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Ann Thorac Surg 1996;61:1435-1440
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Pulmonary Endothelial Permeability Changes After Major Lung Resection

Regional Cardiothoracic Centre, Freeman Hospital, Newcastle-upon-Tyne, United Kingdom

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. Increased pulmonary endothelial permeability has been proposed as a cause of postpneumonectomy pulmonary edema. This study investigated changes in pulmonary endothelial permeability after major lung resection.

Methods. Lung scintigraphy was performed in 21 men (median age, 66 years; range, 34 to 73 years) after pneumonectomy (10 patients) or lobectomy (11 patients). Pulmonary endothelial permeability was measured by the net pulmonary accumulation of intravenous technetium-99m--labeled albumin, calculated as a ratio of lung:heart radioactivity counts. Pulmonary hemodynamics were monitored continuously by a pulmonary artery catheter, and serum levels of inflammatory cytokines were assayed.

Results. The lung:heart radioactivity ratio increased significantly in the initial 8 hours after pneumonectomy but not after lobectomy (p < 0.01). Mean pulmonary artery pressure and pulmonary vascular resistance both increased significantly during pneumonectomy (p < 0.05). The intraoperative increase in mean pulmonary artery pressure was inversely related to preoperative mean pulmonary artery pressure (r = -0.47; p = 0.02). The postoperative change in lung:heart radioactivity ratio was related to the perioperative increase in pulmonary vascular resistance (r = 0.54; p = 0.02) but not to the increase in mean pulmonary artery pressure (r = 0.14; p > 0.05). Serum interleukin-8 and neutrophil elastase levels were elevated in all patients preoperatively. The postoperative change in lung:heart radioactivity ratio was related to preoperative elastase levels (r = 0.61; p = 0.02).

Conclusions. Pulmonary endothelial permeability appears to be increased after pneumonectomy. Preoperative neutrophil activation and the adaptation of the remaining pulmonary vasculature may be etiologic factors.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Postoperative noncardiogenic pulmonary edema is a serious complication of lung resection occurring in up to 4% of cases [1]. The underlying mechanism is not fully understood, but perioperative changes in hydrostatic forces acting on the alveolar-capillary membrane are thought to be contributory [2]. The high protein content in postpneumonectomy pulmonary edema suggests that increased permeability of the alveolar-capillary membrane develops in this syndrome [3]. Furthermore, similarities between the end-stage lung parenchymal changes in postpneumonectomy pulmonary edema and the adult respiratory distress syndrome suggest that there may be a similar etiology [4].

The objectives of this study were to identify and compare any changes in pulmonary endothelial permeability after pneumonectomy and lobectomy. Furthermore, we aimed to correlate postoperative permeability changes with perioperative changes in pulmonary hemodynamics or serum cytokine release.

	Patients and Methods

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Twenty-one consecutive patients undergoing pneumonectomy or lobectomy for benign or malignant conditions were prospectively studied. Female patients were excluded. Written informed consent was obtained in each case. This study was conducted under ethical approval from the Newcastle Health Authority.

Measurement of Pulmonary Endothelial Permeability
Pulmonary endothelial permeability changes were measured at the patients' bedside using a technique previously described in studying adult respiratory distress syndrome caused by sepsis or drug overdose [5]. This involved the measurement of the pulmonary accumulation of intravenous technetium-99m--labeled human serum albumin (estimated dose, 1 mSv) administered 2 hours after operation. Portable scintigraphy was performed using cesium iodode miniscintillation detectors (Mediscint; Oakfield Instruments, Oxon, UK), sensitive to gamma photons, positioned over two standard points on the nonoperative lung field and over the midcardiac blood pool. The position was confirmed as the point of maximal precordial activity after injection before data collection (to allow for postoperative mediastinal shift). Time-activity curves for each probe site were acquired over 12 hours (144 5-minute images). Each curve was smoothed and corrected for technetium-99m decay. The lung curves were divided by the heart curve to give plots representing the lung:heart ratio of counts (L:H). An index of the change in postoperative albumin accumulation was derived by subtracting the L:H at 50 minutes (the time taken for equilibration) from the L:H at 350 minutes into the scanning period.

Pulmonary Hemodynamics
A radial artery cannula and flow-directed pulmonary artery (PA) catheter were placed in each patient before induction of general anesthesia. If the PA catheter was palpated in the ipsilateral PA (side of resection) after thoracotomy the catheter was withdrawn, the vessel occluded, and the catheter tip guided into the contralateral PA. Hemodynamic measurements were made in the nonintubated patient, after intubation (in the thoracotomy position with single-lung ventilation), immediately before and after PA occlusion, and at the end of the operation in the supine position. Measurements were made at 2-hour intervals during the immediate 18-hour postoperative period. The following measurements were recorded at each interval: mean pulmonary artery pressure (MPAP), systemic blood pressure, right atrial pressure, pulmonary capillary wedge pressure (PCWP), and cardiac output. The signals from the PA catheter were processed through a cardiac output computer to derive the following variables: cardiac index, systemic vascular resistance, and pulmonary vascular resistance (PVR). Pulmonary capillary pressure (Pc) was derived from the following formula [6]: Pc = PCWP + 0.4 (MPAP-PCWP).

Cytokine Measurements
Serum samples were obtained before induction of general anesthesia from central venous blood, during operation (after occlusion of the PA supply to the resected lung tissue and just before closure of the chest) by direct aspiration of left atrial blood, and postoperatively from systemic venous blood. Samples were processed using the enzyme-linked immunosorbent assay technique for tumor necrosis factor-alpha, interleukin-8, soluble E-selectin, and neutrophil elastase.

Statistical Analysis
The statistical significance of differences in variables between patients undergoing pneumonectomy or lobectomy was assessed by Wilcoxon rank sum tests and for individuals by Wilcoxon signed rank tests. Correlations between variables were assessed using linear regression analysis. Significance was accepted for p values less than 0.05.

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Patient Characteristics
Pneumonectomy was performed in 10 patients (median age, 56.5 years; range, 34 to 73 years). Lobectomy was performed in 11 patients (median age, 69 years; range, 38 to 73 years). There was no difference in the median 24-hour postoperative fluid balance between these two groups: pneumonectomy, 20 mL/kg (range, 15 to 24 mL/kg); lobectomy, 18 mL/kg (range, 10 to 24 mL/kg).

Pulmonary Endothelial Permeability
After pneumonectomy the median L:H ratio rose significantly from 0.53 (range, 0.12 to 0.7) at 50 minutes to 0.55 (range, 0.16 to 0.85) at 350 minutes (p < 0.05 by Wilcoxon signed rank test) (Table 1; Fig 1). After lobectomy the change in L:H ratio during this period was not significant (p > 0.05). In 10 patients (5 postpneumonectomy, 5 postlobectomy) the L:H ratio was calculated for a further 300 minutes after operation and there was no significant change from the L:H ratio at 350 minutes. In 1 patient, after left pneumonectomy, the clinical syndrome of postpneumonectomy pulmonary edema was identified with radiologic evidence of alveolar edema.

View larger version (30K): [in this window] [in a new window]   Fig 1. . Effect of lung resection on postoperative pulmonary albumin accumulation. (L:H = lung:heart.)

Pulmonary Hemodynamics
MEAN PULMONARY ARTERY PRESSURE.
During pneumonectomy (after pulmonary artery occlusion) MPAP increased significantly (p < 0.05 by Wilcoxon signed rank test) (Table 2). This intraoperative increase in MPAP was significantly greater during pneumonectomy than lobectomy (p < 0.01 by Wilcoxon rank sum test). By the end of the operation MPAP was not significantly different from preoperative values in either group. Preoperative MPAP was inversely related (r = -0.68; p = 0.02) to the subsequent perioperative change in MPAP. The perioperative increase in MPAP did not affect postoperative changes in L:H ratio (r = 0.14; p > 0.05).

View larger version (34K): [in this window] [in a new window]   Fig 2. . Effect of perioperative change in pulmonary vascular resistance (PVR) on postoperative pulmonary albumin accumulation. (L:H = lung:heart.)

Inflammatory Cytokines
Preoperative serum levels of interleukin-8 and neutrophil elastase were greater than standard controls in all 21 patients (Table 6). Serum levels of soluble E-selectin were increased in 12 patients (57%), and tumor necrosis factor-alpha level was found to be increased in only 7 patients (33%). There was no significant difference between patients who subsequently underwent pneumonectomy or lobectomy. There was no significant change in tumor necrosis factor-alpha, soluble E-selectin, or interleukin-8 after either pneumonectomy or lobectomy. Serum levels of neutrophil elastase decreased significantly during pneumonectomy from preoperative values (p < 0.02 by Wilcoxon signed rank test).

View larger version (36K): [in this window] [in a new window]   Fig 3. . Effect of preoperative serum neutrophil elastase on postoperative pulmonary albumin accumulation. (L:H = lung:heart.)

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

A variation of the method we have used for assessing pulmonary endothelial permeability has been validated clinically in patients with radiologic and clinical evidence of permeability pulmonary edema [5]. However, there remain several criticisms of the technique. Lack of radiolabel integrity was excluded by demonstrating excellent retention of radioactivity by albumin in serum samples taken 8 hours after injection. The fixed position of scintillation counters and the relatively narrow field of observation may have failed to detect heterogeneous permeability changes. Variability arising from chest wall activity beneath the probes was reduced by studying men only, thus avoiding problems with varying amounts of mammary tissue in female patients. The original description of the technique suggested its limitations in the presence of independent changes in cardiac or pulmonary blood volumes. We have assumed that any acute changes in pulmonary blood flow have occurred before scanning, on occlusion of the contralateral pulmonary blood flow. The use of dual isotope scintigraphy would have corrected for changes in circulating volume.

Our hemodynamic observations correlate with published data. Crouch and associates [7] noted an increase in PVR of 70% in dogs during pneumonectomy, attributed to a 34% increase in MPAP without significant change in left atrial pressure. In a study of humans undergoing pneumonectomy, Lewis and colleagues [8] found a significant increase in PVR in 30% of patients at PA clamping, although MPAP did not change. They also found that in the majority of patients with preoperative pulmonary hypertension there was no significant increase in MPAP on unilateral arterial occlusion. This concurs with our finding that the preoperative MPAP was inversely related to the perioperative increase in both MPAP and Pc. Preoperative reactive vasoconstriction, in response to tumor-induced underventilation, may result in little subsequent change in pulmonary blood flow after resection.

This study suggests a correlation between increased PVR and increased pulmonary protein accumulation. These findings are similar to those reported by Ohkuda and associates [9], who found that uneven PA obstruction results in an increase in PVR that was associated with an increase in fluid and protein flux in the remaining perfused areas of lung. They further demonstrated that an increase in PA pressure with constant PVR did not increase protein flux. This correlates with our finding that the perioperative change in MPAP did not affect protein accumulation. Increased microvascular flow rate was thought to be the most important factor in inducing permeability changes. The linear velocity of blood in the pulmonary microcirculation is increased when a reduced vascular bed is subjected to a constant cardiac output, which increases tangential and shear stresses and may cause physical injury to the endothelium, leading to increased membrane permeability.

We did not find intraoperative release of cytokines, unlike previous reports [10]. However, we noted (1) variability in preoperative serum cytokine levels and (2) a relationship between preoperative expression of neutrophil activation and subsequent changes in pulmonary endothelial permeability.

The preoperative variability may relate to the variable effects of the underlying lung tumor, a recognized stimulus for cytokine release [11]. We have not identified any relationship with gross tumor characteristics (histologic type, pathologic stage, tumor size), but more detailed analysis is required in future work.

The effects of neutrophil-related enzymes on lung permeability in the postoperative period have been reported previously. Increased pulmonary capillary permeability after esophagectomy has been related to neutrophil elastase release [12], and the detructive effects of neutrophil elastase on type IV collagen, a molecule critical in maintaining the structural integrity of the capillary wall, are well recognized [13].

Our finding that greater permeability changes occur after pneumonectomy than after lobectomy correlates with the greater frequency of clinically apparent postresectional edema after pneumonectomy. As has also been demonstrated clinically [14], fluid overload and increased hydrostatic pressure are not likely to be major etiologic factors in increased permeability edema. This is supported by the lack of correlation between permeability changes and either PA pressure or pulmonary capillary pressure in this study. However, in the presence of increased lung permeability postoperative fluid overload may explain the often delayed presentation of clinical symptoms.

Therapeutic interventions in the developed syndrome of postpneumonectomy pulmonary edema are limited, but prophylactic pulmonary vasodilators, whether intravascular or inhaled, given before vascular occlusion during pneumonectomy may have a preventive role. Increasing the capacitance of the remaining pulmonary vasculature may reduce the increase in velocity of flow and associated endothelial dysfunction.

In conclusion, we have identified a multifactorial etiology for postresectional permeability changes. Both preoperative neutrophil activation and intraoperative hemodynamic forces may result in increased lung injury. These findings have implications for both the etiology and management of postpneumonectomy pulmonary edema.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We thank Mr Graham N. Morritt and Mr Colin J. Hilton for their permission to enter patients under their care into this study. We are endebted to the Fight Against Cancer Trust for their financial support.

	References

Top Abstract Introduction Patients 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): David A. Waller John H. Dark Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Waller, D. A. Articles by Dark, J. H. Search for Related Content PubMed PubMed Citation Articles by Waller, D. A. Articles by Dark, J. H.