Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease.

Intrapulmonary vascular abnormalities consisting of arteriovenous malformations and capillary dilatations have been described in patients with severe liver disease. These intrapulmonary vascular abnormalities can result in intrapulmonary right-to-left shunting and hypoxemia. Twenty-five of 53 patients (47%) with end-stage hepatic disease were found to have contrast echocardiographic evidence of intrapulmonary right-to-left shunting. There was no difference in mean age, gender distribution, or severity of hepatic disease in those with and without evidence of such shunting. Although there was no difference in mean partial arterial oxygen pressure (PaO2) values in the 2 groups (82 +/- 11 vs 76 +/- 11 mm Hg), the mean PaO2 value of those with at least 2+ left ventricular opacification (2 to 4+) was significantly lower (66 +/- 3 mm Hg, n = 8; p less than 0.01). Unexpectedly, patients with evidence of intrapulmonary shunting had a lower mortality rate before transplantation (3 of 25, 12%) than those without evidence of shunting (10 of 28, 36%) resulting in a significant difference in actuarial survival (p less than 0.05) by the end of the follow-up period. It is concluded that intrapulmonary right-to-left shunting occurs frequently in patients with end-stage liver disease and may be a marker of a positive biologic process that, in some way, leads to improved short-term survival.     

Single-lung transplantation for pulmonary hypertension. Three-month hemodynamic follow-up

BACKGROUND. Shorter waiting times, relative technical simplicity, and satisfactory application to a broad spectrum of patients has made single-lung transplantation an attractive option in the treatment of patients with end-stage pulmonary hypertension. METHODS AND RESULTS. Seven patients with pulmonary hypertension underwent single-lung transplantation. Simultaneous closure of associated atrial septal defects was accomplished in two patients. Despite severely compromised pretransplant right ventricular function in all patients, there was no early or late mortality. Right ventricular functional recovery as characterized by hemodynamic assessment before and at a mean of 13 weeks posttransplant was nearly uniform and characterized by a drop in 1) pulmonary arterial systolic pressure from 92 +/- 7 mm Hg to 29 +/- 6 mm Hg (p = 0.001), 2) central venous pressure from 10 +/- 6 mm Hg to 1 +/- 2 mm Hg (p = 0.02), and 3) pulmonary vascular resistance index from 1,924 +/- 663 to 232 +/- 73 dyne.sec.cm-9 (p = 0.001). Radionuclide ventriculography before and at a mean of 17 weeks posttransplant documented a significant (p = 0.006) increase in right ventricular ejection fraction from 22 +/- 15% to 51 +/- 11%. Quantitative pulmonary perfusion scintigraphy at a mean of 17 weeks posttransplant demonstrated a significant (p = 0.001) increase in perfusion to the transplanted lung from 56 +/- 6% to 89 +/- 7%. There was a concomitant, slight but significant (p = 0.004) decrease in ventilation to the transplanted side from 56 +/- 6% to 49 +/- 8%. After transplantation, all patients returned to New York Heart Association functional class I or II from their preoperative levels of class III or IV. CONCLUSIONS. These early follow-up data cautiously support the option of single-lung transplantation in patients with pulmonary hypertension, although long-term durability of these hemodynamic changes deserves documentation before widespread application.     

Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis

To investigate the mechanisms underlying abnormal gas exchange in liver cirrhosis, 15 patients were studied while breathing room air, 11% O2, and 100% O2 in random sequence. Under basal conditions, patients showed mild reductions from normal in systemic and pulmonary vascular resistance, normal PaO2 (mean, 92.5 +/- 2.5 mm Hg), mild hypocapnia (mean, 34 +/- 0.7 mm Hg), and a slightly right-shifted oxyhemoglobin dissociation curve (P50, 27.2 +/- 0.4 mm Hg; 2,3-DPG, 13.1 +/- 0.6 mumol/g). Using the multiple insert gas elimination technique, we found mild to moderate ventilation-perfusion (VA/Q) inequality with a mean of 5% (range, 0 to 20%) of cardiac output (QT) perfusing low VA/Q ratio (less than 0.1) areas but no shunt. Breathing 11% O2, there were significant increases in QT, pulmonary artery pressure, and vascular resistance, whereas no changes occurred in VA/Q distribution, and there was no evidence for alveolar-endcapillary diffusion limitation for O2. In contrast, after 100% O2 shunt developed and VA/Q relationships worsened without significant hemodynamic changes. Furthermore, patients with cutaneous spider nevi (n = 8) showed more hepatocellular dysfunction (lower prothrombin values), lower systemic and pulmonary vascular resistance, less hypoxic pulmonary vasoconstriction (HPV), lower PaO2, and more VA/Q mismatch than did those without spiders. Our results confirm, therefore, that HPV is not fully abolished, as previously described, in hepatic cirrhosis. However, those patients with more advanced hepatic disease exhibit inadequate pulmonary vascular tone, which increases VA/Q inequality and lowers PaO2.     

Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis

To determine and to quantify the pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis, we measured in 10 cirrhotics blood gases, P50, hemodynamics, ventilation, and the distribution of ventilation-perfusion ratios (VA/Q) using the multiple inert gas elimination technique. Seven patients had an arterial hypoxemia (PaO2 = 69 +/- 6 mm Hg, mean +/- SD), and three patients were normoxemic (PaO2 = 89 +/- 6 mm Hg). In each hypoxemic patient, the VA/Q distributions were characterized by the presence of low VA/Q units. A negative logarithmic correlation was found between the dispersion of the blood flow distribution and the arterial PO2. An acute inspiratory hypoxia (FIO2, 0.125) elicited an increase in pulmonary vascular resistance by 58.5% in the hypoxemic group and by 81.6% in the normoxemic one (p = NS between the two groups). The percent change in pulmonary vascular resistance induced by hypoxia was not correlated with the percent change in the dispersion of the blood flow distribution. A theoretical analysis showed that the mean arterial PO2 of 69 mm Hg of the hypoxemic group differed from a normal reference value of 96 mm Hg as a result of the combined effects of reduced hemoglobin (-4 mm Hg), increased P50 (+4 mm Hg), increased ventilation (+10 mm Hg), low VA/Q (-35 mm Hg), and true shunt (-2 mm Hg). These results show that the "hypoxemia of liver cirrhosis" is essentially caused by VA/Q mismatching, which is not explained by an abnormal hypoxic pulmonary vasoconstriction.     

Hypoxemia in acute pulmonary embolism

Most patients with severe, acute pulmonary embolism (PE) have arterial hypoxemia. To further define the respective roles of ventilation to perfusion (VA/Q) mismatch and intrapulmonary shunt in the mechanism of hypoxemia, we used both right heart catheterization and the six inert gas elimination technique in seven patients with severe, acute PE (mean vascular obstruction, 55 percent) and hypoxemia (mean PaO2, 67 +/- 11 mm Hg). None had previous cardiopulmonary disease, and all were studied within the first ten days of initial symptoms. Increased calculated venous admixture (mean QVA/QT 16.6 +/- 5.1 percent) was present in all patients. The relative contributions of VA/Q mismatching and shunt to this venous admixture varied, however, according to pulmonary radiographic abnormalities and the time elapsed from initial symptoms to the gas exchange study. Although all patients had some degree of VA/Q mismatch, the two patients studied early (ie, less than 48 hours following acute PE) had normal chest x-ray film findings and no significant shunt; VA/Q mismatching accounted for most of the hypoxemia. In the others a shunt (3 to 17 percent of cardiac output) was recorded along with radiographic evidence of atelectasis or infiltrates and accounted for most of the venous admixture in one. In all patients, a low mixed venous oxygen tension (27 +/- 5 mm Hg) additionally contributed to the hypoxemia. Our findings suggest that the initial hypoxemia of acute PE is caused by an altered distribution of ventilation to perfusion. Intrapulmonary shunting contributes significantly to hypoxemia only when atelectasis or another cause of lung volume loss develops.     

Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome

The mechanism of orthodeoxia (OD), or decreased partial pressure of arterial oxygen (PaO2) from supine to upright, a characteristic feature of hepatopulmonary syndrome (HPS), has never been comprehensively elucidated. We therefore investigated the intrapulmonary (shunt and ventilation-perfusion [VA/Q] mismatching) and extrapulmonary factors governing PaO2 in 20 patients with mild to severe HPS (14 males, 6 females; 50 +/- 3 years old SE) at upright and supine, in random order. We set out a cutoff value for OD, namely a PaO2 decrease > or = 5% or > or = 4 mm Hg (area under the receiver operating characteristic curve, 0.96 each). Compared to supine, 5 patients showed OD (PaO2 change, -11% +/- 2%, -7 +/- 1 mm Hg, P < .05) with further VA/Q worsening (shunt + low VA/Q mode increased from 19% +/- 7% to 21% +/- 7% of cardiac output [QT], P < .05), as opposed to 15 patients who did not (+2% +/- 2%, +1+/- 1 mm Hg) with VA/Q improvement (from 20% +/- 4% to 16% +/- 4% of QT, P < .01). Cardiac output was significantly lower in OD patients in both positions. Changes in extrapulmonary factors at upright, such as increased minute ventilation and decreased QT, were of similar magnitude in both subsets of patients. In conclusion, our data suggest that gas exchange response to OD in HPS points to a more altered pulmonary vascular tone inducing heterogeneous blood flow redistribution to lung zones with prominent intrapulmonary vascular dilatations.     

Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning

BACKGROUND: Because of the spectrum of intrapulmonary vascular dilation that characterizes hepatopulmonary syndrome (HPS), PaO(2) while breathing 100% oxygen varies. Abnormal extrapulmonary uptake of (99m)Tc macroaggregated albumin (MAA) after lung perfusion is common. GOAL: To describe relationships between (1) severity of liver disease measured by the Child-Pugh (CP) classification; (2) PaO(2) while breathing room air (RA) and 100% oxygen on 100% oxygen; and (3) extrapulmonary (brain) uptake of (99m)Tc MAA after lung scanning. Methods and patients: We prospectively measured PaO(2) on RA, PaO(2) on 100% oxygen, and brain uptake after lung perfusion of (99m)Tc MAA in 25 consecutive HPS patients. RESULTS: Mean PaO(2) on RA, PaO(2) on 100% oxygen, PaCO(2) on RA, and (99m)Tc MAA brain uptake were similar when categorized by CP classification. Brain uptake was abnormal (> or = 6%) in 24 patients (96%). Brain uptake was 29 +/- 20% (mean +/- SD) and correlated inversely with PaO(2) on RA (r = -0.57; p<0.05) and PaO(2) on 100% oxygen (r = -0.41; p<0.05). Seven patients (28%) had additional nonvascular pulmonary abnormalities and lower PaO(2) on 100% oxygen (215+/-133 mm Hg vs 391+/-137 mm Hg; p<0.007). Eight patients (32%) died. Mortality in patients without coexistent pulmonary abnormalities was associated with greater brain uptake of (99m)Tc MAA (48+/-18% vs 25+/-20%; p<0.04) and lower PaO(2) on RA (40+/-7 mm Hg vs 57+/-11 mm Hg; p<0.001). CONCLUSION: The degree of hypoxemia associated with HPS was not related to the CP severity of liver disease. HPS patients with additional nonvascular pulmonary abnormalities exhibited lower PaO(2) on 100% oxygen. Mortality was associated with lower PaO(2) on RA, and with greater brain uptake of (99m)Tc MAA.     

Pulmonary hypertension in patients with end-stage renal disease

BACKGROUND: The aims of this study were to evaluate the incidence of unexplained pulmonary hypertension (PH) among patients with end-stage renal disease (ESRD) and to suggest possible etiologic factors. METHODS: The incidence of PH was prospectively estimated by Doppler echocardiography in 58 patients with ESRD receiving long-term hemodialysis via arteriovenous access, and in control groups of 5 patients receiving peritoneal dialysis (PD) and 12 predialysis patients without a known other cause to suggest the presence of PH. Clinical variables were compared between patients with and without PH receiving hemodialysis. Changes in pulmonary artery pressure (PAP) values before and after onset of hemodialysis via arteriovenous access, arteriovenous access compression, and successful kidney transplantation were recorded. RESULTS: PH > 35 mm Hg was found in 39.7% of patients receiving hemodialysis (mean +/- SD, 44 +/- 7 mm Hg; range, 37 to 65 mm Hg), in none of the patients receiving PD, and in 1 of 12 predialysis patients. Patients with PH receiving hemodialysis had a significantly higher cardiac output (6.9 L/min vs 5.5 L/min, p = 0.017). PH developed in four of six patients with normal PAP after onset of hemodialysis therapy via arteriovenous access. One-minute arteriovenous access compression in four patients decreased the mean systolic PAP from 52 +/- 7 to 41 +/- 4 mm Hg (p = 0.024). PH normalized in four of five patients receiving hemodialysis following kidney transplantation. Kaplan-Meier survival analysis according to PAP values revealed significant survival differences (p < 0.024). CONCLUSIONS: This study demonstrates a surprisingly high incidence of PH among patients with ESRD receiving long-term hemodialysis with surgical arteriovenous access. Both ESRD and long-term hemodialysis via arteriovenous access may be involved in the pathogenesis of PH by affecting pulmonary vascular resistance and cardiac output.     

Mechanisms of hypoxemia in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension is characterized by widespread central obstruction of the pulmonary arteries with organized thrombus and thereby differs substantially from other forms of pulmonary hypertension. We studied 25 patients using the multiple inert gas elimination technique to identify and quantitate the physiologic mechanisms of hypoxemia in this disorder. All patients had chronic obstruction of the central pulmonary arteries, which was demonstrated angiographically and later surgically confirmed. All patients but one were hypoxemic (PaO2 = 65 +/- 11 mm Hg, PaCO2 = 32 +/- 4 mm Hg, AaPO2 = 45 +/- 14 mm Hg), and all patients had pulmonary hypertension (mean Ppa = 45 +/- 11 mm Hg) with an elevated pulmonary vascular resistance (mean PVR = 1,000 +/- 791 dyne/s/cm5, normal less than 300). The cardiac index was reduced (1.7 +/- 0.6 L/min/m2), as was the P-vO2 (31 +/- 5 mm Hg). Inert gas studies revealed widened unimodal Va/Q distributions in 20 of 25 subjects, with a log standard deviation of 1.01 +/- 0.32 (upper limit of normal, 0.6; ages 20 to 40), shunt = 0.03 +/- 0.05 of cardiac output, and dead space of 3.4 +/- 1.1 ml/kg (upper limit of normal, 2.9). The VD/VT ratio was 0.51 +/- 0.10. No low (VA/Q less than 0.1) or high (VA/Q greater than 10.0) regions were present, and no evidence for diffusion limitation of O2 transfer at rest was found. The low cardiac output and resulting low P-VO2 were responsible for approximately 33% of the increased AaPO2. The magnitude of the VA/Q abnormality correlated poorly with the PVR, the mean Ppa, or the magnitude of vascular obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methylene blue improves the hepatopulmonary syndrome

BACKGROUND: The hypoxemia of the hepatopulmonary syndrome, seen in patients with severe chronic liver dysfunction, results from widespread pulmonary vasodilation. No established drug therapy is available for this condition. OBJECTIVE: To study the effect of methylene blue, a potent inhibitor of guanylate cyclase, in patients with severe hepatopulmonary syndrome. DESIGN: Open, uncontrolled trial. SETTING: Medical intensive care unit at the university hospital in Vienna, Austria. PATIENTS: 7 patients with advanced cirrhosis and severe hepatopulmonary syndrome with PaO(2) of 60 mm Hg or less. INTERVENTION: Insertion of a pulmonary artery catheter and an arterial indwelling catheter; intravenous administration of methylene blue, 3 mg/kg of body weight, over a 15-minute period. MEASUREMENTS: Serial measurements of gas exchange and hemodynamic variables. RESULTS: After methylene blue administration, PaO(2) increased in all patients (from a baseline mean +/- SD of 58 +/- 2.5 mm Hg to 74 +/- 11.5 mm Hg 5 hours after infusion; P = 0.006) and the alveolar-arterial difference for partial pressure of oxygen (PAO(2) - PaO(2) ) decreased in all patients, with a maximum effect achieved after 5 hours (from 49 +/- 3.3 mm Hg to 30 +/- 10.4 mm Hg; P = 0.003); even after 10 hours, PAO(2) - PaO(2) was still significantly reduced compared with baseline (P = 0.041). Oxygenation improved because of reduction in shunt fraction (from 41% +/- 3.1% to 25% +/- 4.5%; P < 0.001). Mean pulmonary artery pressure increased (from 20 +/- 5.2 mm Hg to 23 +/- 3.6 mm Hg; P = 0. 028), as did pulmonary vascular resistance (from 58 +/- 23 dyne/sec. cm(-5) to 115 +/- 56 dyne/sec. cm(-5); P = 0.012). Arterial blood pressure did not change significantly. Cardiac output decreased (from 10.6 +/- 2.2 L/min to 8.6 +/- 2.7 L/min; P = 0.008) and systemic vascular resistance increased (from 527 +/- 144 dyne/sec. cm(-5) to 729 +/- 222 dyne/sec. cm(-5); P = 0.037). Heart rate, central venous pressure, and pulmonary capillary wedge pressure remained unchanged. CONCLUSION: Intravenous methylene blue improved hypoxemia and hyperdynamic circulation in patients with liver cirrhosis and severe hepatopulmonary syndrome.     

Hepatopulmonary syndrome and portopulmonary hypertension

Liver disease affects the lungs. The majority of patients exhibit mild to moderate arterial hypoxaemia essentially attributable to an alteration in ventilation/perfusion matching and limited by an increase in ventilation. A minority (some 10%) of patients exhibit a "hepatopulmonary syndrome" defined by severe hypoxaemia with arterial PO2 below 60 mm Hg, dyspnoea, cyanosis, digital clubbing, orthodeoxia, platypnoea and demonstrable pulmonary vascular dilatations causing a true pulmonary shunt and a diffusion/perfusion imbalance. The hepatopulmonary syndrome is incurable but resolves over time after liver transplantation. An even lower proportion of patients, approximately 1%, develop pulmonary hypertension. Clinically this "portopulmonary hypertension" resembles primary pulmonary hypertension, with dyspnoea and fatigue as the main symptoms, histopathology and response to prostacyclin therapy. Portopulmonary hypertension is irreversible. Liver transplantation mortality in patients with portopulmonary hypertension ranges from 50 to 100%. The common cause of the hepatopulmonary syndrome and portopulmonary hypertension is portal hypertension and portosystemic shunting, indicating that vasoactive and angiogenetic factors originating from the liver normally control the pulmonary circulation.     

Frequency and significance of acute heart failure following liver transplantation

Reversible cardiomyopathy has been reported in patients after liver transplantation. However, there are few data on the incidence, risk factors, and prognosis of this condition. Liver transplantation recipients who underwent preoperative right- and left-sided cardiac catheterization as well as preoperative transthoracic echocardiography from 2001 to 2005 were identified. Eighty-six patients met the outlined criteria and were included in the study. The incidence of severe heart failure (HF) after transplantation in this population was 6 of 86 (approximately 7%). Patients who developed HF were slightly older (mean age 61.2 +/- 8.9 vs 55.4 +/- 9.2 years, p = 0.08) but had similar preoperative ejection fractions (60 +/- 5% vs 57 +/- 8%, p = 0.22) and comparable systemic arterial blood pressure (116 +/- 22/62 +/- 11 vs 127 +/- 9/66 +/- 9, p >0.1). In addition, the severity of liver disease as measured by the model for end-stage liver disease score was not different between the 2 groups (23.9 +/- 9.7 vs 26 +/- 10.7, p = 0.5). There was also no significant difference in the preoperative cardiac index (3.8 +/- 1 vs 3.6 +/- 1.5 L/min/m2, p = 0.9) or pulmonary artery wedge pressure (13.6 +/- 5.8 vs 15.3 +/- 2.8 mm Hg, p = 0.42). The incidence of alcohol use as the presumed cause of liver failure was equivalent in the 2 groups (33% vs 25%, p = 0.65). The patients who developed HF did have significantly higher preoperative mean pulmonary arterial systolic pressures (43 +/- 10 vs 30 +/- 9 mm Hg, p = 0.02) and right ventricular systolic pressures (44 +/- 13 vs 34 +/- 8 mm Hg, p = 0.05). In conclusion, severe systolic HF may occur after liver transplantation in patients without traditional risk factors for HF. This study suggests that those patients with preoperative elevated right-sided cardiac pressures, as well as older patients, may be at excess risk for developing HF after transplantation.     

Effects of sublingual nitroglycerin on resting pulmonary gas exchange and hemodynamics in man.

Simultaneous hemodynamic, ventilation and blood gas measurements were performed in 19 males during cardiac catheterization for evaluation of chest pain syndrome before and 3 to 5 min after 0.4 mg sublingual nitroglycerin. Pulmonary arterial pressures and total pulmonary vascular resistance fell (P less than 0.001 for both), and mean systemic arterial pressure decreased (P less than 0.05). However, peripheral vascular resistance, cardiac output, and mixed venous PO2 did not change. Total and tidal ventilation, PCO2, pH, and base excess remained unchanged. However, the arterial PO2 decreased from a mean of 80 +/- 3 (SEM) to 72 +/- 2 mm Hg (P less than 0.001) and mean venous admixture increased from 8.8 +/- 1% to 12.6 +/- 1.5% (P less than 0.001). The alveolar arterial PO2 difference increased (P less than 0.001) and the dead space tidal volume ratio rose (P less than 0.05). We conclude that the decrease in arterial PO2 following sublingual nitroglycerin is caused by redistribution of pulmonary blood flow with imbalance in ventilation-perfusion relationships or shunting.     

Gas exchange and pulmonary hemodynamics during lung resection in patients at increased risk: relationship with preoperative exercise testing

STUDY OBJECTIVES: To evaluate the intraoperative evolution of patients with COPD during lung resection and to test whether exercise testing could be helpful in the prediction of the intraoperative course. DESIGN: Prospective study. SETTING: University teaching hospital. PATIENTS: Forty patients (mean [+/- SD] age, 65 +/- 9 years) with COPD (ie, FEV(1), 55 +/- 11% of predicted) and resectable lung neoplasms. INTERVENTIONS: Preoperatively, pulmonary function testing, quantitative lung perfusion scanning, and exercise performance testing were administered. Intraoperatively, pulmonary, hemodynamic, and blood gas measurements were performed at five stages, including periods of two-lung ventilation (TLV) and periods of one-lung ventilation (OLV). RESULTS: During OLV, compared with TLV, the PaO(2)/fraction of inspired oxygen (FIO(2)) ratio decreased from 458 +/- 120 to 248 +/- 131 mm Hg (p < 0.05), whereas pulmonary artery pressure (PAP) increased from 18 +/- 5 to 23 +/- 5 mm Hg (p < 0.05). Cardiac output (t) also increased from 4.0 +/- 1.2 to 5.1 +/- 1.9 L/min (p < 0.05), yielding to a higher mixed venous PO(2). Both PaO(2) and t during OLV were significantly lower in patients who had undergone right thoracotomies compared with those who had undergone left thoracotomies. The PaO(2)/FIO(2) ratio during OLV correlated with the PaO(2) during exercise (r = 0.39; p = 0.01) and with the perfusion of the non-neoplastic lung (r = 0.44; p = 0.005). CONCLUSIONS: In COPD patients, OLV leads to a significant derangement of gas exchange, which is more pronounced in right thoracotomies. Preoperative measurement of PaO(2) during exercise and the distribution of perfusion by lung scan might be useful to identify those patients who are at the greatest risk of abnormal gas exchange during lung resections.     

Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery.

BACKGROUND. The pathogenesis of salt and water accumulation in patients with chronic obstructive pulmonary disease is unclear and may differ from that in patients with congestive heart failure due to myocardial disease. This study was undertaken to investigate some of the mechanisms involved. METHODS AND RESULTS. Hemodynamics, water and electrolyte spaces, renal function, and plasma hormone concentrations were measured in nine patients with edema due to chronic obstructive pulmonary disease and in six patients after recovery. Mean cardiac output (3.8 +/- 0.26 l/min.m2) was normal, but right atrial (11 +/- 1 mm Hg) and mean pulmonary arterial (41 +/- 3 mm Hg) pressures were increased. Mean pulmonary arterial wedge pressure (11 +/- 1 mm Hg) was normal. Pulmonary vascular resistance (8.6 +/- 1.3 mm Hg.min.m2/l) was increased, but systemic vascular resistance (19.3 +/- 1.3 mm Hg.min.m2/l) and mean arterial pressure (83 +/- 4 mm Hg) were low. All patients were hypoxemic (PaO2, 40 +/- 2 mm Hg) and hypercapnic (PaCO2, 60 +/- 2 mm Hg). There was a significant increase in total body water (+21%), extracellular volume (+45%), plasma volume (+45%), blood volume (+88%), and exchangeable sodium (+38.2%). Renal plasma flow was severely reduced (-63.2%), but glomerular filtration rate was only mildly decreased (-32%). Significant increases were seen in plasma norepinephrine (3.5-fold normal), renin activity (7.6-fold normal), vasopressin (twice normal), atrial natriuretic peptide (9.4-fold normal), growth hormone (10.7-fold normal), and cortisol (1.9-fold normal). After recovery, the PaO2 increased (50 +/- 3 mm Hg) and PaCO2 fell (45 +/- 4 mm Hg), and the patients became free from edema. All the body compartments returned toward normal, although they did not entirely reach normal values. Renal plasma flow increased significantly, and glomerular filtration became normal. Right atrial and pulmonary arterial pressures and pulmonary vascular resistance decreased (p less than 0.01). Cardiac output decreased but not significantly. Blood pressure increased but not significantly. However, systemic vascular resistance increased significantly to a normal value. CONCLUSIONS. We conclude that patients with edema due to chronic obstructive pulmonary disease have severe retention of salt and water, reduction in renal blood flow and glomerular filtration, and neurohormonal activation similar to that seen in patients with edema due to myocardial disease. However, unlike the latter, in chronic obstructive pulmonary disease cardiac output is normal, and systemic vascular resistance and arterial blood pressure are low. This probably is due to the vasodilator properties of hypercapnia. The consequent low arterial blood pressure may be the stimulus for the neurohormonal activation and retention of salt and water.     

High cardiac output of advanced liver disease persists after orthotopic liver transplantation.

This study measured cardiac output before and 1 or 2 yr after orthotopic liver transplantation in 23 patients. Cardiac output was measured by thermodilution before transplantation and by first-pass radionuclide angiocardiography at follow-up. Study patients were selected as those doing well clinically and by standard laboratory tests at 1-yr and 2-yr reevaluations with no evidence of rejection: six had mild recurrent hepatitis shown on biopsy samples. Hepatocyte function was normal at the time of the study as shown by galactose elimination capacity of 442 +/- 90 mg/min. Medications were cyclosporine and prednisone in all patients, azathioprine in 10 patients and a combination of antihypertensive therapy to maintain diastolic blood pressure less than 90 mm Hg in 20 patients. Mean (+/- S.D.) pretransplantation cardiac output was 9.1 +/- 3.1 L/min and remained elevated at 8.3 +/- 2.1 L/min 1 yr, and 9.6 +/- 2.6 L/min (n = 13) 2 yr after transplantation. A significant (p less than 0.001) correlation was found between pretransplant and follow-up cardiac output. End diastolic, end systolic and stroke volumes are all increased in a pattern similar to that seen in end-stage cirrhosis. These data show that the high cardiac output of the hyperdynamic state of advanced liver disease persists after liver transplantation. The mechanisms and consequences of this require further study.     

Arterial oxygenation and pulmonary function with Saralasin in chronic lung disease

During our earlier saralasin infusion study in hypertensive patients, we found a drug-induced rise in arterial oxygen tension (PaO2) associated with unchanged mixed venous PO2 or the PaCO2 and unrelated to cardiopulmonary hemodynamic changes. To test the hypothesis that saralasin improved pulmonary mechanics, blood gases, lung mechanics, lung volumes, diffusing capacity, and distribution of ventilation were analyzed and cardiac output (CO) measured in 12 normotensive men with chronic pulmonary disease before and during a 2 1/2 hour infusion of Saralasin (5 micrograms/kg/min). The PaO2 increased from a mean of 63 +/- 3 (SEM) to 70 +/- 3 mm Hg (p less than 0.001), while the CO decreased from 6.81 +/- 0.52 L/min to 6.18 +/- 0.48 L/min (p less than 0.005). The change in (delta)CO correlated with delta PaO2 (r = -0.67, p less than 0.05). Total systemic vascular resistance rose from 1,201 +/- 134 to 1,353 +/- 147 dynes X sec X cm5 (p less than 0.001). The PaCO2 and other measurements remained unchanged. We conclude that saralasin raised the PaO2 not by changing pulmonary function or mechanics, but by redistributing pulmonary blood flow and improving the ventilation-perfusion relationship.     

Hemodynamic effects of nifedipine on secondary pulmonary hypertension in man

We evaluated the hemodynamic effects of the calcium antagonist nifedipine in 13 consecutive patients admitted to the intensive care unit with secondary pulmonary hypertension. Etiology of secondary pulmonary hypertension was: chronic obstructive pulmonary disease (n = 9), pulmonary emboli (n = 2), pulmonary fibrosis (n = 2). We obtained the resting hemodynamic parameters before, and 60, 120, 180 minutes after the sublingual administration of nifedipine 20 mg. All patients had normal pulmonary artery wedge pressure before nifedipine. After 60 minutes, systolic pulmonary artery pressure fell from 72.3 +/- 7 to 57.3 +/- 5.4 mm Hg (p less than 0.005) and mean pulmonary artery pressure from 44.6 +/- 4.0 to 33.6 +/- 3.2 mm Hg (p less than 0.001). Cardiac output rose from 6.36 +/- 0.56 to 7.65 +/- 0.64 l/min (p less than 0.005). The pulmonary vascular resistance fell from 431 +/- 58 to 238 +/- 36 dynes. sec. cm-5 (p less than 0.001). Heart rate, mean systemic arterial pressure, pulmonary artery wedge pressure, total systemic vascular resistance and arterial partial pressure of O2 (PaO2) remained unchanged. In this heterogenous population we were unable to reproduce the results of other authors, showing a correlation between PaO2 and fall of pulmonary vascular resistance. These findings confirm the pulmonary vasodilating effect of nifedipine in patients with secondary pulmonary hypertension.     

Hypoxemic threshold for lung ventilation in the toad

The relationship between the activity of the buccal force pump, expressed as the time integral of positive buccal pressure, and PaO2 was investigated in conscious toads, Bufo marinus, unidirectionally ventilated at a high flow rate (240-260 ml/min). The high ventilatory flow rate meant that PaO2 was largely independent of the animal's ventilatory activity so that the relationship between pulmonary ventilation and PaO2 was effectively open-loop. The hypoxemic threshold (PaO2) for lung ventilation was 54.2 mm Hg in hypocapnia (PaCO2 = 4.7 +/- 0.3 mm Hg), 82.6 mm Hg in normocapnia (PaCO2 = 11.6 +/- 0.2 mm Hg), and 137.9 mm Hg in hypercapnia (PaCO2 = 20.1 +/- 0.1 mm Hg). Unidirectional ventilation with 20% O2 in N2, a condition in which the toads were normoxic but hypocapnic, stopped pulmonary ventilation cycles. Taken with existing evidence that hyperoxia stops pulmonary ventilation even under conditions in which PaCO2 is elevated this suggests that hypoxic and hypercapnic stimuli summate to drive lung ventilation in the toad. Bilateral denervation of the carotid labyrinths decreased pulmonary ventilation in absolute terms, but did not reduce the proportionate increase in pulmonary ventilation in response to normocapnic hypoxia, suggesting that chemoreceptors within the carotid labyrinth may contribute to, but are not solely responsible for, the hypoxemic ventilatory drive.     

Right ventricular dysfunction in adult severe cystic fibrosis

STUDY OBJECTIVES: This study sought to assess the extent of impairment of cardiac function in adult patients with end-stage cystic fibrosis (CF) and to examine the relationship between cardiovascular abnormalities and the degree of hypoxemia and hypercapnia. DESIGN AND SETTING: A retrospective study in a tertiary cardiac and CF center. PARTICIPANTS AND INTERVENTIONS: A total of 103 adult patients with end-stage CF awaiting lung or heart and lung transplantation (mean age [+/- SD], 26+/-7 years; 54 men) underwent Doppler echocardiography and arterial blood gas analysis (mean PaO(2), 54+/-10 mm Hg; mean PaCO(2), 47+/-8 mm Hg). The findings were compared to those of 17 healthy control subjects (mean age, 24+/-7 years; 13 men) who had no history of cardiac or pulmonary disease. MEASUREMENTS AND RESULTS: All patients were in sinus rhythm with a mean tachycardia of 112+/-18 beats/min (control subjects, 76+/-16; p<0.0001) and had a cardiac output of 5.3 L/min (control subjects, 4.3 L/min; p<0.04). In the patient group, the left ventricular (LV) dimensions, systolic and diastolic function, and wall thickness were all within normal limits. The mean amplitude of long-axis excursion in patients was normal at the LV site, but that of the right ventricular (RV) free wall was significantly reduced as compared with control subjects (1.6+/-0.4 vs. 2.2+/-0.4 cm, respectively; p<0.001), which was found to correlate with the degree of hypoxemia (r = 0.63; p<0.02) and hypercapnia (r = -0.68; p<0.01). RV diastolic function, which was represented by the relative isovolumic relaxation time to cardiac cycle length, was longer in patients than in control subjects (8.7+/-4.8% vs. 5.0+/-3.0%, respectively; p<0.03). The pulmonary flow acceleration time (90+/-22 vs 121+/-34 ms, respectively; p<0.01) and the systolic stroke distance (7.0+/-2.2 vs. 10.5+/-1.9 cm/s(2); p<0.001) were both lower than normal. CONCLUSIONS: This study confirms the presence of significant RV systolic and diastolic dysfunction in the setting of consistent tachycardia and increased cardiac output in adult CF patients with severe disease. No specific LV abnormalities were detected in these patients.