vasopressor support may be indicated to avoid systemic hypotension. The filled dose in the nebulizer should be high enough to compensate for the high depletion rate of the pediatric inhalation system. However, our study allows no final decision about beneficial or detrimental effects of the off label use of inhaled iloprost to reduce pulmonary artery pressure during congenital heart surgery.

 

Keywords: pediatric heart surgery, pulmonary hypertension, iloprost, inhalation therapy

Introduction

Impaired endothelium-dependant vasodilatation is frequently present in children with high pulmonary flow and pressure which might be exacerbated by cardiopulmonary bypass (CPB) leading to pulmonary hypertensive crisis [1].
This acute increase in pulmonary artery resistance and pressure has been associated with an increase in postoperative morbidity and mortality after congenital heart surgery [2,3,4]. Systemic vasodilators have been used to control pulmonary hypertension after cardiac surgery in children [5]. However, the use of inhaled selective pulmonary vasodilators seem to be advantageous after weaning of CPB because of their minor effects on systemic vascular resistance [6], and transpulmonary shunt fraction. Although inhaled nitric oxide (iNO) is widely used to decrease pulmonary vascular resistance in infants undergoing congenital heart surgery [7], the effects of iNO vary among patients and complex apparatuses are necessary to administer the substance safely [8,9]. Furthermore, the approval by the Drug and Food Administration has increased the costs of treatment with licensed iNO. Iloprost, a stable carbacyclin derivate of prostaglandin I2 has been approved in Europe for chronic inhalation therapy in adult patients with pulmonary hypertension. But only preliminary reports are available about the effects of inhaled iloprost (iIlo) in infants at risk of pulmonary hypertension during congenital heart surgery [10, 11]. Because an increase in pulmonary vascular resistance after weaning off CPB is critical in patients with impaired endothelium-dependent vasodilatation, we sought to evaluate the effectiveness and potential side effects of iIlo in decreasing pulmonary artery pressure during pediatric cardiac surgery. Our hypothesis is that iILo can be used after weaning off CPB to decrease pulmonary artery pressure without serious side effects.

 

Methods

Approval for a retrospective case-note review was obtained from the local ethics committee.
An anesthetic information management system (AMS) NarcoData (IMESO GmbH, Hüttenberg, Germany) was used to identify all infants and children who had: 1)congential heart surgery associated with an increased risk of post-CPB pulmonary hypertension (closure of common atrium, ventricular or atrioventricular septal defects, correction of total anomalous pulmonary venous return, bidirectional cavopulmonary connection (BCPC) or total cavopulmonary connection (TCPC) in uni-ventricular hearts, and cardiac transplantation), and 2) received iIlo or iNO after weaning from cardiopulmonary bypass during congenital heart surgery at the Pediatric Heart Centre Giessen from November 01. 2002 to November 01. 2005.
Anesthesia and hospital records were reviewed from all patients treated with iIlo to obtain demographic and perioperative data including dose and timing of iIlo therapy, hemodynamic data including vasoactive and inotropic support, as well as postoperative outcome. Anesthesia and Surgery were carried out following our routine clinical procedures including ventilation with 100% oxygen during and after weaning off cardiopulmonary bypass (CPB) and have been published elsewhere [10].
As a part of our clinical standard, an indwelling 3F pulmonary artery catheter was inserted in the main pulmonary artery before weaning off CPB in infants at risk of postoperative pulmonary hypertensiv crisis. In patients with BCPC or TCPC, pulmonary artery pressures were measured via the vena jugularis catheter. At the pediatric heart center giessen a mean pulmonary artery pressure (MPAP) >25 mmHg after biventricular repair, and a MPAP > 18 mmHg or oxygen saturation <80 % in patients with hemi-fontan or fontan circulation is accepted as indication for pulmonary vasodilators. Furthermore norepnephrine is indicated when mean arterial pressure (MAP) was <45 mmHg despite adequate preload and contractility juged by central venous pressure, transesophageal echocardiografy and direct visualisation of the heart.
The hemodynamic readings from vital data monitors and lung ventilator data were continuously recorded in three minute intervals by the AMS. Great importance was attached to analyse the exact timing of all interventions affecting pulmonary circulation (mechanical ventilation with oxygen, administration of milrinone, inhalation of iloprost). To allow comparison of the concomitant vasoactive therapy a vasoactive-inotropic score described by Gaies et al. was used [12]. The time course of all interventions is shown in figure 1.

 

 

Figure 1

Time course of all interventions affecting pulmonary hemodynamics. T0, T1, T2 indicate the time points of hemodynamic meassurements. CPB = cardiopulmonary bypass.

 

In all cases iIlo was started after weaning off CPB. For analysis, stable systemic pressures during the first ten minutes after weaning from CPB and before starting inhalation therapy were taken as baseline (T0) followed by a second (T1) and third (T3) data set 30 minutes, and 60 minutes after starting iIlo, respectively.
For the inhalation therapy with iloprost an ultrasonic nebulizer (Optineb®; Nebu-Tec, Elsenfeld, Germany) was integrated in the inspiratory limb of a pediatric breathing system (15 cm in front of the Y-piece). The breathing circuit was connected to a Servo 900C anesthesia ventilator (Siemens, Erlangen, Germany).
A single dose of 2.5 μg x kg -1 Iloprost diluted in isotonic saline to obtain a filled-in volume of 3 ml was inhaled over a 20 minutes period. This dosage has previously been shown to be clinically effective in reducing MPAP/MAP [10].
However, the characteristics of an aerosol spray are affected by the nebulizer system, breathing circuit, and ventilator.
To assess the effective amount of iIlo at the tip of the endotracheal tube, the above described ventilator set up was connected to a breathing chamber containing a micro filter. After 20 minutes the residual volume in the nebulizer was measured, and the drug concentration in the micro filter was analyzed by high-performance liquid chromatography as described elsewhere [13].
The essays were performed twice using an filling volume of 2 and 3 ml, a volume controlled ventilation pattern with a respiratory rate of 20 x min-1, and a tidal volume of 50 and 100 ml, respectively. Statistical analysis was performed using IBM SPSS statistics 19.0 (www.spss.com). Data are expressed as median and ranges, or as mean and standard deviation. A paired t-test was used to compare the hemodynamic effects before and after iIlo. Differences in baseline hemodynamics between biventricular and univentricular hearts were analyzed using the unpaired t-test.

 

Results

Patients: In 31 patients iIlo was the sole agent exclusively used in the operating room after weaning off CPB. Demographic data, preoperative cardiac diagnosis, and details of surgery are presented in table 1.

 

 

Table 1

Patients characteristics and perioperative data.

 

The time course of all interventions affecting pulmonary vascular resistance is shown in figure 1. During the observation period from November 01. 2002 to November 01. 2005 corrective or palliative heart surgery with CPB was performed in 312 infants and children at risk of post-CPB pulmonary hypertension.
Effective delivered iloprost dose: Analyzing the clinical setup for the inhalation therapy with iloprost, we found that only 20 to 30% of iloprost is effectively administered using the Optineb® ultrasonic nebulizer together with a pediatric breathing system (Table 2).

 

 

Table 2

Amount of effective administered iloprost after a 20 min inhalation period.

 

Hemodynamic data: Inhalation therapy with iloprost after weaning off CPB decreases significantly the ratio of mean pulmonary artery pressure (MPAP) to mean arterial pressure (MAP) (Figure 2) by reducing primarily MPAP.

 

 

Figure 2

Time course of post-CPB mean pulmonary artery pressure (MPAP) to mean arterial pressure (MAP)- ratio in 31 patients receiving inhaled iloprost during congenital heart surgery.

 

Although great efforts were made to keep right ventricular loading condition stable throughout the observation (a decreased central venous pressure was only observed at T2 in patients undergoing biventricular repair (Table 3), norepinephrine was necessary in 35% of the patients after iIlo to keep systemic pressure (Table 4).

 

 

Table 3

Hemodynamic data after weaning off CPB in patients undergoing biventricular and univentricular repair.

 

 

Table 4

Concomitant vasoactive and inotropic therapy after weaning off CPB. Cumulative Vasoactive-inotropic score (VAS) described by Gaies et al.

 

Comparing univentricular and biventricular repair we found a lower base line MPAP/MAP-ration as well as a lower base line oxygen saturation in patients with univentricular physiology. After iIlo a decrease in MPAP/MAP and trend towards higher oxygen saturation values was observed in both groups (Table 3).
Postoperative Therapy: During the postoperative course in the intensive care unit, pulmonary vasodilators were administered in 87% of patients treated with iIlo for a median time of six days (range: 4-30 days). Median time on mechanical ventilation was five days (range: 1-14 days). No patient died during the postoperative stay in the intensive care unit.

 

Discussion

In this case series, we found a significant decrease in MPAP/MAP ratio in all patients after starting inhalation of 2.5 μg x kg-1 iloprost over 20 minutes. Using the same inhalation apparatus, this dosage has previously been shown to be clinically effective in decreasing pulmonary artery pressure [10]. Although a tested ultrasonic nebulizer was used that provided an aerosol with a mass median diameter of the droplets of 3.4 μm, the effective dose also depends on the assembly of the breathing system. The effectiveness of administration in our set up was only 20 -30% of the filled-in dosage of iloprost. Based on this findings, the effective dosage in the present study was 500 to 750 ng x kg-1 which is higher than the previously reported theoretical alveolar deposition of 250 ng x kg-1 over a 10 minutes period [14]. However, a dose increase up to 2000 ng x kg-1 has recently been reported to achieve a clinical response [15]. This data clearly emphasize the importance of the delivery system when iIlo is used.
In the presented set up iIlo decreases MPAP/MAP by 28% and 31% after 30 and 60 min, respectively. This effect was observed in patients with biventricular physiology as well as in patients with univentricular physiology. Favorable effects of iIlo on MPAP and oxygen saturation after weaning off CPB has been reported by Limsuwan et al. in a small mixed group of patients undergoing corrective biventricular or palliative univentricular surgery [15]. A decrease in MPAP together with an improved oxygen saturation suggests an increase in transpulmonary blood flow.
However, an improvement in pulmonary mismatch could also explain the increase in oxygen saturation.This effect of iIlo has been described in animal models of acute respiratory failure and ischemia-reperfusion injury [16,17]. Although we observed a decrease of MPAP/MAP after iIlo in all patients non-responders to iIlo were reported during pulmonary vasoreactivity testing in children with long-standing pulmonary hypertension related to congenital heart disease [18]. No serious adverse event (i.e. airway irritation, increased postoperative bleeding) was observed in our series. A systemic spill over may be the cause why a vasopressor had to be administered in 35% of the patients receiving iIlo to obtain stable hemodynamics [19]. Otherwise all patients requiring vasopressor support were treated with milrinone; an inotropic agent with significant vasodilator properties. However, the dosage of milrinone has not been changed during the study period.
The main study limitations are the restrospective nature of the chart review, the absence of a control group, and the limited sample size of 31 patients. However, the presented cohort is larger in size to other published reports. Furthermore, an AMS was used to identify patients treated with iIlo as well as to generate and review hemodynamic and intervention data. This should minimize the risk of personal bias.
The timing of all interventions influencing the pulmonary circulation has been exactly reviewed. It should be pointed out that ventilation with oxygen, and inotropic support were started before weaning from CPB. This therapy was not changed after weaning from CPB indicating that the observed decrease in MPAP/MAP can be attributed to iIlo or it can be an effect of time. However, 87% of the patients in this series needed pulmonary vasodilators for a median of 6 days during their postoperative course making the passage of time as the main cause for the observed hemodynamic changes after weaning from CPB not very likely.
In summary, we have shown in a retrospective observational study that a single filled-in dose of 2.5 μg x kg-1 iloprost results in an effective delivered dose of 500 to 750 ng x kg-1 after 20 min inhalation with an ultrasonic nebulizer integrated in a pediatric breathing system. This dosage decreases the MPAP/MAP-ratio for at least 60 minutes. In our series, analyzing the off label use of inhaled iloprost, we observed no non-responder and no rebound phenomenon, two problems reported to be of relevance when iNO was used [7,20]. No major side effects occurred, but vasopressor support was necessary in 35% of the patients. However, the retrospective design and the limited number of patients treated with iIlo warrants further studies to define the role of inhaled iloprost in the treatment of pulmonary hypertension after congenital heart surgery.

 

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Cite as: Muller M, Scholz S, Maxeiner H, Brenck F, Valeske K, Thul J, Akinturk H. Efficacy of inhaled ilprost in the management of pulmonary hypertension after cardiopulmonary bypass in infants undergoing congenital heart surgery. A case series of 31 patients. HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2011; 3(2): 123-130

 

Source of Support: Nil.

 

Conflict of interest: Dr. M. Muller has received a speaker honorarium from Schering AG.