Reliable 18-hour lung preservation with University of Wisconsin solution An ex vivo rat model with a pulsatile perfusion system

Objectives: A common experimental model is necessary to assess therapeutic intervention in lung preservation. This study was designed to establish lung preservation in an ex vivo rat model that would enable post-storage lung function to be stably evaluated during the 2 hours following reperfusion.Subjects and Methods: Lungs isolated from Sprague-Dawley rats (n=36) were flushed and stored in University of Wisconsin solution at 4°C for the following periods: Group 1: no storage (n=12); Group 2: 4 hours (n=8); Group 3: 18 hours (n=8); and Group 4: 24 hours (n=8). After storage in University of Wisconsin solution, all lungs were reperfused with homologous venous blood exsanguinated from donor rats using a pulsatile perfusion system. Pulmonary variables, including lung airway resistance, dynamic lung compliance, total pulmonary vascular resistance, and blood gas analysis, were assessed during reperfusion.Results: All lungs stored for 24 hours failed within 1 hour of reperfusion. Lungs stored for up to 18 hours survived 2-hour reperfusion. pO₂ in groups 1 to 3 (87.1 ± 3.5, 89.7 ± 2.4, and 80.6 ± 6.4, pO₂ mmHg at 30 minutes) was similar during reperfusion, but that in group 4 (49.5 ± 4.6 mmHg, at 30 minutes) deteriorated within 30 minutes after reperfusion onset. Lung airway resistance, dynamic lung compliance, and shunt fraction also deteriorated in group 4, whereas these variables were similar in groups 1, 2, and 3 during reperfusion.Conclusions: These results indicate that this experimental model provided a reliable evaluation of preserved lung function after 18-hour cold storage. Any therapeutic intervention for extending storage periods or ameliorating poststorage lung function is easily tested using this system.     

Preventive influence of inhaled nitric oxide on lung ischemia-reperfusion injury

n = 9). The control group was not administered NO (group II, n = 8). Severe ischemia-reperfusion injury occurred as evidenced by hypoxia and lung edema. PaO₂ at 120 min after reperfusion was 325 ± 41 mmHg in group I and 40 ± 6 mmHg in group II. The pulmonary blood flow of the left lung at 120 min after reperfusion was 51% ± 3% in group I and 20% ± 5% in group II. The wet-to-dry weight ratio was 5.5 ± 0.2 for the right lungs, 5.8 ± 0.8 for the left lung in group I, and 6.1 ± 0.4 for the left lung in group II. Histopathologically, marked hemorrhage, hyaline membrane formation, and leukocyte infiltration were observed in group II but not in group I. These data suggested that inhaled NO reduced warm ischemia-reperfusion injury in the lung, and also contributed to a better preserved lung function. (Received for publication on July, 13, 1998; accepted on Mar. 11, 1999)     

Reliable 18-hour lung preservation with University of Wisconsin solution

Objectives: A common experimental model is necessary to assess therapeutic intervention in lung preservation. This study was designed to establish lung preservation in an ex vivo rat model that would enable post-storage lung function to be stably evaluated during the 2 hours following reperfusion.Subjects and Methods: Lungs isolated from Sprague-Dawley rats (n=36) were flushed and stored in University of Wisconsin solution at 4°C for the following periods: Group 1: no storage (n=12); Group 2: 4 hours (n=8); Group 3: 18 hours (n=8); and Group 4: 24 hours (n=8). After storage in University of Wisconsin solution, all lungs were reperfused with homologous venous blood exsanguinated from donor rats using a pulsatile perfusion system. Pulmonary variables, including lung airway resistance, dynamic lung compliance, total pulmonary vascular resistance, and blood gas analysis, were assessed during reperfusion.Results: All lungs stored for 24 hours failed within 1 hour of reperfusion. Lungs stored for up to 18 hours survived 2-hour reperfusion. pO₂ in groups 1 to 3 (87.1 ± 3.5, 89.7 ± 2.4, and 80.6 ± 6.4, pO₂ mmHg at 30 minutes) was similar during reperfusion, but that in group 4 (49.5 ± 4.6 mmHg, at 30 minutes) deteriorated within 30 minutes after reperfusion onset. Lung airway resistance, dynamic lung compliance, and shunt fraction also deteriorated in group 4, whereas these variables were similar in groups 1, 2, and 3 during reperfusion.Conclusions: These results indicate that this experimental model provided a reliable evaluation of preserved lung function after 18-hour cold storage. Any therapeutic intervention for extending storage periods or ameliorating poststorage lung function is easily tested using this system.     

Improvement of arterial oxygenation by selective infusion of prostaglandin E1 to ventilated lung during one-lung ventilation

Background:One-lung anesthesia provides a better surgical field for thoracic procedures but also impairs the arterial oxygenation and venous admixture. During one-lung ventilation, pulmonary vasoconstriction is assumed to be present within both ventilated and collapsed lungs. We propose that arterial oxygenation could be optimized by offsetting the vasoconstriction within the microcirculation of ventilated lung. Method:In an anesthetized dog model, incremental doses of prostaglandin E₁ (PGE₁) were selectively infused into the main trunk of the pulmonary artery of the ventilated lung after one-lung ventilation for 60 min (PGE₁ group, n=9). Arterial oxygenation and calculated venous admixture (Qs/Qt) was also assessed in a time-course control group (Control group, n =5). During two-lung ventilation (FIO₂: 0.66), arterial PO₂ and venous admixture was 44.22 ± 3.5 kPa and 10.7±2.3%, respectively. One-lung ventilation (FIO₂: 0.66) with left lung collapsed reduced arterial PO₂ to 11.6±1.7 kPa and increased venous admixture to 40.7±5.8% (P<0.001). Venous O₂ tension also decreased from 6.3±0.7 kPa to 5.0±0.6 kPa with a slight increase in mean pulmonary artery pressure and pulmonary vascular resistance (P <0.05). Results: During selective infusion of PGE₁ at a dose of 0.04 to 0.2 μg kg^-1 min^-1, there was a dose-dependent improvement in arterial PO₂ with a parallel reduction of venous admixture during one-lung ventilation. Arterial PO₂ increased to a maximum of 23.0±4.3 kPa, and the venous admixture decreased significantly to a minimum of 27.4±4.2% by PGE₁ at a dose of 0.04-0.4 μg kg^-1 min^-1 (P<0.01). PGE₁ resulted in a small increase in cardiac output and decreases of pulmonary pressure and pulmonary vascular resistance at a relatively high dose of 0.4 μg kg^-1 min^-1 during selective infusion (P<0.05). Conclusion: These results suggest that a selective pulmonary artery infusion of PGE₁ to the ventilated lung within the dose range of 0.04-0.4 μg kg^-1 min^-1 is practical and effective to improve arterial oxygenation and reduce venous admixture during one-lung ventilation.     

Ex vivo lung perfusion to improve donor lung function and increase the number of organs available for transplantation

This paper describes the initial clinical experience of ex vivo lung perfusion (EVLP) at the Fondazione Ca’ Granda in Milan between January 2011 and May 2013. EVLP was considered if donor PaO₂/FiO₂ was below 300 mmHg or if lung function was doubtful. Donors with massive lung contusion, aspiration, purulent secretions, pneumonia, or sepsis were excluded. EVLP was run with a low‐flow, open atrium and low hematocrit technique. Thirty‐five lung transplants from brain death donors were performed, seven of which after EVLP. EVLP donors were older (54 ± 9 years vs. 40 ± 15 years, EVLP versus Standard, P < 0.05), had lower PaO₂/FiO₂ (264 ± 78 mmHg vs. 453 ± 119 mmHg, P < 0.05), and more chest X‐ray abnormalities (P < 0.05). EVLP recipients were more often admitted to intensive care unit as urgent cases (57% vs. 18%, P = 0.05); lung allocation score at transplantation was higher (79 [40–84] vs. 39 [36–46], P < 0.05). After transplantation, primary graft dysfunction (PGD₇₂ grade 3, 32% vs. 28%, EVLP versus Standard, P = 1), mortality at 30 days (0% vs. 0%, P = 1), and overall survival (71% vs. 86%, EVLP versus Standard P = 0.27) were not different between groups. EVLP enabled a 20% increase in available donor organs and resulted in successful transplants with lungs that would have otherwise been rejected (ClinicalTrials.gov number: NCT01967953).     

Donor pretreatment with ambroxol or dexamethasone fails to ameliorate reperfusion injury in experimental lung transplantation

Based on the known properties of ambroxol and dexamethasone to inhibit inflammation and increase endogenous surfactant levels, the potential advantage of donor pretreatment with either drug was investigated in an acute rat double-lung transplant model. Donor animals were randomly assigned to one of three treatment groups: an ambroxol group (AMB; 0.4 mg/kg), a dexamethasone group (DX; 2 mg/kg); or an untreated control group (CN). Drugs were given intraperitoneally 6 h prior to harvest. Following standard preservation and 16 h of cold ischemia, the donor double lung block was implanted into syngeneic recipients using custom-designed stents for the vascular anastomosis. During reperfusion, serial measurements of graft pulmonary vascular resistance and alveolar-arterial oxygen difference were obtained. Separate graft ventilation allowed determination of graft dynamic lung compliance. Final assessment included weight gain and histology. For phospholipid analysis, lung lavages were performed in the three study groups at the end of reperfusion and compared to levels before graft harvest. Donor pretreatment did not significantly affect preharvest phospholipid levels. Survival following graft ischemia and reperfusion was shortest after AMB (92 ± 5 min) and longest after DX (110 ± 5 min; DX vs AMB P < 0.03) and CN (116 ± 4 min; CN vs AMB P < 0.02). DX pretreatment provided better compliance (P < 0.02) and lower vascular resistance (P < 0.0001) than AMB treatment. Airway resistance was lower in the AMB and DX groups than in controls (P < 0.04 and P < 0.02, respectively). The alveolar-arterial oxygen difference was markedly similar in all groups. Graft weight gain amounted to 114 % ± 10 % in AMB, 88 % ± 12 % in DX, and 98 % ± 13 % in CN (P = NS). Thus, in this rat lung transplantation model, donor pretreatment with dexamethasone did not improve graft function compared to untreated controls and donor pretreatment with ambroxol was found to be potentially detrimental to graft function during reperfusion. Received: 5 September 1997 Received after revision: 28 November 1997 Accepted: 14 January 1998     

The effects of bilateral lung transplantation on ventilatory efficiency,oxygen uptake and the right heart: a two‐yr follow‐up

Habedank D, Ewert R, Hummel M, Dandel M, Habedank F, Knosalla C, Lehmkuhl HB, Anker SD, Hetzer R. The effects of bilateral lung transplantation on ventilatory efficiency, oxygen uptake and the right heart: a two‐yr follow‐up.
Clin Transplant 2011: 25: E38–E45. © 2010 John Wiley & Sons A/S. Abstract: Background: This study was to examine the course of ventilation/perfusion mismatch (VE/VCO₂‐slope) before and during two‐yr follow‐up after bilateral lung transplantation (BLTx) and to relate exercise parameters with the reverse right ventricular remodeling. Methods: We prospectively examined 20 patients (nine women; age 46.0 ± 13.0 yr) by cardiopulmonary exercise testing (before and at 3, 6, 12, and 24 months after BLTx), and by echocardiography and blood gas analysis. Etiology of pulmonary failure was chronic obstructive pulmonary disease as well (n = 8), pulmonary hypertension (n = 7), idiopathic fibrosis (n = 3), others (n = 2). Results: The VE/VCO₂‐slope before BLTx was 47.5 (interquartile range 24.5) and declined at 3 months ?25.9%, 6 months ?30.9%, 12 months ?33.9%, and 24 months ?35.1% (all p ≤ 0.003) and was then not different from normal. The right ventricular end diastolic diameter RVEDd narrowed from 35.0 (22.5) before to 31.0 (9.0) mm at 3 months after LTx. Similarly, right ventricular systolic pressure (RV_sys) decreased from 53.6 ± 28.3 to 26.2 ± 5.2 mmHg (all p < 0.01). RVEDd correlated with VE/VCO₂‐slope before (p < 0.0001) but not after BLTx. PeakVO₂ increased from 10.0 ± 2.3 mL/min per kg before BLTx by 86.5% at 24 months (p < 0.01). Conclusions: The functional status (VE/VCO₂‐slope, peakVO₂) improves quickly after lung transplantation and is accompanied by reverse remodeling of the right heart. A correlation between exercise parameters and right heart function was found before BLTx only.     

Effect of peak inspiratory flow on gas exchange, pulmonary mechanics, and lung histology in rabbits with injured lungs

Purpose The aim of this study was to evaluate, using a rabbit model, the little-known effect of different levels of peak inspiratory flow on acutely injured lungs. Methods Fourteen male rabbits (body weight, 2711 ± 146 g) were anesthetized and their lungs were injured by alveolar overstretch with mechanical ventilation until Pa_O2 was reduced below 300 mmHg. Injured animals were randomly assigned to: the P group—to receive pressure-regulated volume-control ventilation (PRVCV; n = 7); and the V group—to receive volume-control ventilation (VCV; n = 7). Other ventilator settings were: fraction of inspired oxygen (FI_O2), 1.0; tidal volume, 20 ml·kg⁻¹; positive end-expiratory pressure (PEEP) 5 cmH₂O; and respiratory rate, 20 min⁻¹. The animals were thus ventilated for 4 h. Throughout the protocol, ventilatory parameters and blood gas were measured every 30 min. After the protocol, the lung wet-to-dry ratio and histological lung injury score were evaluated in the excised lungs. Results Throughout the protocol, peak inspiratory flow and mean inspiratory flow values in the P group were significantly higher than those in the V group (26.7 ± 5.0 l·min⁻¹ vs 1.2 ± 0.2 l·min⁻¹, and 4.3 ± 0.3 l·min⁻¹ vs 1.1 ± 0.1 l·min⁻¹; P < 0.05). The wet-to-dry ratio in the P group was also significantly higher than that in the V group (7.7 ± 0.9 vs 6.3 ± 0.5; P < 0.05). More animals in the P group than in the V group had end-of-protocol Pa_O2/FI_O2 ratios below 200 mmHg (43% vs 0%; P = 0.06). Conclusion In rabbits with injured lungs, high peak inspiratory flow with high tidal volume (V_T) reduces the Pa_O2/FI_O2 ratio and increases the lung wet-to-dry ratio.     

Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a frequent indication for lung transplantation (LTX) with pulmonary hypertension (PH) negatively affecting outcome. The optimal procedure type remains a debated topic. The aim of this study was to evaluate the impact of pretransplant PH in IPF patients. Single LTX (SLTX, n = 46) was the standard procedure type. Double LTX (DLTX, n = 30) was only performed in cases of relevant PH or additional suppurative lung disease. There was no significant difference for pretransplant clinical parameters. Preoperative mean pulmonary arterial pressure was significantly higher in DLTX recipients (22.7 ± 0.8 mmHg vs. 35.9 ± 1.8 mmHg, P < 0.001). After transplantation, 6‐min‐walk distance and BEST‐FEV₁ were significantly higher for DLTX patients (6‐MWD: 410 ± 25 m vs. 498 ± 23 m, P = 0.02; BEST‐FEV₁: 71.2 ± 3.0 (% pred) vs. 86.2 ± 4.2 (% pred), P = 0.004). Double LTX recipients demonstrated a significantly better 1‐year‐, overall‐ and Bronchiolitis obliterans Syndrome (BOS)‐free survival (P < 0.05). Cox regression analysis confirmed SLTX to be a significant predictor for death and BOS. Single LTX offers acceptable survival rates for IPF patients. Double LTX provides a significant benefit in selected recipients. Our data warrant further trials of SLTX versus DLTX stratifying for potential confounders including PH.     

Improved ventilation-perfusion matching with increasing abdominal pressure during CO(2) -pneumoperitoneum in pigs

Background: CO₂‐pneumoperitoneum (PP) is performed at varying abdominal pressures. We studied in an animal preparation the effect of increasing abdominal pressures on gas exchange during PP. Methods: Eighteen anaesthetized pigs were studied. Three abdominal pressures (8, 12 and 16 mmHg) were randomly selected in each animal. In six pigs, single‐photon emission computed tomography (SPECT) was used for the analysis of V/Q distributions; in another six pigs, multiple inert gas elimination technique (MIGET) was used for assessing V/Q matching. In further six pigs, computed tomography (CT) was performed for the analysis of regional aeration. MIGET, CT and central haemodynamics and pulmonary gas exchange were recorded during anaesthesia and after 60 min on each of the three abdominal pressures. SPECT was performed three times, corresponding to each PP level. Results: Atelectasis, as assessed by CT, increased during PP and in proportion to abdominal pressure [from 9 ± 2% (mean ± standard deviation) at 8 mmHg to 15 ± 2% at 16 mmHg, P<0.05]. SPECT during increasing abdominal CO₂ pressures showed a shift of blood flow towards better ventilated areas. V/Q analysis by MIGET showed no change in shunt during 8 mmHg PP (9 ± 1.9% compared with baseline 9 ± 1.2%) but a decrease during 12 mmHg PP (7 ± 0.9%, P<0.05) and 16 mmHg PP (5 ± 1%, P<0.01). PaO₂ increased from 39 ± 10 to 52 ± 9 kPa (baseline to 16 mmHg PP, P<0.01). Arterial carbon dioxide (PCO₂) increased during PP and increased further with increasing abdominal pressures. Conclusion: With increasing abdominal pressure during PP perfusion was redistributed more than ventilation away from dorsal, collapsed lung regions. This resulted in a better V/Q match. A possible mechanism is enhanced hypoxic pulmonary vasoconstriction mediated by increasing PCO₂.     

The value of 99mTc macroaggregated albumin lung perfusion scanning in the prediction of postpneumonectomy function and pulmonary artery pressure

^99mTc macroaggregated albumin lung perfusion scans were performed with assessment of pulmonary hemodynamics in 14 male patients with a centrally located lung tumor, subjected to pneumonectomy. In 7 patients perfusion of the affected lung was less than one third of total perfusion. However, all tumors were resectable. Results show that predictive value of the perfusion scan was significant (p<0.02) with regard to forced expiratory volume in the first second (FEV₁, r=0.80). A fair but not significant correlation existed in the prediction of vital capacity (VC, r=0.64) and total lung capacity (TLC, r=0.71). No correlation was found between perioperative change in mean pulmonary artery pressure (MPAP) and either relative radionuclide uptake of the affected lung or predicted FEV₁. So, the lung perfusion scan cannot be used in preoperative estimation of postoperative MPAP.     

Endocrine heart after lung transplantation: increased brain natriuretic peptide is related to right ventricular function

Brain natriuretic peptide (BNP) increases in proportion to the extent of right ventricular dysfunction in pulmonary hypertension and after heart transplantation. No data are available after lung transplantation. Clinical, biological, respiratory, echocardiographic characteristics and circulating BNP and its second messenger cyclic guanosine monophosphate (cGMP) were determined in thirty matched subjects (10 lung‐, 10 heart‐transplant recipients (Ltx, Htx) and 10 healthy controls). Eventual correlations between these parameters were investigated. Heart rate and pulmonary arterial blood pressure were slightly increased after transplantation. Creatinine clearance was decreased. Mean of forced expiratory volume in 1 s was 76.6 ± 5.3% and vital capacity was 85.3 ± 6.4% of the predicted values in Ltx. BNP was similarly increased in Ltx and Htx, as compared with control values (54.1 ± 14.2 and 45.6 ± 9.2 vs. 6.2 ± 1.8 pg/ml, respectively). Significant relationships were observed between plasma BNP and cGMP values (r = 0.62; P < 0.05 and r = 0.75; P < 0.01, in Ltx and Htx) and between BNP and right ventricular fractional shortening and tricuspid E/Ea ratio in Ltx (r = ?0.75 and r = 0.93; P < 0.01, respectively). BNP is increased after lung transplantation, like after heart transplantation. The relationships observed suggest that the cardiac hormone might counterbalance possible deleterious effects of lung‐transplantation on right functioning of patient’s heart.     

Effects ofl-arginine andN-nitro-l-arginine treatment on hemodynamics, DO2, VO2, and extravascular lung water in a dog endotoxin shock model

To verify the effect of nitric oxide pathway modification during sepsis, experiments were conducted in four groups of anesthetized dogs which received lipopolysaccharide (LPS) intravenously (group 1), 300 mg·kg⁻¹ ofl-arginine plus LPS (group 2), 20 mg·kg⁻¹ ofN-nitro-l-arginine plus LPS (l-NNA, group 3), and normal saline as the control group. Hemodynamic and oxygenation data as well as extravascular lung water (EVLW) were measured or calculated. The results showed thatl-arginine increases cardiac output index (CI) and decreased the peripheral vascular resistance index (PVRI) without a significant influence on oxygen extraction ratio (O₂ER), oxygen delivery (DO₂), or oxygen consumption (VO₂). All of the untoward hemodynamic effects of LPS were exacerbated by the addition ofl-NNA. Therefore, as DO₂ was significantlys decreased byl-NNA, and although O₂ER was increased (insufficiently), VO₂ was still decreased significantly. EVLW was markedly increased byl-NNA. These results support the hypothesis that inhibition of nitric oxide synthesis may exacerbate hemodynamic and oxygenation consequences in septic shock.     

Analysis of lung density by computed tomography before and during general anaesthesia

Pulmonary structure was analysed by means of computed tomography (CT) in 20 lung-healthy patients, relating tissue density to the attenuation value (AV) of a picture element. Regional density of pulmonary tissue (r_lung) was determined using mean lung density in five regions of interest (ROI_1–5) (sector method). Vertical and horizontal distributions of x-ray attenuation were analysed by density profiles, relating AV values to evenly distributed and normalised length scales. In group I (n= 12), CT-densitometry was obtained in awake, supine patients and after induction of general anaesthesia. In group II (n = 8), the effect of mechanical ventilation with positive end-expiratory pressure (PEEP, 1.0 kPa [10 cmH₂O]) was studied. In the awake state, a vertical tissue density difference between the top and the bottom of the lung was found in all patients, accounting for a mean of 0.235 g'cm^-3 (right lung) and 0.199 g'cm^-3 (left lung). Only minor changes were seen in the horizontal lung density profiles. After induction of anaesthesia, x-ray attenuation of ROI_1–4 showed no significant differences when compared with the awake state. The basal lung areas (ROI₅) revealed a significantly increased tissue density (P ≤ 0.01), reaching mean values of 0.94 g cm^-3 (right lung) and 0.814 g-cm^-3 (left lung). Similarly, vertical density profiles showed a markedly enhanced r_lung of the bottom of the lung in all patients, interpreted as atelectasis. The amount of atelectasis accounted for 4.8 ± 2.6% (right lung) and 4.7 ± 2.1% (left lung) of the intrapulmonary area. There was no evidence of “non-gravitational” inhomogeneity of density distribution seen in the horizontal density profiles. After application of PEEP, basal lung densities decreased significantly, although small basal densities remained in most patients (2.27 ± 2.57% of right intrapulmonary area [P ≤ 0.01], 2.2 ± 2.37% left intrapulmonary area [P ≤ 0.01]). Calculated alveolar recruitment was 7.7 cm² and 8.4 cm², whereas expansion of both lungs was smaller (4.3 cm² and 4.4 cm² [right and left lung]). Mean density of aerated tissue had decreased by 25%, and both horizontal and vertical attenuation profiles revealed an even distribution of r_lung. Analysis of r_lung provides useful information about regional pulmonary morphology during anaesthesia and may be related to lung function.     

Hypoxia-induced vasoconstriction in human lung exposed to enflurane anaesthesia

The degree of hypoxic pulmonary vasoconstriction was studied in eight subjects during enflurane anaesthesia and was compared with that during intravenous pentobarbital anaesthesia in the same subjects. The lungs were ventilated separately with the aid of a double-lumen endobronchial catheter. After preoxygenation of both lungs for 30 min, during intravenous anaesthesia, the right lung (test lung) was rendered hypoxic by ventilation with 6% O2 in nitrogen. The left lung (control lung) was ventilated continuously with 100% oxygen. Cardiac output (QT) was determined by thermodilution, and the distribution of blood flow between the lungs was assessed from the elimination of a continuously infused, poorly soluble inert gas (SF6). The hypoxic challenge resulted in a reduction of the distribution of perfusion to the test lung from 57% to 36% of QT. Mean pulmonary arterial pressure increased by 37% and pulmonary vascular resistance of the test lung doubled. Arterial oxygen tension decreased from 45.9 to 9.5 kPa. Administration of enflurane to an end-tidal concentration of 2% to both lungs caused no significant change in the distribution of the pulmonary blood flow, PVR, or any other circulatory variable. The arterial blood gases remained unaltered. When the hypoxic challenge was discontinued, all variables returned towards control values. The findings suggest that the inhalational anaesthetic enflurane does not reduce the hypoxic vasoconstrictor response in the human lung.     

Iloprost inhalation redistributes pulmonary perfusion and decreases arterial oxygenation in healthy volunteers

Background: Previous studies have shown that ventilation–perfusion matching is improved in the prone as compared with that in the supine position. Regional differences in the regulation of vascular tone may explain this. We have recently demonstrated higher production of nitric oxide in dorsal compared with ventral human lung tissue. The purpose of the present study was to investigate regional differences in actions by another vasoactive mediator, namely prostacyclin. The effects on gas exchange and regional pulmonary perfusion in different body positions were investigated at increased prostacyclin levels by inhalation of a synthetic prostacyclin analogue and decreased prostacyclin levels by unselective cyclooxygenase (COX) inhibition. Methods: In 19 volunteers, regional pulmonary perfusion in the prone and supine position was assessed by single photon emission computed tomography using ^99mTc macro‐aggregated albumin before and after inhalation of iloprost, a stable prostacyclin analogue, or an intravenous infusion of a non‐selective COX inhibitor, diclofenac. In addition, gas distribution was assessed in seven subjects using ^99mTc‐labelled ultra‐fine carbon particles before and after iloprost inhalation in the supine position. Results: Iloprost inhalation decreased arterial PaO₂ in both prone (from 14.2±0.5 to 11.7±1.7 kPa, P<0.01) and supine (from 13.7±1.4 to 10.9±2.1 kPa, P<0.01) positions. Iloprost inhalation redistributed lung perfusion from non‐dependent to dependent lung regions in both prone and supine positions, while ventilation in the supine position was distributed in the opposite direction. No significant effects of non‐selective COX inhibition were found in this study. Conclusions: Iloprost inhalation decreases arterial oxygenation and results in a more gravity‐dependent pulmonary perfusion in both supine and prone positions in healthy humans.     

Evaluating acellular versus cellular perfusate composition during prolonged ex vivo lung perfusion after initial cold ischaemia for 24 hours

Normothermic ex vivo lung perfusion (EVLP) has developed as a powerful technique to evaluate particularly marginal donor lungs prior to transplantation. In this study, acellular and cellular perfusate compositions were compared in an identical experimental setting as no consensus has been reached on a preferred technique yet. Porcine lungs underwent EVLP for 12 h on the basis of an acellular or a cellular perfusate composition after 24 h of cold ischaemia as defined organ stress. During perfusion, haemodynamic and respiratory parameters were monitored. After EVLP, the lung condition was assessed by light and transmission electron microscopy. Aerodynamic parameters did not show significant differences between groups and remained within the in vivo range during EVLP. Mean oxygenation indices were 491 ± 39 in the acellular group and 513 ± 53 in the cellular group. Groups only differed significantly in terms of higher pulmonary artery pressure and vascular resistance in the cellular group. Lung histology and ultrastructure were largely well preserved after prolonged EVLP and showed only minor structural alterations which were similarly present in both groups. Prolonged acellular and cellular EVLP for 12 h are both feasible with lungs prechallenged by ischaemic organ stress. Physiological and ultrastructural analysis showed no superiority of either acellular or cellular perfusate composition.     

Calculated versus measured oxygen consumption during and after cardiac surgery. Is it possible to estimate lung oxygen consumption?

Background: Lung tissue is metabolically active and consumes oxygen. The oxygen content difference between arterial and mixed venous blood does not include the effect of pulmonary tissue oxygen uptake. Thus, oxygen consumption (VO₂) of the lung should be reflected as a difference between VO₂ measured by gas exchange and VO₂ derived by the Fick principle. The purpose of this study was to measure in clinical conditions this difference (taken to represent the VO₂ of the lung), and to evaluate the sources of error in lung VO₂ estimation. Methods: Nine patients undergoing coronary artery bypass grafting were studied. VO₂ was measured by indirect calorimetry (VO₂gasex) and compared to Fick-derived VO₂ (VO₂Fick) after induction of anaesthesia, after closure of the chest, at admission to intensive care, after stabilization of haemodynamics and during weaning from mechanical ventilation. The Fick-derived VO₂ was calculated from blood samples taken at the beginning and at the end of each 20 min measurement period, and the mean of 12 consecutive thermodilution cardiac output measurements taken during each 20 min measurement period. Results: VO₂gasex was higher than VO₂Fick (P <0.01; in all except 4 of 45 measurements). The difference between the measured and the calculated VO₂ was 33 ±25 ml/min (mean±SD, range -16–100 ml/min). This difference represented 14±3% (range 11–18%) of the whole body VO₂. The VO₂-difference was highest after the induction of anaesthesia (50±19 ml/min; range 20–81 ml/min, P < 0.03) and lowest on arrival at the intensive care unit (10±16 ml/min; range -16–39 ml/min). Core temperature did not correlate with the oxygen consumption difference. Conclusions: A constant difference between measured and calculated VO₂ can be detected in carefully controlled clinical conditions. The difference between the two methods is due to both lung oxygen consumption and errors in the measurement of VO₂, thermodilution cardiac output, haemoglobin and blood oxygen contents. We suggest that the perioperative changes of the VO₂-difference are due not only to variation of the measurements but also to changes in lung metabolic activity.     

Intestinal microcirculation and gut permeability in acute pancreatitis: Early changes and therapeutic implications

Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis, pancreatic capillary perfusion remained unchanged (2.13 ± 0.06 vs. 1.98 ± 0.04 nl-min^−l.cap ⁻¹ [control]; P = NS), whereas mucosal (1.59 _± 0.03 vs. 2.28 ± 0.03 nl.min^−l.cap ⁻¹ [control]; P <0.01) and subserosal (2.47 ± 0.04 vs. 3.74 ± 0.05 nl-min^−l.cap ^-1 [control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked reduction in both pancreatic (1.06 = 0.03 vs. 1.98 ± 0.04 nl’min^-1.cap ^-1 [control]; P <0.01) and colonic (mucosal: 0.59 = 0.01 vs. 2.28 ± 0.03 nl.min^−l.cap ^-1 [control], P < 0.01; subserosal: 1.96 ± 0.05 vs. 3.74 ± 0.05 nl.min^−l.cap ^-1 [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control: 147 ±19 nmol.hr^−l.cm {−2}2; mild pancreatitis: 158±23 nmol-hr^−l.cm^-2; severe pancreatitis: 181 ±33 nmol.hr^−l.cm^-2; P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result in improved intestinal microcirculation. Presented at the Thirty-Seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 19–22, 1996. Supported in part by Deutsche Forschungsgemeinschaft (DFG Fo 197/3).     

Pulmonary effects of autotransfused blood. A comparison of fresh autologous and stored blood with blood retrieved from the pleural cavity in an in situ lung perfusion model

An in situ pulmonary lobe perfusion model in dogs was used to examine the pulmonary effects of autotransfused blood as compared with fresh and stored blood. Fresh arterial blood was collected in heparin solution from ten dogs and was drained into and collected from the pleural cavity using a commercially available autotransfusion device for continuous filtration. Results of perfusion with autotransfused blood were compared with results of perfusion of blood stored at 4 °C in ACD solution for twenty-four hours in seven dogs and those of perfusion of blood stored for twenty-one days at 4 °C in ACD solution in seven dogs. The fresh and stored blood samples were passed through a standard recipient set filter prior to perfusion.Perfusion with autotransfused blood resulted in a decreased arteriovenous pO₂ gradient as compared with results in control blood, but there was no concomitant elevation in pulmonary vascular resistance (PVR) or endobronchial pressure (P_b) for the autotransfused blood. Stored blood by comparison showed significantly increased PVR and P_b but a progressive decline in A-VpO₂ which was in excess of the level reached by perfusion of autotransfused blood. Fresh blood showed essentially no change in pulmonary functional parameters during perfusion.The great majority of animals whose lungs were perfused with stored blood had microscopic evidence of interstitial pulmonary edema, perivascular hemorrhage, intra-alveolar fluid, and alveolar congestion. Significantly fewer animals showed these changes when lungs were perfused with autotransfused or fresh blood. Wet-dry weight ratios of lung tissue after perfusion indicated significantly higher uptake of water by the lung perfused with stored blood than by those perfused with autotransfused or fresh blood.