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Ann Thorac Surg 1995;60:1617-1622
© 1995 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Prostaglandin E₁ or Prostacyclin in Euro-Collins Solution Fails to Improve Lung Preservation

Departments of Anesthesiology and Thoracic and Cardiovascular Surgery, Helsinki University Central Hospital, Helsinki, Finland

Accepted for publication August 3, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. In search of the ideal composition of the flush solution for pulmonary preservation, we studied the effects of prostaglandin E₁ (PGE₁) and prostacyclin as an additive to Euro-Collins solution (ECS) on pulmonary hemodynamics and gas exchange in a porcine single lung transplantation model using extracorporeal circulation and right heart bypass.

Methods. Twenty-two pigs served as donors. The animals were randomized to receive either modified ECS alone (control group, n = 8), ECS with 100 µg/L of PGE₁ (PGE₁ group, n = 6), or ECS with 200 µg/L of prostacyclin (prostacyclin group, n = 8). Left lung transplantation was performed in 22 recipients after approximately 4 hours of cold ischemia.

Results. Carbon dioxide elimination was significantly depressed in the two prostaglandin groups, and the use of PGE₁ was associated with a significant decrease in arterial oxygen tension compared with the control group. Both drugs were inefficient in alleviating the increase in pulmonary vascular resistance after transplantation.

Conclusion. The use of prostaglandins as constituents of the flush solution was not followed by any improvement of early graft function after cold ischemia.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Single flush perfusion with modified Euro-Collins solution (ECS) is a widely accepted technique in clinical lung preservation. To improve the uniformity of distribution of the solution through the lungs, prostaglandin E₁ (PGE₁) or prostacyclin is often applied as an adjunct to the perfusate [1]. These agents are used because of their pulmonary vasodilatory properties to counteract reflex cold vasoconstriction, and because they also possess a wide variety of biologic effects considered beneficial in organ preservation, ie, inhibition of platelet aggregation and neutrophil sequestration, prevention of lysosomal enzyme release, and superoxide anion production by neutrophils [1–4]. Despite these attributes, several studies have questioned the value of prostaglandins in lung preservation, and PGE₁ has even been found to impair early graft function [1, 5, 6]. Comparisons among different investigations are limited because of the wide variety of indices and techniques used to assess lung preservation. We have previously described a porcine single lung transplantation model in which we are able to adjust individually the blood flow in each lung and study gas exchange and flow distribution between the native and the transplanted lung at equal pulmonary artery pressures, as well as measure pulmonary vascular resistance (PVR) in both lungs at a constant flow rate without the need for a contralateral pneumonectomy or pulmonary artery ligation [7]. The purpose of this study was to investigate, using this perfusion model, the effects of PGE₁ and prostacyclin (100 and 200 µg/L, respectively) as an additive to ECS on pulmonary preservation during the first 3 hours after single-lung transplantation.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Procedure
Forty-four size-matched infant pigs (weight 16 to 23 kg) were used in this study. All animals received humane care in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985). The details of the experimental design have been described earlier [7]. In short, after the donor animals (n = 22) were premedicated with ketamine hydrochloride intramuscularly, anesthesia was induced and maintained with pentobarbital and fentanyl, and muscle relaxation was achieved with pancuronium. After tracheal intubation, the animals were ventilated (tidal volume 20 mL/kg, 20 times/min) with a volume-controlled ventilator (Servo 900C; Siemens-Elema AB, Solna, Sweden). The fraction of inspired oxygen of the gas mixture (O₂-N₂) was 0.5, and a positive end-expiratory pressure of 5 cm H₂O was applied throughout the operation. After median sternotomy, 500 IU/kg of heparin was given, the main pulmonary artery was ligated, and the left atrium was cut open. The donor animals were randomized to receive in blinded fashion either ECS (Fresenius AG, Bad Homburg, Germany) alone (control group, n = 8), ECS to which 100 µg/L of PGE₁ (Prostivas; Upjohn, Puurs, Belgium) had been added (PGE₁ group, n = 6), or ECS with 200 µg/L of prostacyclin (Flolan; Wellcome Foundation Ltd., London, UK) (prostacyclin group, n = 8). The prostaglandins were added to the perfusate just before their use. In all three groups, 1,000 mL of the cold (4°C) solution was administered from a pressurized bag into the main pulmonary artery over 4 minutes. Cooling of the lungs was supplemented by irrigation of the chest cavity with cold saline solution. On completion, the ventilation was discontinued and the trachea was clamped at manual midinflation with room air. The excised heart-lung block was stored immersed in cold (4°C) saline solution.

The recipient operation began 2 hours later. The premedication and induction of anesthesia of the animals (n = 22) were identical to those in the donor procedure. The intubation tube was introduced into the trachea through a tracheostomy, and the animals were ventilated as described earlier. Anesthesia was maintained with a continuous infusion of pentobarbital (5 mg•kg^-1•h^-1), fentanyl (10 µg•kg^-1•h^-1), and pancuronium (0.2 mg• kg^-1•h^-1). The left femoral vein and artery were cannulated for intravenous drug administration and right atrial pressure and systemic arterial pressure monitoring, respectively. After median sternotomy and administration of heparin (500 IU/kg), the left lung was removed. The new left lung to be transplanted was dissected free from the heart-lung block and reanastomosed with the recipient's left atrium. The new left main bronchus was intubated, and the tubes from both lungs were connected with a Y-piece to the ventilator. A venous type wire-reinforced cannula was introduced into the right atrium to drain the whole venous return by gravity into a cardiotomy reservoir. Separate perfusions of the lungs were achieved with similar cannulas in the right and left pulmonary arteries and two calibrated roller pumps. Pulmonary artery pressures (PAP) were monitored through catheters located inside the perfusion cannulas and advanced beyond their tips. Left atrial pressure (LAP) was measured with a cannula introduced directly into the left atrium. All pressures were recorded with the zero reference at the level of the left atrium.

Once the extracorporeal circulation started, the proximal part of the right pulmonary artery was ligated. The total blood flow was kept at 2 L/min (100 ± 15 mL/kg) and divided between the lungs (by adjusting the pump flows) to generate equal pressures (mean) in both pulmonary arteries, while the systemic circulation was maintained by the animal's own left ventricle. The following hemodynamic measurements were recorded after a 15-minute stabilization period: systemic arterial pressure, right atrial pressure, LAP, and PAP (right/left). Blood samples were drawn from the femoral artery for blood gas analysis. End-tidal CO₂ values were registered sequentially with a capnograph (Datex OY, Helsinki, Finland) through separate sample lines from the right and left intubation tubes as well as from the common expiratory limb. For the measurement of standardized PVR, the blood flow was adjusted to be 1 L/min to each lung and the hemodynamic recordings were repeated. All these measurements were repeated 30, 60, 90, 120, 150, and 180 minutes after the initiation of reperfusion. Mean systemic arterial pressure, mean pulmonary arterial pressure (MPAP), and PVR were calculated using standard formulas. At the end of the experiment, the animals were sacrificed.

Statistical Analysis
All results are expressed as mean ± standard error of the mean (SEM) unless otherwise stated. The difference between the PGE₁ group or the prostacyclin group and the control group was tested initially using three-way analysis of variance for repeated measures (Multivariate General Linear Hypothesis, Systat; Systat Inc, Evanston IL) for the effects of time, drug, and lung (native/transplanted). The effects of time and drug on each lung were tested with two-way analysis of variance, when appropriate. Differences were considered significant at p less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The median duration of ischemia was 270 minutes (range, 262 to 302 minutes) in the control group, 258 minutes (range, 233 to 284 minutes) in the PGE₁ group, and 253 minutes (range, 228 to 270 minutes) in the prostacyclin group. All animals survived the operation.

Despite normal LAP, fulminant pulmonary edema of the transplanted lung was the cause of two early deaths in the prostacyclin group, occurring immediately at the onset of reperfusion in 1 animal and after 30 minutes of reperfusion in the other. In the control group, 1 animal was excluded from the study because of left heart failure and high LAP.

When the pulmonary blood flows were adjusted to maintain equal pressure in each lung, the median flow difference (native/transplanted lung) was 0.8 L/min (range, 1.5 to 0.7 L/min) in the control group, 1.0 L/min (range, 1.4 to 0.7 L/min) in the PGE₁ group, and 1.1 L/min (range, 1.2 to 0.8 L/min) in the prostacyclin group. In the control group, the pulmonary artery blood flow of the graft increased over time (p < 0.05), but the flow difference between the lungs remained significant throughout the study in all three groups (p < 0.001) (Fig 1). At equal pressures in the native and in the transplanted lung, MPAP was significantly higher in the PGE₁ group than in the control group (p < 0.05, Fig 2).

View larger version (19K): [in this window] [in a new window]   Fig 1. . Pulmonary artery blood flow in the transplanted lung (A) was significantly reduced compared with the native lung (B) (p < 0.001). Data are shown as mean ± standard error of the mean. Prostacyclin or prostaglandin E1 (PGE1) in Euro-Collins solution diverted blood away from the transplanted lung.

View larger version (26K): [in this window] [in a new window]   Fig 2. . Mean pulmonary artery pressure (MPAP). At equal pulmonary artery pressures in the native and in the transplanted lung (A, B), MPAP was significantly higher in the prostaglandin E1 (PGE1) group (p < 0.05). When pulmonary blood flows were equal (C, D), MPAP was significantly higher in the transplanted lung compared with the native lung (p < 0.001). Data are shown as mean ± standard error of the mean.

View larger version (23K): [in this window] [in a new window]   Fig 3. . Pulmonary vascular resistance (PVR) was significantly higher in the transplanted lung (A) compared with the native lung (B) (p < 0.001). Data are shown as mean ± standard error of the mean. In the transplanted lung, PVR decreased during the first study hour in all three groups. In the native lung, the decrease of PVR over time was significant in the prostacyclin group (p < 0.05). (PGE1 = prostaglandin E1.)

View larger version (18K): [in this window] [in a new window]   Fig 4. . Systemic arterial oxygen tension (pO2) was significantly lower in the prostaglandin E1 (PGE1) group than in the control group (p < 0.05). Data are shown as mean ± standard error of the mean.

View larger version (16K): [in this window] [in a new window]   Fig 5. . Arterial carbon dioxide tension (pCO2) was significantly higher in the prostacyclin and the prostaglandin E1 (PGE1) groups than in the control group (p < 0.05). Data are shown as mean ± standard error of the mean.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

In most of the single lung transplantation studies, it has been possible to investigate the changes in the transplanted lung only after a contralateral pneumonectomy or after ligation of the native lung's pulmonary artery and bronchus. Our study design using extracorporeal circulation, right heart bypass, and separate, controlled perfusions of the native and the transplanted lung eliminates the hemodynamic consequences of these techniques. We were also able to measure MPAP, pulmonary blood flow, and PVR individually in each lung and to compare the responses of the transplanted lung to those of the native lung. Because of extracorporeal circulation, the study period was limited to the first few hours after transplantation. The equal-pressure model is comparable to the clinical situation during operation, while constant flow rate is a prerequisite for the reliable calculation of PVR and eliminates the impact of changes in cardiac output and blood flow distribution on pulmonary hemodynamic measurements.

At equal PAP, prostaglandin treatment did not decrease the resistance to blood flow in the transplanted lung. Our previous report showed that PGE₁ infusion during reperfusion also had no effect on the blood flow distribution between the lungs [7]. Earlier pulmonary preservation studies have not measured the individual flow to each lung. The significantly higher MPAP of the PGE₁ group compared with the control group reflects the pressure/flow relation in the graft, where even the reduced blood flow is able to generate high PAP. The lower MPAP level in the prostacyclin group may be an overestimate because of the early deaths of the 2 animals with initially high MPAP values. Our results are in agreement with a previous investigation, in which the use of PGE₁ in ECS resulted in high PAP [9].

The standardized PVR of the transplanted lung was significantly higher than that in the native lung in all three study groups. In our experiment, the use of prostaglandins did not prevent this elevation of PVR. This is in contrast to an earlier study, in which prostacyclin administered both in donor pretreatment and in the pulmonary perfusate ameliorated the increase in PVR index after 60 minutes of warm ischemia and after ligation of the pulmonary artery of the native lung [10]. Endothelial dysfunction after flush solution (with or without high potassium content), ischemia and cold storage, and reperfusion has been advocated as a possible explanation for this enhanced vasoconstriction [11, 12]. In the native lung, PVR decreased in the prostacyclin group during the first 60 minutes of extracorporeal circulation and remained at this lower level during the rest of the study, suggesting a possible residual effect of the drug due to the large dose and prolongation of half-life in the cold ECS. Increasing the flow to the transplanted lung for the measurement of PVR was followed by a distinct elevation of MPAP. At the same time, decreasing the flow to the native lung resulted in alterations of the pressure level of a much smaller magnitude. This is indicative of an impaired recruitment response of the transplanted lung.

Two animals in the prostacyclin group died of pulmonary edema shortly after the onset of reperfusion despite normal LAP. We were unable to identify any technical reasons for these early deaths, but because pulmonary venous pressures were not measured, these cannot be completely excluded. In a previous study on isolated blood-perfused lungs, prostacyclin, either alone or after thromboxane A₂ analogue-induced vasoconstriction, increased fluid filtration by increasing vascular surface area and pulmonary microvascular permeability to protein [13]. In another investigation, PGE₁ as a constituent of flush solution (ECS 30 mL/kg, after removal of the left lung) was found to increase the wet/dry lung weight ratio compared with a control group [6]. On the other hand, the use of Wallwork's solution containing 20% blood, Ringer's lactate (potassium content 4 mmol/L), and prostacyclin for flushing at a rate of 40 mL/kg resulted in reduced pulmonary weight gain after 30 minutes of reperfusion [14]. When suboptimal amounts of ECS (20 mL/kg) were administered together with Iloprost, the synthetic analogue of prostacyclin, both in donor pretreatment and as a constituent of the perfusate, there was no difference in the lung water content between the control and the prostaglandin group [15]. Compared with earlier studies, our prostacyclin dose was in the upper range, and it is possible that the use of a high dose of a potent pulmonary vasodilator in ECS during hydrostatic stress (high volume, high flow) and vasoconstriction induced by the high potassium content of the solution may have rendered the lungs more prone to edema formation.

Many investigators consider oxygenation to be perhaps the most sensitive indicator of lung preservation. In our study, the arterial oxygen tension was significantly lower in the PGE₁ group compared with the control group. Most studies do not support the concept that donor treatment with PGE₁ is helpful in improving oxygenation during the early reperfusion period [3, 5, 10, 16]. Even deleterious effects have been reported [6]. The use of prostacyclin either in pretreatment or in ECS has been found to improve pulmonary oxygen transfer in experimental designs, where the contralateral pulmonary artery is ligated [3, 10, 17]. Our results of the effect of prostacyclin on oxygenation may be too optimistic, because of the two nonsurvivors, but no improvement was detected compared with the control group. The use of prostaglandins was followed by significantly depressed CO₂ elimination, which has not been reported previously in the literature. Adding PGE₁ or prostacyclin to the pulmonary flush solution therefore seems to be associated with deterioration of gas exchange of varying degree because of an increased ventilation-perfusion mismatch.

We conclude that PGE₁ and prostacyclin as constituents of modified ECS are inefficient in counteracting the mechanism responsible for the elevation of PVR after transplantation. The changes in the alveolar-capillary network after high-flow, high-volume crystalloid flush solution containing a powerful pulmonary vasodilator and followed by ischemia and cold storage and reperfusion are associated with untoward changes in gas exchange after single-lung transplantation.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by the Finnish Academy. We thank Dr Klaus Olkkola for his statistical advice and Mrs Pirkko Uhlbäck for her excellent technical assistance.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Kukkonen, Department of Anesthesiology, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Kirk AJ, Colquhoun IW, Dark JH. Lung preservation: a review of current practice and future directions. Ann Thorac Surg 1993;56:990–1000.[Abstract]
2. Moncada S, Flower RJ, Vane JR. Prostaglandins, prostacyclin, thromboxane A₂, and leukotrienes. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds. The pharmacologic basis of therapeutics. New York: Macmillan, 1985:660–74.
3. Novick RJ, Reid KR, Denning L, Duplan J, Menkis AH, McKenzie FN. Prolonged preservation of canine lung allografts: the role of prostaglandins. Ann Thorac Surg 1991;51:853–9.[Abstract]
4. Fantone JC, Marasco WA, Elgas LJ, Ward PA. Stimulus specificity of prostaglandin inhibition of rabbit polymorphonuclear leukocyte lysosomal enzyme release and superoxide anion production. Am J Pathol 1984;115:9–16.[Abstract]
5. Bonser RS, Fragomeni LS, Jamieson SW, et al. Effects of prostaglandin E₁ in twelve-hour lung preservation. J Heart Lung Transplant 1991;10:310–6.[Medline]
6. Bonser RS, Fragomeni LS, Edwards BJ, et al. Allopurinol and deferroxamine improve canine lung preservation. Transplant Proc 1990;22:557–8.[Medline]
7. Kukkonen S, Heikkilä L, Verkkala K, Mattila S, Toivonen H. The pulmonary vasodilatory properties of PGE₁ are blunted after experimental single lung transplantation. J Heart Lung Transplant 1995;3:280–8.
8. Jellinek H, Hiesmayr M, Simon P, Klepetko W, Haider W. Arterial to end-tidal CO₂ tension difference after bilateral lung transplantation. Crit Care Med 1993;21:1035–40.[Medline]
9. Ueno T, Yokomise H, Oka T, et al. The effect of PGE₁ and temperature on lung function following preservation. Transplantation 1991;52:626–30.[Medline]
10. Hooper TL, Thomson DS, Jones MT, et al. Amelioration of lung ischemic injury with prostacyclin. Transplantation 1990;49:1031–5.[Medline]
11. Kimblad PO, Sjöberg T, Massa G, Solem J-O, Steen S. High potassium contents in organ preservation solutions cause strong pulmonary vasoconstriction. Ann Thorac Surg 1991;52:523–8.[Abstract]
12. Kimblad PO, Sjöberg T, Steen S. Pulmonary vascular resistance related to endothelial function after lung transplantation. Ann Thorac Surg 1994;58:416–20.[Abstract]
13. Yoshimura K, Tod ML, Pier KG, Rubin LJ. Effects of thromboxane A₂ analogue and prostacyclin on lung fluid balance in newborn lambs. Circ Res 1989;65:1409–16.[Abstract/Free Full Text]
14. Mulvin D, Jones K, Howard R, Grosso M, Repine J, Johnston M. The effect of prostacyclin as a constituent of a preservation solution in protecting lungs from ischemic injury because of its vasodilatory properties. Transplantation 1990;49:828–30.[Medline]
15. Hooper TL, Fetherston GJ, Flecknell PA, Dark JH, McGregor CG. The use of a prostacyclin analog Iloprost, as an adjunct to pulmonary preservation with Euro-Collins solution. Transplantation 1990;49:495–9.[Medline]
16. Puskas JD, Cardoso PF, Mayer E, Shi S, Slutsky AS, Patterson GA. Equivalent eighteen-hour lung preservation with low-potassium dextran or Euro-Collins solution after prostaglandin E₁ infusion. J Thorac Cardiovasc Surg 1992;104:83–9.[Abstract]
17. Klepetko W, Müller MR, Khünl-Brady G, et al. Beneficial effects of Iloprost on early pulmonary function after lung preservation with modified Euro-Collins solution. Thorac Cardiovasc Surg 1989;37:174–9.[Medline]

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