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Ann Thorac Surg 2003;76:711-718
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy

^a Departments of Cardiothoracic and Vascular Surgery, Mainz, Germany
^b and Anesthesiology, Mainz, Germany
^c Institute For Medical Statistics, Johannes Gutenberg-University Medical School, Mainz, Germany

Accepted for publication April 18, 2003.

^* Address reprint requests to Dr Kramm, Department for Cardiothoracic and Vascular Surgery, Johannes Gutenberg-University Medical School, Langenbeckstrasse 1, D-55131 Mainz, Germany.
e-mail: kramm{at}mail.uni-mainz.de

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
BACKGROUND: In primary pulmonary hypertension, aerosolized prostanoids selectively reduce pulmonary vascular resistance and improve right ventricular function. In this study, hemodynamic effects of inhaled iloprost, a stable prostacyclin analogue, were evaluated in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and early after pulmonary thromboendarterctomy (PTE).

METHODS: Ten patients (mean age 49 years old [32 to 70 years old], New York Heart Association functional class III and IV) received a dose of 33 µg aerosolized iloprost immediately before surgery (T1), after intensive care unit admission (T2), and 12-hours postoperatively (T3). Effects on pulmonary and systemic hemodynamics and gas exchange were recorded and compared with preinhalation baseline values.

RESULTS: Preoperatively, inhaled iloprost did not significantly change mean pulmonary artery pressure (mPAP), cardiac index (CI), or pulmonary vascular resistance (PVR). Postoperatively, inhaled iloprost induced a significant reduction of mPAP and PVR and a significant increase of CI at T2 and T3. Preinhalation versus postinhalation PVR was as follows: at T1, 847 versus 729 dynes · s · cm^-5, p = 0.45; at T2, 502 versus 316 dynes · s · cm^-5, p = 0.008; and at T3, 299 versus 227 dynes · s · cm^-5, p = 0.004.

CONCLUSIONS: In patients with CTEPH, inhalation of iloprost elicits no significant pulmonary vasodilation before surgery, and may have detrimental effects on systemic hemodynamics. Postoperatively, it significantly reduces mPAP and PVR, and enhances CI. Following PTE, inhalation of iloprost is useful to improve early postoperative hemodynamics.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
In patients with primary pulmonary hypertension, inhalational administration of the stable prostacyclin analogue iloprost has favorable effects upon symptoms, hemodynamics, and prognosis [1–4]. This has also been observed for patient groups with secondary pulmonary hypertension, e.g., due to ARDS or CREST syndrome. Additionally, a cytoprotective effect on the endothelium has been postulated [5–8].

In chronic thromboembolic pulmonary hypertension (CTEPH), however, surgical treatment by pulmonary thrombendarterectomy (PTE) has become the standard therapeutic approach, due to the statistically significant, clinically relevant, and long-lasting functional improvement conferred by this procedure [9–11]. Nevertheless, the degree of elevation of pulmonary vascular resistance seen in CTEPH exceeds that which is attributable solely to mechanical obstruction of the pulmonary vasculature. Hemodynamic progression involves vascular remodeling and the development of a generalized hypertensive pulmonary arteriopathy, histologically evident in both involved and uninvolved portions of the pulmonary vasculature and similar to changes in pulmonary hypertension due to other causes [12]. Thus, even without further thromboembolic events, pulmonary hemodynamics deteriorate progressively in CTEPH [13, 14]. Although a certain degree of residual vasoreactivity has been demonstrated in these patients, e.g., a reduction of PVR during oxygen inhalation [15], there are currently no controlled data suggesting an acute or long-term benefit from prostanoid inhalation in CTEPH patients eligible for PTE [9, 16].

Pulmonary thrombendarterectomy is a major cardiovascular procedure requiring cardiopulmonary bypass and deep hypothermic circulatory arrest. Perioperative mortality occurs almost exclusively during the early postoperative period. It still ranges between 5% and 10% even in those centers with the largest experience [11]. Specific risk factors that contribute to this early morbidity and mortality are persistent postoperative pulmonary hypertension due to nonaccessible peripheral obstruction or unrecognized small vessel disease with subsequent right heart failure as well as reperfusion pulmonary edema (RPE) with progression to ARDS and multiorgan failure. RPE is typically a high-permeability edema and develops in the majority of patients, but to variable degrees of severity [6, 11].

Although pulmonary vascular resistance returns to near normal within days after successful PTE, the extended cardiopulmonary bypass time with induction of inflammatory mediator cascades, as well as the ischemia and reperfusion injury to the lung, quite reproducibly elicit a transient postoperative elevation of PVR during the first postoperative hours [6, 11]. This residual postoperative PVR elevation, even after extensive mechanical endarterectomy of the pulmonary vasculature, is not entirely benign because it may: (1) aggravate low cardiac output and precipitate right ventricular failure; (2) endanger fresh suture lines in brittle, endarterectomized pulmonary artery walls; and (3) cause high transcapillary filtration pressures that contribute to protein leakage, interstitial edema, alveolar flooding, and hypoxemia [17]. The administration of nitric oxide (NO) as a selective pulmonary vasodilator in this context has been advocated, but remains controversial [18]. A recent randomized controlled trial of inhaled NO on reperfusion after PTE did not reduce the risk of developing RPE, nor did it significantly shorten the duration of postoperative mechanical ventilation or reduce perioperative mortality [19]. Effects of aerosolized iloprost in this scenario have not been thoroughly studied. Specifically, it has not known whether any effects of aerosolized iloprost differ before and after PTE.

Therefore, the present study was to evaluate the effects of inhaled iloprost on pulmonary and systemic hemodynamics and gas exchange in patients with CTEPH, in order to assess the value of this therapy in the immediate postoperative period after PTE.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
With approval from the state’s ethics committee and written informed patient consent [20], we designed the study as an open-label, observational trial in 10 patients with CTEPH (4 women, 6 men; mean age 49 years old [range 32 to 70 years old], New York Heart Association (NYHA) functional class III [n = 6] and class IV [n = 4]) undergoing PTE. Each patient served as his or her own control. Emergency or redo procedures were excluded.

Anesthesia and surgery
Patients received standard premedication doses of oral flunitrazepam followed by general anesthesia with endotracheal intubation. Anesthesia consisted of induction doses of midazolam, sufentanil and etomidate, followed by continuous intravenous infusion of sufentanil and propofol; neuromuscular blockade was achieved with repetitive doses of pancuronium. In addition to standard perioperative monitoring, invasive instrumentation consisted of a radial arterial line, a Swan-Ganz catheter (CCO Intellicath/SvO₂; Baxter Healthcare Corp., Deerfield, IL) for continuous measurement and display of right atrial pressure (RAP), pulmonary artery pressure (PAP), and cardiac output (Vigilance Monitor, Baxter Healthcare Corp.). During surgery, a left atrial catheter was placed to monitor left atrial pressure (LAP). Arterial blood gases were sampled intermittently as well as monitored online by means of a photometric sensor introduced percutaneously into the femoral artery (TrendCare TCM 6000-Modul; Diametrics Inc., Roseville, MN). Deep hypothermic circulatory arrest (nasopharyngeal temperature, 14° to 15°C; rectal temperature, < 18°C) with intermittent reperfusion was used in order to facilitate thorough endarterectomy of subsegmental PA branches. Termination of cardiopulmonary bypass was attempted only after rewarming to more than 36.5°C rectal temperature.

Drug administration protocol
Aerosolized iloprost was prepared as follows: a total dose of 100 µg Ilomedin (Schering GmbH, Berlin, Germany) was diluted in 6 mL normal saline (NS) and divided into three equal 2-mL doses of 33 µg each. The time points of inhalation were (T1) during steady-state anesthesia before incision, (T2) postoperatively immediately after intensive care unit (ICU) admission, and (T3) at least 12-hours after surgery but before weaning from mechanical ventilation. The aerosol was generated and added to the inspired gas using a jet-nebulizer (ILO-NEB III; Nebu-Tec, Elsenfeld, Germany), which was switched into the inspiratory limb of the respirator circuit in the operating room (respirator: Servo 900C; Siemens, Munich, Germany) and in the ICU (respirator: Evita 4; Dräger, Lübeck, Germany) [21].

The following baseline ventilator settings and blood gas levels were established before and kept constant during inhalation at each time point: pressure-controlled ventilation, I:E ratio = 1:1; PEEP = 6 cm H₂O; PaO₂ = 80 to 90 mm Hg; PaCO₂ = 35 to 45 mm Hg. Under stable hemodynamic and blood gas conditions, inhalation of 2 mL normal saline was performed first for 15 minutes in order to establish a baseline and to compensate any influence of the jet-nebulizer flow. Thereafter, without any changes in other variables, 33-µg iloprost dissolved in 2 mL were aerosolized and inhaled, again for 15 minutes, in order to ensure complete aerosolization of the substance.

Measurements
Invasive systemic and pulmonary hemodynamics as well as arterial and mixed-venous blood gas status were followed and recorded during and after inhalation for at least 35 minutes before skin incision, and for 2 hours during each postoperative study period [2, 16]. In addition to measured variables (RAP, PAP, CO, pulmonary capillary wedge pressure [PCWP], arterial partial pressures of oxygen [PaO₂], and carbon dioxide [PaCO₂]), the following measurements were calculated using standard formulae:

Cardiac index (CI, L · min^-1 · m^-2);

Pulmonary vascular resistance (PVR, dynes · s · cm^-5);

Systemic vascular resistance (SVR, dynes · s · cm^-5);

Ratio of PaO₂ to the fraction of inspired oxygen (PaO₂/Fio₂, mm Hg);

The ratio of PVR/SVR has been suggested as an indicator of the efficacy of selective pulmonary vasodilation; predominantly pulmonary vasodilation will result in a reduction of this value [2, 22]. PaO₂/FIO₂ ratio is used to monitor oxygenation efficacy of the lungs at variable FIO₂ [23].

Adverse events
In order to detect an increased incidence of postoperative bleeding complications, a potential risk of iloprost [24], the need for packed red cell transfusion, blood loss from chest drains, and the patients’ hemoglobin concentrations at discharge from ICU were recorded. Results were compared with respective data from a historic cohort of CTEPH patients who had undergone PTE immediately before the current series.

Hemodynamic and oxygenation criteria to terminate the administration and/or observational period prematurely were prospectively defined as follows: decline of PaO₂ to less than 60 mm Hg during or after inhalation, and/or decline of mean arterial pressure (mAP) to less than 55 mm Hg, and/or decline of CI to less than 1.5 L · min^-1 · m^-2 and/or by more than 30% of baseline.

If one or more of these conditions occurred, inhalation was aborted, medical treatment was initiated and at T1, surgery was begun immediately.

Statistical analysis
Description of continous variables was based on means, quartiles, and standard deviations. Results at T1, T2, and T3 have been appraised independently at each time. Continous data were analyzed using analysis of variance with correction for repeated measurements. Local statistical significance was considered at p less than 0.05. All statistical analyses were drawn out using SAS (Release 6.1.2 for Windows; SAS Inc., Cary, NC). Graphics were generated using Prism 3 (GraphPad Software Inc., San Diego, CA) [25].

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Biometric and hemodynamic data are summarized in Table 1. There were no significant changes in hemodynamics and gas exchange observed during saline inhalation at T1, T2, or T3, respectively (Table 2). A steady state was achieved before iloprost inhalation.

View larger version (18K): [in this window] [in a new window]   Fig 1. Preoperative and postoperative changes of (A) cardiac index (CI), (B) mean pulmonary artery pressure (mPAP), and (C) mean systemic pressure (mAP) during and after normal saline (NaCl) (not significant) followed by iloprost (Ilo) inhalation. (ICU = intensive care unit.)

View larger version (19K): [in this window] [in a new window]   Fig 2. (A) Preoperative and (B, C) postoperative time courses of systemic () and pulmonary vascular resistance () during iloprost inhalation. (B) ICU admission. (C) 12 h postoperatively. (ICU = intensive care unit; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance.) = SVR/dynes · s · cm-5; = PVR/dynes · s · cm-5.

View larger version (47K): [in this window] [in a new window]   Fig 3. Calculated PVR/SVR ratio during iloprost inhalation at (A) T1, (B) T2, and (C) T3. (A) Increase of ratio demonstrating overwhelming systemic side effects with premature abort of measurements (50 minutes), *p less than 0.05 versus ILO-start. (B, C) Significant decrease of ratio indicating predominant pulmonary vasodilatation, *p less than 0.05, p less than 0.01 versus ILO-start. (ILO = iloprost; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance.)

There was no significant increase in heart rate throughout T2 and T3. Also at T2 and T3, the ratio of PaO₂/FIO₂ did not indicate significant changes in oxygenation during iloprost inhalation compared with saline (Table 2). The facial flush syndrome occurred in the same 6 patients in whom it was observed preoperatively at T2 and T3, respectively.

Nine patients survived with improved hemodynamics and improved clinical condition. One patient died on the 17^th postoperative day due to persistent pulmonary hypertension with subsequent right heart and multiorgan failure. However, a decline of mPAP (79 vs 66 mm Hg), increase of CI (1.8 vs 2.2 L · min · m²), and a reduction of PVR (1417 vs 900 dynes · s · cm^-5) were evident in response to inhaled iloprost in this patient.

In 1 of 10 patients there were no significant changes of mPAP, CI, or PVR in comparison to baseline values. Thus, this patient was classified as a nonresponder.

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
PTE is considered the treatment of choice for symptomatic patients with CTEPH. Reasons for early postoperative death after PTE include persistent pulmonary hypertension with right heart failure, respiratory failure due to pulmonary reperfusion edema, or both. Treatment of these conditions is primarily supportive. In the setting of respiratory failure, pulmonary hypertension, compromised right ventricular and sustained left ventricular function, the inhalational administration of nitric oxide (NO) has been used for selective pulmonary vasodilatation and to improve gas exchange. Two large trials in ARDS patients demonstrated that NO was effective in these regards, however, without improving regression of ARDS or survival rate [28, 29]. Procedures in cardiothoracic surgery where NO has been reported to improve oxygenation and elevated pulmonary vascular resistance include lung transplantation, cardiac transplantation [30], mitral valve surgery, and case reports of PTE [31]. In general, however, the lack of controlled studies, the potential toxicity, and the rebound pulmonary hypertension after NO withdrawal discourage routine use of NO in adult cardiac and thoracic surgical patients [18, 32]. There is only one prospective placebo-controlled randomized trial of NO inhalation after PTE. In this study, postoperative NO inhalation did not influence reperfusion edema and did not improve survival after PTE [19]. In contrast, several clinical trials have demonstrated that medical therapy with inhaled iloprost can improve cardiopulmonary functional status in patients with different types of pulmonary hypertension, including those with CTEPH not amenable to surgery [33–35]. Potential toxicity has not been evaluated [36, 37]. These results offer an alternative to both systemic treatment with prostacyclin and inhalational NO therapy [36, 38, 39]. Compared with inhaled NO, iloprost has been described as more potent in selective pulmonary vasodilation, with superior improvement in gas exchange [16]. However, aerosolized iloprost has not yet been evaluated in the immediate postoperative period after PTE.

In our study, aerosolized saline inhalation was used as an intraindividual negative control and also in order to exclude any impact of the additional inspiratory gas flow required by the jet-nebulizer. The arterial blood gas status during the study period was maintained within a physiologic and safe range, which should also minimize the effect of hypoxic pulmonary vasoconstriction [40, 41]. Under these conditions, preoperative administration of inhaled iloprost had no significant effects on pulmonary circulation, whereas there was a significant decrease of both SVR and CI. These preoperative findings differ from those reported by the German Primary Pulmonary Hypertension Study Group and others who treated nonsurgical CTEPH patients with inhalational iloprost and achieved acute benefits [2, 42]. Two explanations may be given. First, CTEPH patients in a series reported by Olschewski and cowokers [REF??] received iloprost aerosol awake and during spontaneous breathing on room air or supplemental O₂, with some degree of hypoxic pulmonary vasoconstriction still present. In contrast, our patients were anesthetized and normoxemic on pressure-controlled mechanical normoventilation during inhalation and measurements. Second, medically managed CTEPH patients in the series by Olschewski and cowokers [REF??] had disease patterns with predominantly peripheral distribution of the thromboembolic obstructions, which most probably was the reason why PTE was not considered for this group; our cohort, however, consisted of patients positively selected for PTE with obstructions involving the main and proximal segmental pulmonary vessels. In such patients, the involved portions of the pulmonary vasculature may not be able to react to vasodilators because the organized thromboembolic material is integrated into the thickened vessel wall. On the other hand, in order to maintain pulmonary artery blood flow, uninvolved and potentially reactive vessels are chronically dilated and hyperperfused. Thus, no additional sufficient vasodilation can be provoked. The unchanged excessive PVR precludes an effective increase of left ventricular preload and CI. Moreover, as a systemic side effect of iloprost inhalation, mean arterial pressure decreases because systemic vasodilation cannot be compensated by an increase of CI. This may compromise the coronary artery perfusion pressure which is critical to the contractility of the hypertrophied, pressure-loaded right ventricle. Because, in CTEPH patients, impairment of coronary perfusion may cause acute right ventricular failure, preoperative data recording was aborted in all patients who developed impaired coronary perfusion pressures, and medical treatment was initiated in 2 patients. Declining mPAP at increasing central venous pressure indicated imminent right ventricular failure (Table 2). Thus, in this immediate preoperative scenario, inhalative iloprost does not appear to be beneficial, eg, bridging to PTE. This might also explain why in patients with CTEPH, who were included in iloprost trials, initial substantial improvement was followed by long-term symptomatic deterioration, and why greatest benefits of inhaled iloprost therapy are reported in primary pulmonary hypertension [1, 34, 43].

In 9 of 10 patients, PTE per se produced a significant improvement of mPAP, PVR, and CI. Despite removal of thromboembolic material, mPAP was not adequately reduced in 1 patient, who died with persistent pulmonary hypertension on the 17th postoperative day. Even in this patient, however, a temporary improvement of pulmonary hemodynamics could be achieved by iloprost inhalation [44]. Retrospectively, this patient appeared to have suffered from primary pulmonary hypertension with secondary in situ thrombosis.

In addition to hemodynamic improvements from PTE, iloprost inhalation caused a further significant reduction of mPAP and PVR as well as an increase in CI in 8 of 10 patients. After inhalation of iloprost, there was also a statistically and clinically insignificant decrease in mAP and SVR in all patients.

During PTE, the endarterectomy plane is established between the intima with the fibrotic material and the media. The medial muscular layer remains intact. Postoperatively, the pulmonary vasculature demonstrates an increased smooth muscle tone caused by a host of mechanisms, e.g., mechanical irritation, ischemia-reperfusion injury, hypothermia, and inflammatory activation due to extracorporeal circulation [45]. This temporary pulmonary vasoconstriction might be one reason for early residual postoperative pulmonary hypertension, which sometimes exceeds preoperative values, even after successful PTE. In this period, pharmacologic reduction of right ventricular afterload may be more effective than preoperatively, because the number and irritability of potentially reactive vessels is increased after PTE.

The present study demonstrates that postoperative inhalation of 33-µg iloprost achieves preferential but not selective pulmonary vasodilatation. The extent of systemic side effects is dose dependent. Compared with the dose of 33 µg per inhalation in our protocol, patients with primary pulmonary hypertension are treated usually six to eight times per day with single doses up to 25-µg iloprost, with an initial test dose maximum of 25 µg [1, 21, 44, 46]. Data about the efficacy of and dose response to inhaled iloprost in patients with CTEPH during anesthesia and mechanical ventilation is still lacking. However, a dose of 33 µg as in our protocol should provide delivery of an adequate dose of drug to the alveolar space. A dose-finding protocol to minimize systemic side effects both preoperatively and during postoperative inhalations was not performed in our study.

In contrast to the preoperative inhalation period, all patients received norepinephrine (0.1 to 0.2 µg · kg^-1 · min^-1 through a left atrial catheter) to maintain adequate coronary perfusion pressure for the right ventricle. This regimen might have balanced systemic vasodilation from iloprost to some degree. However, no adjustments of systemic vasopressor dosage were necessary during iloprost inhalation and onset of pulmonary vasodilation. Also, vasopressor support could be reduced or stopped in all patients at the end of the observation period as consequence of the hemodynamic improvement after iloprost administration.

None of the patients in this study developed clinical or radiologic signs of massive reperfusion edema. In our clinical series of CTEPH patients undergoing PTE outside this protocol, the incidence of reperfusion edema is approximately 10%. One of 10 study patients was classified as a nonresponder. The response rate to iloprost published in the literature is approximately 90%, which is superior to that of inhaled nitric oxide (about 40%) or prostaglandins [16]. However, our study group was definitely undersized to allow comparison with the literature data.

Further studies with a reduced dose and a randomized, placebo-controlled study design are necessary. For aerosolization a certified jet-nebulizer was used in this series. With improved devices, e.g., ultrasound nebulizers, a more effective active-substance enrichment in the alveolar space may be achieved, thus reducing total dose requirements per inhalation [22].

Conclusion
Preoperative inhalation of iloprost in CTEPH patients scheduled for PTE may critically impair hemodynamics by systemic vasodilation, hypotension and decrease of CI. Postoperatively, inhalation of aerosolized iloprost reduces right ventricular afterload in addition to the effect of surgical desobliteration; there is significant reduction of mPAP and PVR, resulting in enhancement of CI without major systemic side effects. These effects may contribute to reduce pulmonary reperfusion injury and to improve early results after PTE.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
We thank Dr John D. Puskas, Emory University Clinic (Atlanta, GA), for his helpful suggestions regarding the manuscript.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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