Lower Pulmonary Vascular Resistance Research Articles

Hemodynamic Effects of Aerosolized Iloprost in Pulmonary Hypertension at Rest and During Exercise

Aerosolized iloprost, a stable prostacyclin analog, improves functional capacity even in patients with pulmonary hypertension who did not show a vigorous hemodynamic response after iloprost inhalation at rest. We therefore speculated that aerosolized iloprost elicits more beneficial effects on pulmonary hemodynamics during exercise than at rest. A prospective, open, uncontrolled study at a university hospital. Sixteen patients with primary or secondary pulmonary hypertension. Right-heart catheterization at rest and during exercise before and after the inhalation iloprost, 14 to 28 microg. Before iloprost treatment, exercise increased mean (+/- SD) pulmonary artery pressure (PAPm) from 45 +/- 8 to 70 +/- 13 mm Hg, cardiac output from 3.7 +/- 1.0 to 5.8 +/- 2.4 L/min, and pulmonary vascular resistance (PVR) from 904 +/- 322 to 1,013 +/- 432 dyne.s.cm(-5) (each p < 0.05). After recovery, iloprost reduced PAPm from 44 +/- 8 to 41 +/- 6 mm Hg, increased cardiac output from 3.7 +/- 1.0 to 4.9 +/- 1.4 L/min, and lowered PVR from 902 +/- 350 to 636 +/- 248 dyne x s x cm(-5) (each p < 0.05). During exercise after iloprost, PAPm increased to 57 +/- 8 mm Hg, cardiac output to 7.0 +/- 3.0 L/min, and PVR to 673 +/- 279 dyne x s x cm(-5) (each p < 0.05 vs first exercise test). Systemic BP was not altered significantly by iloprost treatment during exercise. Aerosolized iloprost treatment exerts more favorable effects on pulmonary hemodynamics during exercise than at rest. These findings explain the functional improvement observed in patients with pulmonary hypertension who show only a moderate pulmonary vasodilatory response during iloprost inhalation at rest. Whether these beneficial effects have prognostic significance needs to be elucidated by further study.

Effects of dilutional and modified ultrafiltration in plasma endothelin-1 and pulmonary vascular resistance after the Fontan procedure

Background. Pulmonary vascular resistance (PVR) is closely related with patients’ hemodynamics after the Fontan procedure and endothelin-1 (ET-1) may play an important role in pulmonary circulation. Modified ultrafiltration (MUF) is known to remove inflammatory mediators after cardiopulmonary bypass (CPB) surgery. The time courses of plasma ET-1 and PVR were examined before and after the Fontan procedure with MUF. Methods. Twenty-two patients who underwent the Fontan procedure were divided into two groups: a dilutional ultrafiltration/modified ultrafiltration (DUF/MUF) group (n =11) and a control group (n = 11). Conventional ultrafiltration was performed during CPB in the control group. DUF was performed semicontinuously during CPB and MUF was continued until 15 to 20 minutes after the CPB with polyacrylonitonile membrane in the DUF/MUF group. The plasma ET-1 concentration was mea-sured before and after CPB, after MUF in the DUF/MUF group, and 6 and 24 hours after CPB. PVR was calculated simultaneously using a thermodilutional catheter. Results. Plasma ET-1 levels increased significantly after CPB in the control group but they did not increase immediately after CPB in the DUF/MUF group. Similarly, PVR increased significantly after CPB in the control group but it did not increase after CPB in the DUF/MUF group and remained low at 6 and 24 hours after CPB. Conclusions. DUF and MUF suppress the increase in the plasma ET-1 concentration that occurs immediately after the completion of the Fontan procedure and may be an effective intervention for maintaining low PVR after the procedure

Treatment of persistent pulmonary hypertension of the newborn

OBJECTIVE: To review the medical literature, emphasizing the new scientific advances in the treatment of persistent pulmonary hypertension of the newborn. SOURCES: Literature review using Medline and Cochrane library. SUMMARY OF THE FINDINGS: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by an increase in pulmonary vascular resistance associated with right to left shunt through the foramen ovale or ductus arteriosus, leading to marked hypoxemia and respiratory failure. The balance between the vasoconstrictor (endothelin) and vasodilator (nitric oxide and prostaglandin I2) mediators plays an important role in the regulation of the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance. In addition to general management, cardiovascular support, the treatment of the cause of the PPHN, and the use of selective pulmonary vasodilator such as inhaled nitric oxide (iNO) are indicated. Furthermore, the combined therapy with iNO and high-frequency oscillatory ventilation significantly improved the oxygenation of patients who were refractory to iNO therapy and conventional ventilation. The practice of hyperventilation and the administration of nonspecific pulmonary vasodilators (tolazoline) should be avoided. On the other hand, the administration of surfactant to patients with PPHN due to meconium aspiration should be considered. However, if all these therapies fail, extracorporeal membrane oxygenation (ECMO) should be considered as rescue therapy. CONCLUSIONS: The mortality due to PPHN has significantly decreased with the use of new therapies, and the major concern today is the quality of life of these patients, especially in terms of neuropsychomotor development.

New Mechanisms for Inhaled NO

New Mechanisms for Inhaled NO

Role of Inducible Nitric Oxide Synthase in the Pulmonary Vascular Response to Birth-Related Stimuli in the Ovine Fetus

To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists N-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation with low FIO(2) (<10%), high FIO(2) (100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with low and high FIO(2) decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high FIO(2) (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO(2) to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased FIO(2) may activate NOS II release at birth.

In vivo Adenoviral Gene Transfer of CGRP and Related Peptides to the Rat and Mouse

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) play an important role in maintaining low pulmonary vascular resistance (PVR) and may be involved in modulating the pulmonary vascular response to chronic hypoxia. Adenoviral vectors encoding prepro-CGRP (AdRSVCGRP) and ADM (AdRSVADM) were used to examine the effects of in vivo gene transfer of the peptides to the lung on increases in PVR, right ventricular mass, and pulmonary vascular remodelling that occurs in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP or AdRSVADM, followed by 16 days of chronic hypoxia (FIO2 0.10), increased lung CGRP and ADM levels, respectively. The increase in pulmonary arterial pressure (PAP), PVR, right ventricular mass, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP or ADM whereas systemic arterial pressure was not altered. In chronically hypoxic mice, increases in PAP in response to i.v. injections of angiotensin II and endothelin-1 were attenuated following in vivo gene transfer. These data show that in vivo transfer of the CGRP or ADM gene to the lung attenuates the increase in PVR and right ventricular mass, pulmonary vascular remodeling, and responsiveness in chronically hypoxic mice with little effect on the systemic circulation. In order to study the roles of RAMP 1, 2, and 3 in mediating responses to CGRP and related peptides in the pulmonary and systemic vascular beds, gene transfer of adenovirus vectors encoding CRLR and RAMP 1, 2, or 3 were delivered to the lung and/or hindlimb of the mouse. Transfection of CRLR and RAMP 2 to the pulmonary and hindlimb vascular beds of the mouse resulted in enhanced vasodilator responses to ADM, but not CGRP.

Short-term inhaled nitric oxide in canine lung transplantation from non-heart-beating donor

Background. Use of lungs harvested from non-heart-beating donors (NHBDs) would increase the pulmonary donor pool; however, this strategy would have higher risk of early postoperative graft dysfunction due to unavoidable warm ischemic time. We evaluated the effects of short-term inhaled nitric oxide (NO) during reperfusion in canine left single-lung allotransplantation from a non-heart-beating donor. Methods. The donor dogs were sacrificed without heparinization and left at room temperature for 3 hours. Then, recipient dogs received a left single-lung allotransplantation. After implantation, the right bronchus and pulmonary artery were ligated. In group 1 (n = 6), NO gas was administered continuously at a concentration of 40 parts per million throughout a 6-hour assessment period. In group 2 (n = 6), NO gas was administered for the initial 1 hour during reperfusion. In group 3 (n = 6), nitrogen gas was administered for control. Results. Groups treated with NO exhibited lower pulmonary vascular resistance, as well as improved survival and oxygenation. There was no significant difference in these parameters between group 1 and group 2. Myeloperoxidase activity was significantly lower in NO-treated groups. Conclusions. Inhaled NO during reperfusion is beneficial in lung transplantation from non-beating heart donors. The beneficial effect is obtained mainly during the first hour of reperfusion.

Relationship between decreased oxyhaemoglobin saturation and exhaled nitric oxide during exercise.

Decreases in oxyhaemoglobin saturation (SaO2) are frequently observed in highly trained male endurance athletes during heavy work and has been termed exercise-induced hypoxaemia (EIH). Ventilation perfusion (VA/Q) mismatching and diffusion limitations are thought to be responsible. Nitric oxide (NO), a potent vasodilator, is present in the exhaled air of resting and exercising humans. Endogenously produced NO is thought to play a role in VA/Q matching and maintenance of low pulmonary vascular resistance. The purpose of this study was to determine the relationship between exhaled NO and EIH. It was hypothesized that athletes with EIH would have lower NO levels compared with non-EIH athletes. Eighteen highly trained male cyclists (VO2max=67.7 +/- 5.2 mL kg-1 min-1, mean +/- SD) were divided into normal (NORM, n=12, SaO2= 93.9 +/- 0.8) or low (LOW, n=6, SaO2=90.3 +/- 1.0) group, based on significantly different peak exercise SaO2 values (P < 0.05). All other descriptive and physiological characteristics were similar between the groups. Subjects performed a ramped cycle test to exhaustion breathing NO-free gas. The concentration (CNO) and production rate (VNO) of NO were determined from mixed gas samples at rest and during exercise at 100, 200, 250, 300, 350, 400 and 450 W using a chemiluminescent analyser. CNO remained unchanged from resting values in all subjects. VNO increased significantly during exercise in all subjects but was not different between LOW and NORM groups. The correlation between change in SaO2 and VNO from rest to maximal exercise was not significant (r=-0.12, P > 0.05). Collectively, these data suggest that exhaled NO is not related to decreased SaO2 during heavy exercise in highly trained male cyclists.

Incidence and implications of systemic to pulmonary collaterals after bidirectional cavopulmonary anastomosis

Background. Systemic to pulmonary arterial collaterals often develop after bidirectional cavopulmonary anastomosis (BCPA). It has been proposed that such collaterals may be related to perioperative outcome and duration of effusions after the modified Fontan procedure. However, the incidence and significance of collaterals after BCPA remain uncertain.Methods. To evaluate risk factors for, and significance of, such collaterals, we reviewed angiographic and clinical data for all 76 patients who underwent BCPA between January 1990 and June 1996 and had follow-up catheterization during or before 1997.Results. The median age at BCPA was 10 months, and the median duration from BCPA to follow-up catheterization was 18 months. Arterial collaterals were detected on follow-up catheterization in 45 patients (59%). Factors associated with collateral development included a prior right-sided systemic-to-pulmonary arterial shunt, lower pre-BCPA end-diastolic ventricular pressure and pulmonary vascular resistance, and use and duration of cardiopulmonary bypass during the BCPA operation. Fourteen of the 45 patients (30%) underwent coil embolization of the collaterals. Forty-three patients have undergone extracardiac conduit Fontan, with 1 early and 1 late death. Collaterals were present in 22 of these patients, 7 of whom underwent pre-Fontan embolization. The duration from BCPA to Fontan was longer in patients with collaterals, but these patients were not more likely to have prolonged effusions than those without, and the duration of tube thoracostomy was significantly shorter in patients with collaterals. Embolization of collaterals did not affect the duration of effusions.Conclusions. Systemic-to-pulmonary arterial collaterals are common after BCPA. In contrast to prior reports, collaterals were not associated with a higher incidence of prolonged effusions after the Fontan procedure in our experience, and did not correlate with poor outcome.

Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb.

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (I(NO)) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (I(CO)) may have similar effects on the perinatal lung. To determine whether I(CO) can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of I(CO) on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O(2) fraction < 0.10) to maintain a constant fetal arterial PO(2). After 60 min (baseline), the lambs were treated with I(CO) [5-2,500 parts/million (ppm)]. Comparisons were made with I(NO) (5 and 20 ppm) and combined I(NO) (5 ppm) and I(CO) (100 and 2,500 ppm). We found that I(CO) did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose I(NO) decreased PVR by 47% (P < 0.005). The combination of I(NO) and I(CO) did not enhance the vasodilator response to I(NO). To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that I(CO) does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

In Vivo Gene Transfer of Prepro-Calcitonin Gene–Related Peptide to the Lung Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension in the Mouse

Calcitonin gene-related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and in modulating pulmonary vascular responses to chronic hypoxia; however, the effects of adenovirally mediated gene transfer of CGRP on the response to hypoxia are unknown. In the present study, an adenoviral vector encoding prepro-CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP on increases in PVR, right ventricular mass (RVM), and pulmonary vascular remodeling that occur in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP, followed by 16 days of chronic hypoxia (FIO(2) 0.10), increased lung CGRP and cAMP levels. The increase in pulmonary arterial pressure (PAP), PVR, RVM, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP, whereas systemic pressure was not altered while in chronically hypoxic mice, angiotensin II and endothelin-1-induced increases in PAP were reduced, whereas decreases in PAP in response to CGRP and adrenomedullin were not changed and decreases in PAP in response to a cAMP phosphodiesterase inhibitor were enhanced by AdRSVCGRP. In vivo CGRP lung gene transfer attenuates the increase in PVR and RVM, pulmonary vascular remodeling, and pressor responses in chronically hypoxic mice, suggesting that CGRP gene transfer alone and with a cAMP phosphodiesterase inhibitor may be useful for the treatment of pulmonary hypertensive disorders.

Lowering reperfusion pressure reduces the injury after pulmonary ischemia

Background. Controlled reperfusion with a modified solution limits pulmonary injury following ischemia. Our initial studies infused this modified reperfusate at a pressure of 40 to 50 mm Hg to insure distribution. However, perhaps a lower pressure, which is closer to the normal physiologic pressure in the lung, would improve results by decreasing sheer stress.Methods. Fifteen adult pigs underwent 2 hours of lung ischemia by clamping the left bronchus and pulmonary artery. Five (group 1) then underwent uncontrolled reperfusion by removing the vascular clamps and allowing unmodified blood to reperfuse the lung at a pulmonary artery pressure of 20 to 30 mm Hg. The other 10 pigs underwent controlled reperfusion by mixing blood from the femoral artery with a crystalloid solution, and infusing this modified reperfusate into the ischemic lung through the pulmonary artery for 10 minutes before removing the arterial clamp. In 5 (group 2), the modified solution was infused at a pressure of 40 to 50 mm Hg, and in 5 (group 3) 20 to 30 mm Hg. Lung function was assessed 60 minutes after reperfusion and expressed as percentage of control.Results. Compared to uncontrolled reperfusion (group 1), controlled reperfusion at a pressure of 40 to 50 mm Hg (group 2) significantly improved postreperfusion pulmonary compliance (77% versus 86%; p < 0.001 versus group 1), and arterial/alveolar ratio (a/A) ratio (27% versus 52%; p < 0.001 versus group 1); as well as decreased pulmonary vascular resistance (PVR) (198% versus 154%; p < 0.001 versus group 1), lung water (84.3% versus 83.5%; p < 0.001 versus group 1), and myeloperoxidase (0.35 versus 0.23 optical density/min/mg protein). Reducing the pressure of the modified reperfusate to 20 to 30 mm Hg further improved postreperfusion compliance (92% ± 1%; p < 0.001 versus groups 1 and 2) and a/A ratio (76% ± 1%; p < 0.001 versus groups 1 and 2); and lowered PVR (133% ± 2%; p < 0.001 versus groups 1 and 2), lung water (82.7% ± 0.1%; p < 0.001 versus groups 1 and 2), and myeloperoxidase (0.16% ± 0.01%; p < 0.001 versus groups 1 and 2).Conclusions. After 2 hours of pulmonary ischemia, a severe lung injury occurs following uncontrolled reperfusion, controlled reperfusion with a modified solution reduces this reperfusion injury, and lowering the pressure of the modified reperfusate to more physiologic levels (20 to 30 mm Hg) further reduces the reperfusion injury improving pulmonary function.

Changes in ANP responsiveness of normal and hypertensive porcine intrapulmonary arteries during maturation.

Pulmonary vascular resistance falls rapidly after birth, but endothelium-dependent relaxation is relatively poor during the perinatal period. Atrial natriuretic peptide (ANP) is a potent vasodilator; however, its role in the process of perinatal adaptation is uncertain. Porcine intrapulmonary conduit arteries (IPA) from fetal, newborn (< 5 min), 3-, 6-, and 17-d-old, and adult pigs, and from piglets made hypoxic from 0 to 3, 3 to 6, or 14 to 17 d, were isolated and mounted for isometric force recording. Rings were precontracted with prostaglandin-F2 alpha (PGF2 alpha, 10 microM) or KCl (40 mM). ANP was added cumulatively (10 pM to 100 nM). C-type natriuretic peptide (CNP) was added as a single concentration of 100 nM. Accumulation of cGMP under basal conditions and stimulated by ANP or CNP was measured by radioimmunoassay system. Frozen sections of lung tissue were incubated with 125I-labeled alpha-ANP, and binding site density was assessed on IPA with an image analysis system. ANP relaxed IPA in pigs at all ages, but the effect was significantly greater at 6 and 17 d of age. Hypoxia in animals from 14 to 17 d old impaired ANP-induced relaxation. CNP relaxed IPA poorly: < 12% at all ages. ANP increased cGMP accumulation in both normal and hypoxic animals. CNP did not increase cGMP generation in IPA from normal animals but did so in IPA from 3-d-old hypoxic animals. ANP-specific binding sites were demonstrated on the pulmonary artery smooth muscle cells, with greater binding in the young animals. The increased relaxant responses to ANP during adaptation may be important in maintaining low pulmonary vascular resistance. In contrast, CNP was largely ineffective in relaxing pulmonary arteries.

Continuous venovenous hemofiltration improves cardiac performance by mechanisms other than tumor necrosis factor-alpha attenuation during endotoxic shock.

To assess the effects of continuous venovenous hemofiltration (CWH) on global and regional hemodynamics, plasma lactate, and tumor necrosis factor-oa (TNF-a) levels during endotoxic shock in dogs. Thirty pentobarbital-anesthetized and mechanically ventilated dogs were divided into six groups of five dogs each. Group 1 served as a control, undergoing CWH at 3 Uhr without endotoxin. Group 2 served as the endotoxin-alone time-matching group. Group 3 received CWH 1 hr after endotoxin at 3 Uhr for 270 mins. Group 4 received CWH 1 hr after endotoxin at 3 Uhr for 150 mins and at 6 Uhr for an additional 120 mins. Group 5 and group 6 received the ultrafiltrate from group 1 and group 3, respectively. Three hours after endotoxin challenge, dogs treated with CWH at 3 Uhr had a higher cardiac output (4.9 + 0.6 vs. 2.9 + 0.6 Umin; p < .05) and stroke volume (35 + 7 vs. 20 + 4 mL; p < .05) and a lower pulmonary vascular resistance (116 26 vs. 331 + 126 dyne-sec/cm5; p < .05) than the endotoxin-alone group. Five hours after endotoxin, dogs treated with CWH at 6 Uhr also had higher hepatic (464 + 164 vs. 126 + 75 mUmin; p < .05) and femoral (95 + 46 vs. 30 + 34 mL/min; p < .05) blood flow. Moreover, dogs treated with CWH at 6 Uhr had higher mean arterial blood pressure (84 + 24 vs. 40 + 15 mm Hg; p < .05) and left ventricular stroke work index (1.1 + 0.6 vs. 0.2 + 0.2 g/kg; p < .05) than the endotoxin-alone group. Plasma lactate levels were lower in the CWH group at 6 Uhr (2.7 + 1.1 mmol/L) than in the endotoxin-alone group (4.4 + 0.6 mmol/L; p < .05). Plasma TNF-ao levels were unaffected, and only minor amounts of TNF-o were found in the ultrafiltrate. In this acute endotoxic shock model, CWH at 3 Uhr improved cardiac performance and decreased pulmonary vasoconstriction. Moreover, CWH at 6 LUhr also increased arterial blood pressure and left ventricular stroke work, increased hepatic and femoral arterial blood flow, and decreased blood lactate levels. These effects were not attributable to TNF-alpha removal.

Pulmonary hypertension following hepatopulmonary syndrome in a patient with cirrhosis

We report the case of a patient with liver cirrhosis who successively developed hepatopulmonary syndrome and portopulmonary hypertension. Initially, the patient presented with severe dyspnea and hypoxemia at rest. Technetium-99 macroaggregated albumin lung perfusion scan demonstrated right-to-left shunt, and hemodynamic study revealed a hyperdynamic state with low pulmonary vascular resistance, thus confirming the diagnosis of hepatopulmonary syndrome. More than 2 years after the onset of pulmonary symptoms, a marked improvement in dyspnea and gas exchange was observed. Lung perfusion scan did not disclose any right-to-left shunt and right-sided heart catheterization showed evidence of severe pulmonary hypertension. We conclude that hepatopulmonary syndrome and portopulmonary hypertension are not mutually exclusive. We hypothesize that, by reversing the phenomenon of intrapulmonary vasodilatation, the development of portopulmonary hypertension interfered with each of the potential causes of hypoxemia in hepatopulmonary syndrome (ventilation-perfusion inequalities, intrapulmonary shunting, oxygen diffusion limitation) and, as a result, led to a correction of hypoxemia.

Combined use of prostacyclin and higher perfusate temperatures further enhances the superior lung preservation by celsior solution in the isolated rat lung

Background: The poor tolerance of the lung to ischemia and reperfusion (IR) still represents one of the limitations in clinically successful lung transplantation. Modified Euro-Collins (EC) is routinely used in lung preservation, but alternative solutions have been developed for improvement of pulmonary preservation. Celsior is an extracellular solution that has significantly reduced the IR-induced pulmonary damage in animal studies. So far, no extensive experimental studies exist concerning the influence of Celsior on pulmonary gas exchange following IR. Methods In an extracorporeal rat lung model 10 lungs, each, were preserved with Celsior (CE) and Celsior/prostacyclin (CEPC, 6 μg/100 ml) at 4° and 15°C, each, and compared to low-potassium Euro-Collins (EC-40, 40 mmol/liter potassium). After 2 hours of ischemia lungs were reventilated and reperfused using a roller pump. Oxygenation in terms of oxygen partial tension in the left atrial effluent, pulmonary vascular resistance (PVR), peak inspiratory pressure, and wet/dry ratio were monitored for 50 minutes. Furthermore, edema formation was evaluated by light microscopy. Statistical analysis was performed using ANOVA models. Results Compared to the EC-40 group, oxygenation was increased and amount of edema was reduced in most Celsior-preserved organs ( p < 0.032) with exception of the CEPC group at 4°C ( p = 0.06). Additional application of prostacyclin did not have any significant effect on oxygenation in the Celsior group. However, after temperature elevation of the CEPC perfusate to 15°C, a superior partial tension of oxygen was observed ( p < 0.023) in contrast to the 4°C groups CE and CEPC. The lowest PVR was found in the CE 4°C group ( p < 0.02). Conclusions Celsior provides better lung preservation than EC-40 solution. Application of prostacyclin at higher perfusate temperatures results in additional functional improvement. In vivo experiments and ultrastructural analysis are warranted for further evaluation of Celsior in lung preservation.

Hepatopulmonary syndrome associated with cardiorespiratory disease

Background/Aims: Hepatopulmonary syndrome is defined as a clinical triad including chronic liver disease, abnormal pulmonary gas exchange resulting ultimately in profound arterial hypoxaemia, and evidence of intrapulmonary vascular dilatations. We report five patients with liver cirrhosis diagnosed with hepatopulmonary syndrome whohad associated chronic obstructive or restrictive respiratory diseases. Methods: Clinical, radiographic and constrast-enhanced echocardiographic findings, and systemic and pulmonary haemodynamic and gas exchange, including ventilation-perfusion distributions, measurements were assessed in all five patients. Results: Echocardiography was consistent with the presence of intrapulmonary vasodilation without intracardiac abnormalities, and high resolution computed tomographic scan features were compatible with clinical (3 cases) or histopathological diagnoses (2 cases) of associated respiratory disorders. The most common prominent functional findings were moderate to severe arterial hypoxaemia, caused by moderately to severely increased intrapulmonary shunting and/or mild to moderate low ventilation-perfusion areas, and hypocarbia along with an increased cardiac output and a low pulmonary artery pressure and vascular resistance. Conclusions: These functional characteristics, classically reported in the setting of clinically stable, uncomplicated hepatopulmonary syndrome, conform to a distinctively unique, chronic gas exchange pattern. Equally important, these pulmonary haemodynamicgas exchange hallmarks are not influenced by the coexistence of chronic cardiorespiratory disease states. These data may have clinical relevance for elective indication of hepatic transplantation in patients with life-threatening hepatopulmonary syndrome.

The use of milrinone in pre-transplant assessment of patients with congestive heart failure and pulmonary hypertension

Background: Pulmonary hypertension in patients with congestive heart failure (CHF) is a risk factor for increased mortality after orthotopic cardiac transplantation. Reversibility of elevated pulmonary vascular resistance (PVR) by pharmacologic agents predicts improved outcomes. Milrinone, a phosphodiesterase inhibitor with vasodilating and positive inotropic properties, has been shown to lower PVR in one previous study. However, no study has documented outcomes after cardiac transplantation in patients in whom reversibility of pulmonary hypertension was demonstrated after administration of milrinone. Methods We retrospectively reviewed 19 patients with CHF and pulmonary hypertension defined as PVR ≥ 3 Wood units, PVRI (pulmonary vascular resistance index) ≥ 4 resistance units, or TPG (transpulmonary gradient = mean pulmonary artery pressure − mean capillary wedge pressure) ≥ 12 mmHg being assessed for cardiac transplantation. A sub-group of 14 patients with severe pulmonary hypertension defined as PVR ≥ 4, PVRI ≥ 6 and TPG ≥ 15 was also examined. Milrinone was administered as a bolus (50 ug/kg) and hemodynamic parameters were measured at 5, 10 and 15 minutes. Six patients received cardiac transplants. Results Administration of milrinone significantly lowered PVR, PVRI, mean pulmonary artery pressure (PAM) (all p = 0.002) and pulmonary capillary wedge pressure (PCWP) ( p = 0.006). Cardiac output (CO) increased significantly ( p = 0.001). TPG did not change ( p = 0.33). In patients with severe pulmonary hypertension, the magnitude of these changes was greater. In addition, TPG was significantly lowered ( p = 0.02). Conclusion Milrinone lowered PVR by decreasing PAM and increasing CO significantly. In addition, PCWP was significantly lowered. These finding confirm both vasodilatory and inotropic effects of milrinone. Patients with severe pulmonary hypertension had more pronounced effects. There were no deaths in the group of patients proceeding to cardiac transplantation. Our study demonstrates the efficacy of milrinone in lowering PVR as well as suggesting safety in use in patients undergoing cardiac transplantation.

Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity.

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.

CARDIAC OUTPUT AND PULMONARY VASCULAR PRESSURE GRADIENT DURING 60 MIN's HIGH INTENSITY EXERCISE IN NORMOXIA

1066 Prolonged exercise at high intensities requires low transpulmonary pressure gradient (Ppam-Paod) and low pulmonary vascular resistance at high cardiac output. Therefore, we examined pulmonary circulation in trained athletes. Methods: 17 healthy, male subjects performed 60 min of cycling approx. 86% of ˙Vo2max (25±4 yrs, 77.1±6.5 kg, ˙Vo2max 4.1±0.6 1·min-1). Cardiac output (˙Qc) was measured by acetylene rebreathing. Pulmonary artery pressure (Ppam) and pulmonary occlusion pressure (Paod) and Ppam-Paod were measured by a Swan-Ganz-catheter and systemic arterial pressure in a. radialis (Psam) at rest, 8, 40, and 55 min during exercise, and 25 min after the test. Pulmonary and systemic vascular resistance (PVR, SVR) were calculated according to Gorlin. Results: During the test, mean power was 232±37 W, and mean ˙Qc was 22.1 1·min-1. Ppam-Paod increased from 8.3±3 to 19±3mmHg (8′, p<0.001) and decreased during the test to 15±6mmHg (55′, p<0.05). However, in 5 subjects Ppam-Paod increased from 18.4 (8′) to 21.2 mmHg (40′) as well as PVR. ˙Qc was constantly lower during the test (p<0.05) as well as stroke volume (131 vs. 106 ml at 40′, p<0.05). Interestingly, Psam as well as SVR were higher (p<0.05) in these subjects. However, the power achieved was not different. Conclusion: In 5 of 17 healthy subjects, increased transpulmonary pressure gradient was observed during constantly high intensive exercise. The lower stroke volume in these subjects may contribute to lower pulmonary and systemic blood flow as well as higher sympathetic drive to higher pulmonary and systemic vascular resistance.