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Ann Thorac Surg 1996;61:956-962
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Inhalation of Nitric Oxide After Lung Transplantation

Departments of Cardiothoracic Surgery and Anesthesiology and Intensive Care, University Hospital of Lund, Lund, Sweden

Accepted for publication October 31, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Pulmonary hypertension is a postoperative complication that may adversely affect the outcome of lung transplantation. The effect of nitric oxide (NO) inhalation on pulmonary hemodynamic indices after lung transplantation was studied and compared with findings in control pigs.

Methods. Varying concentrations of NO were inhaled by 5 pigs after left lung transplantation and right pneumonectomy and by 5 controls after right pneumonectomy at an inspired oxygen fraction of 0.21 and 0.5. Hemodynamic data were recorded continuously, and fast circulatory courses were analyzed.

Results. Inhalation of NO reduced pulmonary vascular resistance and mean pulmonary arterial pressure in all pigs, but the decrease was pronounced and dose dependent only at an inspired oxygen fraction of 0.21 in the pigs that had transplantation. These were the only pigs that became hypoxic. With the termination of NO, there was a dose-independent rebound pulmonary vasoconstriction in the controls, especially at an inspired oxygen fraction of 0.21, but not in the pigs that had transplantation. This response was transient and could be blunted with a higher inspired oxygen fraction.

Conclusion. Inhalation of NO reduced pulmonary vascular resistance in the transplanted lung and may be useful in the treatment of pulmonary hypertension after lung transplantation. The rebound pulmonary vasoconstriction with the termination of NO inhalation stresses the need to be aware of this effect and to wean NO carefully in clinical situations. This study showed oxygen dependency, which has to be taken into consideration in dose-response studies involving NO inhalation.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Lung transplantation has become an established treatment for end-stage pulmonary disease. The perioperative management remains challenging, and transient graft dysfunction may occur depending on the donor's pulmonary status, whether the operation involves cardiopulmonary bypass, the lung preservation time and technique, and other factors [1].

Pulmonary hypertension after lung transplantation is a well documented postoperative complication and may adversely affect lung perfusion and gas exchange. It may also compromise right ventricular function and cardiac output; in severe cases, right heart failure may develop. Intravenously administered vasodilators such as nitroprusside, nitroglycerin, prostaglandin E₁, and prostacyclin have been used to reduce pulmonary vasoconstriction and to improve right ventricular performance [2], but unfortunately they reduce systemic arterial pressure as well and may increase intrapulmonary shunting. The search for a selective pulmonary vasodilator has been extensive, but a promising possibility did not arise until 1987, when it was suggested that nitric oxide (NO) is identical to an endothelium-derived relaxing factor [3]. Higenbottam and co-workers [4] compared the vasodilatory effects of inhaled NO and intravenously given prostacyclin in patients with primary pulmonary hypertension and showed that NO causes selective pulmonary vasodilation [4]. This finding has been confirmed by several studies since then.

In humans, inhalation of NO has been shown to reduce pulmonary hypertension in several clinical conditions such as adult respiratory distress syndrome [5], after cardiac operations [6], after lung transplantation [7], and in newborns with persistent pulmonary hypertension [8]. In animal models, NO has been shown to reduce pulmonary hypertension caused by hypoxia [9], the heparin-protamine reaction [10], and endotoxemia [11]. Nitric oxide inhalation in animals also prevented the rise in pulmonary arterial pressure seen in oxidant-induced acute lung injury [12] and in smoke inhalation lung injury [13].

We used a pig model to evaluate pulmonary and systemic hemodynamic indices after left lung transplantation followed by right pneumonectomy, that is, with the animals totally dependent on the left transplanted lung [14]. By comparing such pigs after transplantation with controls that had undergone right pneumonectomy only, we evaluated the specific effects on lung function and pulmonary circulation caused by lung transplantation. We have found that pulmonary vascular resistance increases after lung transplantation [14, 15] and that there is a correlation between this increase and the degree of dysfunction of the endothelium-dependent relaxation in the pulmonary artery [16]. The specific effects of lung transplantation on pulmonary hemodynamics and the effects of NO inhalation are difficult to evaluate in the clinical setting.

The aim of the present study was thus to investigate the effects of inhaled NO on pulmonary hemodynamic indices and blood gases in the transplanted versus the intact lung.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Fifteen pigs (5 donors, 5 recipients, 5 controls) with a mean weight of 56 kg (range, 51 to 58 kg) were fasted overnight. All of the 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).

Anesthesia and Surgical Preparation
Anesthesia was induced with intramuscular ketamine (Ketalar; Parke-Davis, Morris Plains, NJ), 30 mg/kg body weight. Sodium thiopental (Pentothal; Abbot, North Chicago, IL), 100 to 200 mg, and atropine (Kabi Pharmacia, Uppsala, Sweden), 1 mg, were given intravenously before tracheostomy (Portex tracheal tube no. 7; Hythe, Kent, England). Anesthesia was maintained with a continuous infusion of 30 mL/h of a solution containing 8 g (16 mg/mL) ketamine, 300 mg (0.6 mg/mL) pancuronium (Pavulon; Organon Teknika, Boxtel, the Netherlands), and 30 mg (0.06 mg/mL) midazolam (Dormicum; Roche, Basel, Switzerland) in 500 mL 10% glucose. A Servo Ventilator 300 (Siemens-Elema AB, Solna, Sweden) was used for mechanical ventilation. Identical settings were used in all pigs: volume-controlled pressure-regulated ventilation, 10 L/min, 20 breaths/min, inspired oxygen fraction (FiO₂) 0.5, and positive end-expiratory pressure 8 cm H₂O. Catheters were placed in the right internal jugular vein and in the right carotid artery. A modified Swan-Ganz catheter (right ventricular ejection fraction/volumetric oximetry thermodilution catheter 93A-750H-7.5F; Baxter Healthcare Corp, Santa Ana, CA) was inserted through the right external jugular vein, and was flow directed into the pulmonary artery. The catheter was connected to an Edwards Critical-Care Explorer Multiple Parameter Hemodynamic Monitor (Baxter Healthcare Corp). A Foley catheter was inserted into the urinary bladder through a suprapubic cystostomy. In the transplantation group, left thoracotomy was performed followed by left pneumonectomy, and a left lung, which had been preserved in buffered Perfadex (Medisan, Uppsala, Sweden) for 24 hours, was transplanted (for further details, see reference 15). A catheter was inserted into the left atrium for pressure measurements, and an ultrasonic blood flow probe (14 mm) was placed around the pulmonary artery. Right pneumonectomy was then performed using a TA-90 surgical stapler instrument (United States Surgical Corporation, Norwalk, CT).

Five pigs were used as controls. Left thoracotomy and dissection of the left pulmonary artery were carried out, and the Transonic flow probe was placed in the same position as if the lung had been transplanted. Right pneumonectomy was then performed in the same way as in the pigs that had transplantation (Fig 1). After a 24-hour follow-up period, all the pigs inhaled NO according to the NO protocol at an FiO₂ of 0.5 and 0.21.

View larger version (37K): [in this window] [in a new window]   Fig 1. . The experimental model. In the control group, a right pneumonectomy was performed; in the transplantation group, a left lung was transplanted followed by right pneumonectomy. (AP = arterial pressure; CO = cardiac output; CVP = central venous pressure; LAP = left atrial pressure; PAP = pulmonary arterial pressure.)

Nitric Oxide Delivery
Gas cylinders (AGA AB, Lidingö, Sweden) with 2,500 ppm (parts per million) or 10,000 ppm NO in nitrogen were used to administer up to 20 ppm or 80 ppm NO, respectively. Nitric oxide was delivered into the inspiratory limb of the breathing circuit of the ventilator by a microprocessor-governed valve. The system provides a precision of ±10% of set value when tested with a chemiluminescence analyzer (Model 952A; Beckman Instruments Inc, Process Instruments & Controls Groups, Fullerton, CA).

The effects of 5, 10, and 20 ppm NO were investigated at an FiO₂ of 0.5; and 5, 20, and 80 ppm NO were analyzed at an FiO₂ of 0.21. The doses were given in random order over 8 to 10 minutes.

Statistical Analysis
All data are expressed as the mean ± standard error of the mean. Baseline values were compared with the maximum response during NO inhalation and the maximum rebound effect after cessation of NO. Student's t test for paired and unpaired data was used. Differences were considered significant at p < 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Table 1 presents the status of the pigs 24 hours after operation, before inhalation of NO. The mean pulmonary arterial pressure was significantly higher at an FiO₂ of 0.21 in the pigs that had transplantation. The arterial oxygen tension and the dynamic lung compliance were significantly lower in the transplantation group.

Pulmonary Vascular Resistance
Pulmonary vascular resistance decreased in a dose-independent manner by about 5% to 7% in both the controls and the transplantation group performing NO inhalation at an FiO₂ of 0.5 (Fig 2). A slight but nonsignificant, transient increase in pulmonary vascular resistance was seen upon termination of NO inhalation in the control pigs.

View larger version (44K): [in this window] [in a new window]   Fig 2. . Pulmonary vascular resistance at an inspired oxygen fraction (FIO2) of 0.5 during inhalation of 5, 10, and 20 ppm nitric oxide (NO) in control pigs (left) and after transplantation (right). Data are shown as the mean ± standard error of the mean of the percentage change, n = 5. Nitric oxide inhalation starts at 0 minutes and stops at 0 minutes after the break line.

View larger version (46K): [in this window] [in a new window]   Fig 3. . Pulmonary vascular resistance at an inspired oxygen fraction (FIO2) of 0.21 during inhalation of 5, 20, and 80 ppm nitric oxide (NO) in control pigs (left) and after transplantation (right). Data are shown as the mean ± standard error of the mean of the percentage change, n = 5. Nitric oxide inhalation starts at 0 minutes and stops at 0 minutes after the break line. Statistical comparison was performed between the groups: *p < 0.05 and **p < 0.01.

At an FiO₂ of 0.21, a dose-dependent reduction of mean pulmonary arterial pressure was seen in the transplantation group, with a 20% decrease when the highest dose of NO was given. In the control pigs, the reduction was dose independent (Fig 4). A significant transient rebound increase was seen with the termination of NO in the control, but not in the transplantation group (see Fig 4). This increase reached its peak value after 2 minutes and returned to the basal level within the next 3 minutes. Statistical significance between the groups regarding the rebound increase in mean pulmonary arterial pressure was reached only with the termination of 20 and 80 ppm NO (see Fig 4).

View larger version (46K): [in this window] [in a new window]   Fig 4. . Mean pulmonary arterial pressure at an inspired oxygen fraction (FIO2) of 0.21 during inhalation of 5, 20, and 80 ppm nitric oxide (NO) in control pigs (left) and after transplantation (right). Data are shown as the mean ± standard error of the mean of the percentage change, n = 5. Nitric oxide inhalation starts at 0 minutes and stops at 0 minutes after the break line. Statistical comparison was performed between the groups: *p < 0.05 and **p < 0.01, and ***p < 0.001.

View larger version (44K): [in this window] [in a new window]   Fig 5. . Systemic vascular resistance at an inspired oxygen fraction (FIO2) of 0.21 during inhalation of 5, 20, and 80 ppm nitric oxide (NO) in control pigs (left) and after transplantation (right). Data are shown as the mean ± standard error of the mean of the percentage change, n = 5. Nitric oxide inhalation starts at 0 minutes and stops at 0 minutes after the break line.

View larger version (41K): [in this window] [in a new window]   Fig 6. . Cardiac output at an inspired oxygen fraction (FIO2) of 0.21 during inhalation of 5, 20, and 80 ppm nitric oxide (NO) in control pigs (left) and after transplantation (right). Data are shown as the mean ± standard error of the mean of the percentage change, n = 5. Nitric oxide inhalation starts at 0 minutes and stops at 0 minutes after the break line. Statistical comparison was performed between the groups: *p < 0.05.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

We have shown earlier that endothelium-dependent relaxation in the pulmonary artery is significantly reduced after lung transplantation [16]. In the present study, we investigated the hemodynamic reaction of transplanted lungs to NO inhalation. The results of this study demonstrate interesting differences in the response to NO between the control pigs and those having transplantation, and this may shed some light on pulmonary vascular regulation after lung transplantation.

Inhalation of NO reduced the pulmonary vascular resistance and pulmonary arterial pressure in both the pigs having transplantation and the control pigs having pneumonectomy during mechanical ventilation. These responses were independent of dose when FiO₂ was 0.5, but when FiO₂ was decreased to 0.21 (with the consequence that the transplantation group became hypoxic), the response to NO inhalation in the transplantation group became more pronounced and dose dependent, up to the highest dose tested (80 ppm). The reason for this dose dependency after transplantation may have been a deficiency in the pulmonary vessels' endogenous relaxing capacity. This deficiency may have been substituted for in a dose-dependent manner by the NO inhalation. In the normoxic animals, the maximum vasodilating effect of NO inhalation was reached already at the lowest dose tested, indicating a better-preserved endogenous relaxing capacity.

Unexpectedly, a marked rebound vasoconstriction occurred when NO inhalation was stopped in the control animals, especially when they were ventilated with air. Maximal vasoconstriction was reached during the first 2 minutes after the termination of NO inhalation, and in about 4 to 5 minutes, the vessels gradually dilated and resumed their baseline tonus. It can be hypothesized that inhaled NO may inhibit the action of nitric oxide synthase. After the inhalation was stopped, a deficiency in endogenously produced NO would occur, causing vasoconstriction, which would subside when endogenous NO production resumed. This finding is in agreement with those of Buga and associates [17], who suggested that NO plays an important negative feedback regulatory role on endothelial nitric oxide synthase. Kiff and colleagues [18] found that NO in isolated blood vessels could inhibit the action of a nitric oxide synthase. Nitric oxide synthase seems to be a P-450–type heme protein, and this type of enzyme is inhibited by carbon monoxide and therefore probably by NO. The molecular reaction behind this negative feedback and how oxygen influences nitric oxide synthase are still unclear [19]. It seems unlikely that the withdrawal of NO should induce the release of vasoconstrictors, but the details of regulation of the pulmonary circulation are still poorly understood. Ventilation with oxygen-rich gas seems to protect the vessels from this negative feedback mechanism, as it was much less pronounced in the control animals ventilated with an FiO₂ of 0.5. A rebound pulmonary vasoconstriction may be dangerous if it appears after abrupt cessation of NO inhalation in susceptible patients with hypoxemia and right heart failure, and a gradual weaning of NO treatment is probably best in such patients. Rebound deterioration of both pulmonary pressure and oxygenation after withdrawal of inhaled NO has also been noticed by others.

If the basal NO production was more severely decreased, as we think it was in the transplantation group at an FiO₂ of 0.21, the nitric oxide synthase activity would already be very low and the vessels would be constricted. Inhalation of NO would be an effective vasodilator, as it substitutes the missing endogenous NO production. With the termination of NO inhalation, the vessels would resume their state of intense vasoconstriction with low or abolished NO production, as nitric oxide synthase would not have any activity to regain. This could explain why the rebound vasoconstriction did not appear in the animals having transplantation.

Pulmonary vascular resistance increased more in the transplantation than in the control group when FiO₂ was decreased. This indicates that the perfusion, storage, reperfusion, and denervation of the transplanted lung influenced pulmonary vascular regulation. The mechanism for this could be direct damage to the endothelial or smooth muscle cells or changes in factors that regulate the diffusion or use of oxygen in the cells. This increased sensitivity to hypoxia has clinical implications because it is known that the pulmonary vessels in lung transplantation patients may be extremely reactive to hypoxic episodes, sometimes with disastrous consequences.

The improvement in oxygenation caused by NO in patients with severe adult respiratory distress syndrome is assumed to be caused mainly by a redistribution of the blood flow away from lung regions with low V/Q ratios and toward lung regions with normal V/Q ratios [5]. This mechanism is probably of minor importance in our model because the whole cardiac output went through one lung, which ought to give a fairly homogeneous V/Q ratio. We analyzed blood gases in the transplantation group with an FiO₂ of 0.21 and found a small, nonsignificant increase in arterial oxygenation.

The increase in cardiac output seen when NO inhalation was started in the air-ventilated transplantation group was probably caused by the decrease in pulmonary vascular resistance and a sudden increase in left ventricular filling. The reverse reaction appeared after cessation of NO inhalation. In all the control pigs and the transplantation group at an FiO₂ of 0.5, there seems not to have been any restriction to left ventricular filling, and therefore there was no change in cardiac output during NO inhalation in these groups. The slight decrease in systemic vascular resistance at inhalation of 80 ppm NO may be a sign of an increased level of nitrosylating (NO binding), biologically active proteins in the systemic circulating blood.

We found that the pulmonary vascular resistance and mean pulmonary arterial pressure responses to NO inhalation varied, depending on the degree of lung injury and of oxygenation. In the control pigs, which had minor lung injury, the maximal response was achieved at a lower NO dose. In the preserved and transplanted lungs, a higher dose was needed and the effect of NO inhalation was significantly better.

The rebound pulmonary vasoconstriction was more pronounced in the lungs of the control pigs, which indicates that the rebound phenomenon may be a bigger problem in ``normal'' vessels exposed to hypoxia. It remains to be seen whether this rebound pulmonary vasoconstriction can be blunted in clinical practice by increasing FiO₂. This oxygen dependency also emphasizes the importance of considering FiO₂, oxygenation, and the degree of pulmonary disease in dose-response studies on NO inhalation and its effect on pulmonary vascular resistance and mean pulmonary arterial pressure.

In summary, NO inhalation is a valuable selective pulmonary vasodilator that may reduce pulmonary hypertension after lung transplantation, especially during hypoxemia. However, the response varies depending on both preoperative and postoperative pulmonary status and oxygenation.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by grants from the Swedish Heart-Lung Foundation, T. Westerströms Foundation, and the Medical Faculty, University of Lund.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Steen, Department of Cardiothoracic Surgery, University Hospital of Lund, S-221 85 Lund, Sweden.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Richard Ingemansson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lindberg, L. Articles by Steen, S. Search for Related Content PubMed PubMed Citation Articles by Lindberg, L. Articles by Steen, S.