Elevation of serum potassium during beta blockade: absence of relationship to the renin-aldosterone system.

Eighteen patients with essential hypertension were treated in a single-blind, crossover study with pindolol and with propranolol. The two drugs were compared because of known differences between them on renin secretion. We noted that plasma renin activity and plasma aldosterone concentration were suppressed by propranolol but not by pindolol. Blood pressure was reduced about equally by both drugs. Serum potassium levels rose in 17 patients on pindolol (p < 0.001) and in 14 patients on propranolol (p = 0.08). Our data suggest that serum potassium elevations induced by beta blockade do not depend on the renin-angiotensin-aldosterone system. Alternative possibilities are discussed.

Inhibition of angiotensin converting enzyme by ramipril in serum and tissue of man.

Studies in animal models have indicated that ramipril is a potent inhibitor of angiotensin converting enzyme (ACE) in serum and tissue. In our study, the normal range of ACE activity and the inhibitory effect of short-term oral administration of ramipril on ACE activity in human serum and tissue samples of renal cortex, heart and blood vessels were determined. ACE activity in the renal cortex (125.2 +/- 11.5 nmol/mg per min) was greater than 600 times that of the heart (0.20 +/- 0.01 nmol/mg per min), greater than 500 times that of the veins (0.23 +/- 0.09 nmol/mg per min) and greater than 150 times that of the arteries (0.80 +/- 0.23 nmol/mg per min). ACE activity in the renal cortex and arteries 2 h after last dosing was almost completely inhibited by ramipril whereas ACE activity in the veins and heart was inhibited to a lesser extent. Our results demonstrate in man, for the first time, an inhibition of tissue ACE following short-term oral treatment with an ACE inhibitor.

Comparison of the metabolic response of the hypertrophic and the normal heart to hypothermic cardioplegia. The effect of temperature.

The aim of this study was to test for metabolic differences in the response of hypertrophic and normal hearts to hypothermic cardioplegia. Hypertrophic dog hearts and normal control hearts were subjected to 6 hours of hypothermic cardioplegia with the St. Thomas' Hospital solution. Levels before arrest of subepicardial and subendocardial adenosine triphosphate, creatine phosphate, and lactate in eight hypertrophic hearts were the same as those levels in 12 normal hearts. In hypertrophic hearts, but not in normal hearts, the induction of arrest was slow and was associated with an 11% increase in adenosine triphosphate levels, a 59% decrease in creatine phosphate levels, and a 12-fold increase in lactate levels. Seven hypertrophic hearts and eight normal hearts were studied during 6 hours of arrest and showed no further differences in metabolic response. Reducing the myocardial temperature from 20 degrees C to 12 degrees C slowed the rate of depletion of adenosine triphosphate and the rate of accumulation of lactate in both groups. We conclude that in the nonfailing, severely hypertrophic heart, levels before arrest of high-energy phosphates and lactate are normal, but that marked biochemical changes may occur if the induction of arrest is prolonged because of underdosing with cardioplegic solution. Cooling from 20 degrees C to 12 degrees C improves myocardial preservation in both hypertrophic and normal hearts.

The relationship between coronary pressure during reperfusion and myocardial recovery after hypothermic cardioplegia.

The aim of this study was to document the relationship between coronary pressure during reperfusion and myocardial recovery after hypothermic cardioplegia. Isolated canine hearts perfused by a support dog were subjected to 2 hours of cardioplegia at 20 degrees C. Three hearts were reperfused at each of the following pressures: 20, 40, 60, 80, 100, and 150 mm Hg. The reperfusion period lasted 30 minutes, with the pressure being raised gradually from zero to the test level over the first 2 minutes, then being held constant until the end of the period. The results showed that the normal dog heart after 2 hours of hypothermic cardioplegia is tolerant to a wide range of coronary pressures during reperfusion. Hearts reperfused at pressures between 40 and 100 mm Hg had similar values for coronary blood flow, coronary sinus oxygen saturation, myocardial oxygen consumption, lactate flux, contractility, and myocardial adenosine triphosphate content. If coronary reperfusion pressure was 20 mm Hg, [corrected] myocardial rewarming was delayed, myocardial oxygen consumption was decreased, and myocardial ischemia was manifested by marked lactate efflux, high myocardial lactate concentration, and depletion of adenosine triphosphate. If pressure was 150 mm Hg, coronary flow was excessive. To place these results in the context of coronary artery disease, we measured reperfusion pressure in coronary arteries distal to a stenosis in 10 patients studied at the time of coronary bypass grafting. In 13 arteries with major stenoses, distal mean coronary pressure averaged 31 mm Hg while the simultaneously measured mean aortic or radial artery pressure averaged 66 mm Hg. Thus the average gradient across the stenoses was 35 mm Hg (range 15 to 60 mm Hg). We concluded that in normal hearts without ischemic damage, reperfusion can be conducted satisfactorily at mean coronary pressures from 40 to 100 mm Hg. In setting the tolerable limits for reperfusion pressure in patients with severe coronary artery disease, one should make allowance for pressure gradients of up to 60 mm Hg between the aorta and the distal coronary artery.

Adverse effects of low-pressure reperfusion after hypothermic cardioplegia in normal and hypertrophic hearts.

The aim of this study was to determine the effect of low-pressure and high-pressure reperfusion, with and without ventricular fibrillation, on the recovery of hypertrophic and normal hearts after hypothermic cardioplegia. Fourteen hearts rendered hypertrophic by valvular aortic stenosis and 18 normal canine hearts were subjected to 1 hour of cardioplegic arrest at 28 degrees C during cardiopulmonary bypass. Each heart was then reperfused at a coronary pressure of either 40 mm Hg (low) or 80 mm Hg (high), initially in the empty beating state and then during ventricular fibrillation. Low-pressure reperfusion produced left ventricular subendocardial ischemia in hypertrophic and in normal hearts, shown by marked depression of subendocardial blood flow, myocardial pH, and myocardial oxygen consumption. In hypertrophic hearts the ischemia was more severe and resulted in a persistent depression of left ventricular function and myocardial oxygen consumption even when coronary pressure was returned to normal levels. High-pressure reperfusion was associated with rapid and complete recovery of myocardial metabolism and function in hypertrophic and in normal hearts. During low-pressure reperfusion, ventricular fibrillation exacerbated ischemia in hypertrophic and in normal hearts. During high-pressure reperfusion, a short period of ventricular fibrillation produced no adverse effects either in hypertrophic or in normal hearts. We conclude that low-pressure reperfusion produces subendocardial ischemia in normal and in hypertrophic hearts even in the empty beating state; in hypertrophic hearts it also impairs recovery of myocardial metabolism and function. The adverse effects of low-pressure reperfusion are exacerbated by ventricular fibrillation.

Sensitivity of the recently infarcted heart to cardioplegic arrest. Beneficial effect of pretreatment with orotic acid.

The mortality and morbidity of cardiac operations are increased in the presence of an established, recent myocardial infarct. To help understand the mechanisms for this and to develop a therapeutic strategy, we studied the response of the recently infarcted canine heart to hypothermic cardioplegia and the effect of pretreatment with orotic acid. Orotic acid is a precursor of nucleic acids with the ability to enhance protein synthesis. In 21 greyhound dogs, a myocardial infarct was produced by ligation of the left anterior descending coronary artery. Ten of these then received oral orotic acid (100 mg/kg/day) for 4 days and 11 were untreated. A sham group of eight dogs had a thoracotomy only and therefore had normal hearts (normal group). Four days later, all dogs underwent 60 minutes of cardioplegic arrest at 28 degrees C. Before arrest, stroke work index was lower and myocardial oxygen consumption at comparable work levels was higher in both the orotic acid and untreated infarct groups than in the normal group. After arrest and reperfusion, there was a severe depression of ventricular function in the untreated infarct group, with only 18% recovery of prearrest stroke work. In the orotic acid infarct group, recovery of prearrest function (43%) was similar to that in the normal group (56%) and significantly greater than in the untreated infarct group (p less than 0.01). After reperfusion, the untreated infarct group had a lower oxygen consumption, lower myocardial levels of adenosine triphosphate and glycogen, and higher lactate and water contents than before arrest (all p less than 0.05). In the orotic acid and normal groups, these variables returned to prearrest levels. We conclude that an established, recent myocardial infarct places the noninfarcted myocardium under stress and increases its sensitivity to hypothermic cardioplegia. This sensitivity is markedly reduced by treatment with orotic acid.

Successful long-term outcome with prolonged ischemic time cardiac allografts.

BACKGROUND: The limited availability of cardiac allografts together with the increasing number of patients on the waiting list restricts treatment of this population with heart transplantation. An increase in the available donor pool has been facilitated by the use of allografts with prolonged ischemic time (> 240 minutes). METHODS: Short- and long-term outcomes were compared in 150 heart transplant recipients on the basis of allograft ischemic time (< 241 minutes, 241 to 300 minutes, and > 300 minutes). RESULTS: No difference was found in allograft functional capacity, the development of transplant-associated coronary disease, or actuarial survival in the short and long term. CONCLUSIONS: Improved population treatment with prolonged ischemic time cardiac allografts can be safely undertaken without long-term risk to heart transplant recipients.

Body mass index as a predictor of survival in adults with cystic fibrosis referred for lung transplantation.

BACKGROUND: The timing of referral and listing for lung transplantation in adults with cystic fibrosis is influenced by many factors including pulmonary function, body mass index (BMI), sex, and patient and physician choice. This study aimed to analyze the effect of these variables on waiting list and postoperative mortality rates. In particular, low BMI is suggested to portend a poor outcome after transplantation. METHODS: All patients with cystic fibrosis referred to our institution (n = 92) between 1989 and 1996 were reviewed, and the effect on survival of BMI, sex, and other covariates was analyzed by use of Cox proportional hazards regression. RESULTS: Forty-five transplantations were undertaken with a mean waiting time of 226 days (range 1 to 678). Fifteen of the 62 listed patients died before transplantation with a mean time to death of 160 days (range 8 to 533). Fifteen patients died after transplantation. BMI at the time of listing predicted waiting list mortality (P < .05). Female sex tended to increase waiting list mortality rates, such that the combination of BMI less than 18 kg/m2, and female sex was associated with a 21% 1-year waiting list survival without transplantation. Age, forced expiratory volume in 1 second, sex, BMI, and date of transplantation did not predict postoperative survival. CONCLUSION: Patients with cystic fibrosis (particularly women) referred for lung transplantation with a BMI less than 18 kg/m2 are at high risk of death over the next 12 months. With this in mind, they should not be denied transplantation unduly while attempts are made to increase weight, especially because pretransplantation BMI does not influence posttransplantation survival.

Reverse telescope anastomotic technique reduces the incidence of bronchial stricture.

BACKGROUND: Bronchial stricture remains a major problem after lung transplantation. We hypothesized that a "reverse" telescope anastomosis, where the donor bronchus is sleeved external to the recipient bronchus, would be associated with a lower incidence of anastomotic stricture. METHODS: Over a 12-month period our Unit performed 35 consecutive single and bilateral sequential lung transplantations. The 56 bronchial anastomoses were constructed as a conventional (n = 27) or as a reverse (n = 29) telescope. RESULTS: Bronchial strictures developed in 48% of the conventional anastomoses but in only 7% of the reverse anastomoses (p < or = 0.05). Furthermore, the reverse telescope anastomosis eliminated the need for stenting. CONCLUSIONS: This technique greatly reduced the need for dilatation, debridement, and stent placement and may reduce the morbidity and mortality associated with anastomotic complications.

Pulmonary allograft ischemic time: an important predictor of survival after lung transplantation.

BACKGROUND: Traditionally organ availability in human lung transplantation has been limited by aiming to keep the graft ischemic time under 6 hours. To maximize organ supply in a country with a widely spread population, we have routinely procured organs beyond this time. Our experience outlines the clinical consequences of a prolonged allograft ischemic time. METHODS: Between 1990 and 1994 we performed 106 lung or heart-lung transplantations. The average graft ischemic time was 323 +/- 93 minutes. Lung preservation included a prostacyclin infusion (40 to 80 ng/kg/min for 10 minutes) and cold modified Euro-Collins solution flush. Organs were stored and transported on ice at 6 degrees to 10 degrees C. Graft ischemic time, transplant type, age, gender, cytomegalovirus status, and anesthetic time were subject to multivariate Cox regression analysis. RESULTS: Survival and graft ischemic times for heart-lung (n = 38), single lung (n = 33), and bilateral lung transplantation (n = 35) were not significantly different. Graft ischemic time was an independent predictor of survival (p < 0.01). Subgroup analysis notes the effect to be most pronounced beyond 5 hours (p = 0.02, hazard ratio 3.44, confidence interval 1.12 to 9.8). CONCLUSIONS: Pulmonary allograft ischemic time beyond 5 hours does not result in acceptable outcomes although survival is reduced. Attempts should be made to minimize graft ischemic times with careful coordination of transport and personnel.

Predictors of perioperative morbidity and mortality in lung volume reduction surgery.

BACKGROUND: Selection criteria for lung volume reduction surgery are still being refined. We sought to determine whether preoperative features could be used to predict early morbidity or mortality. METHODS: We reviewed preoperative characteristics of the first 89 patients who underwent lung volume reduction surgery at the Alfred Hospital. Data included arterial blood gases, prednisolone use, pulmonary function tests, 6-minute walk test, and anesthetic time. Length of stay and reintubation for respiratory failure were used as markers of morbidity. RESULTS: Findings included PaCO2 of 43 +/- 0.7 mm Hg, PaO2 70 +/- 1.1 mm Hg, percent predicted values for forced expiratory volume in 1 second 29.6% +/- 0.8%, TLCO% predicted 35.2 +/- 1.4%, and 6-minute walk test of 315 +/- 10.6 m (mean +/- SEM). Mean length of stay was 19 +/- 2 days, with 17 (19%) patients reintubated for respiratory failure. Mortality rate was 5.6% at 1 year post surgery, with no deaths in patients less than 65 years old. Multivariate analysis revealed that length of stay, reintubation and mortality were predicted by age and surgical time (p < 0.05), with no correlation with any other variables tested. Age greater than 70 years was associated with a significant risk of mortality (OR 9.0; p = 0.04). CONCLUSIONS: Age greater than 70 years and anesthetic time greater than 210 minutes predict both perioperative morbidity and mortality.

Continuous perfusion improves preservation of donor rat hearts: importance of the implantation phase.

BACKGROUND: Continuous hypothermic perfusion of donor hearts may provide extra protection for long ischemic times and suboptimal donors. The aim of three separate studies was to assess the effect of continuous hypothermic perfusion during simulated donor heart storage and implantation. METHODS: In study 1 twelve isolated rat hearts underwent 10 minutes of normothermic ischemia to simulate the effect of brain death on the heart and 5 hours of cardioplegic arrest, using University of Wisconsin solution. Six hearts were statically stored in University of Wisconsin solution at 2 degrees C, and six were perfused with University of Wisconsin solution. To assess the effect of simulated implantation, in study 2 an additional 12 hearts were statically stored for 5.5 hours in University of Wisconsin solution, six of which were rewarmed to a mean of 16 degrees C over the last 30 minutes of arrest. To assess the effect of simulated perfusion, in study 3 during implantation 12 hearts were rewarmed to a mean of 16 degrees C over the last 30 minutes of arrest, during which time six were perfused with 2 degrees C solution. RESULTS: Hearts perfused during storage demonstrated greater recovery of prearrest power, 85.8% +/- 1.8%, than hearts preserved by static storage, 72.7% +/- 3.0% (p < 0.01). The simulated warm implantation period reduced recovery of power from 68.3% +/- 5.1% to 40.2% +/- 2.0% (p < 0.001). Perfusion during warm implantation improved recovery to 61.8% +/- 3.9% (p < 0.01). In all experiments improved function was accompanied by improved metabolic energy status. CONCLUSIONS: During the implantation period of heart transplantation the donor heart sustains injury that could amount to 50% of total ischemic injury. Continuous perfusion during the cold storage phase and during simulated implantation improves recovery of the donor heart.

Bilateral sequential single lung transplantation for pulmonary hypertension and Eisenmenger's syndrome.

BACKGROUND: Lung transplantation, with and without intracardiac repair for pulmonary hypertension (PH) and Eisenmenger's syndrome (EIS), has become an alternative transplant strategy to combined heart and lung transplantation (HLT). METHODS: Thirty-five patients with PH or EIS underwent either bilateral sequential single lung transplantation (BSSLT, group I, n = 13) or HLT (group II, n = 22). Another 74 patients, who underwent BSSLT for other indications, served as controls (group III). Immediate allograft function, early and medium-term outcomes, lung function, and 2-year survival were compared between the groups. RESULTS: Comparisons between groups I and II showed no significant difference in any variables except percent predicted forced vital capacity. Immediate allograft function was significantly inferior (p < 0.05) and the blood loss was greater (p < 0.01) in group I when compared with those in group III. However, this resulted in no significant difference in early and medium-term outcomes, and 2-year survival between the 2 groups. CONCLUSIONS: BSSLT for PH and EIS can be performed as an alternative procedure to HLT without an increase in early and medium-term morbidity and mortality. Results are comparable with BSSLT performed for other indications.

Impact of graft ischemic time on outcomes after bilateral sequential single-lung transplantation.

BACKGROUND: Graft ischemic time (GIT) is a potential limiting factor in lung transplantation. METHODS: Seventy-four patients who underwent bilateral sequential single-lung transplantation were divided into three groups: group I, GIT less than 5 hours (n = 20); group II, GIT between 5 and 8 hours (n = 39); and group III, GIT more than 8 hours (n = 15). We compared early allograft function (ratio of arterial oxygen tension to inspired oxygen fraction and alveolar-arterial oxygen gradient), blood loss, the need for tracheostomy, the duration of ventilation, intensive care unit stay, and hospital stay. We also compared prevalences of acute and chronic rejection, airway complications, lung function test, and 2-year survival. RESULTS: Early allograft function in group III was significantly worse than those in groups I and II. However, there was no significant difference in any other variables of early and medium-term outcomes among the three groups. No significant correlation was detected between GIT and duration of intensive care unit stay or hospital stay. CONCLUSIONS: The limitation of acceptable GIT could be extended from the traditionally approved 4 to 5 hours, to 5 to 8 hours or even longer.

Albumin determination in frozen urines--underestimated results.

Albumin determination by radioimmunoassay in fresh and frozen urine collections from 73 patients were performed. The values for albumin in fresh urines were 1-200 mg/24 h and were significantly higher (p less than 0.001) than the corresponding values in urines frozen for seven days (40.7 mg/24 h +/- 5.0 vs. 32.0 mg/24 h +/- 4.3). Similar results were obtained for protein determination, using turbidimetry, in urine collections from 45 proteinuric patients. Iodinated human albumin added to urine specimens was higher (p less than 0.001) in the pellets from frozen urines compared to urines kept at 4 degrees C for 1 and/or 7 days. By contrast, the radioactivity in the pellet of fresh urines kept at 4 degrees C for 1 or 7 days did not show any significant change. We suggest that freezing results in a partial albumin and protein sedimentation. Thus, determination of albumin in frozen urine specimens underestimates the real value by about 20%. This underestimation will limit our ability to diagnose borderline cases of microalbuminuria.

Coronary blood flow and myocardial metabolism during reperfusion after hypothermic cardioplegia in the dog.

There have been many studies of reperfusion injury after normothermic ischemia. However, there have been few clinically relevant studies on the nature and time course of recovery of the myocardium during reperfusion after hypothermic cardioplegia. We studied reperfusion in the isolated dog heart supported by another dog. After 2 h of cardioplegic arrest at 20 degrees C, 11 normal hearts were reperfused for 30 min at optimal coronary pressures (60-100 mm Hg mean). The following events occurred: rapid rewarming, a transient hyperemia followed by a rapid return of both coronary blood flow and myocardial oxygen consumption to normal, washout of lactate, recovery of contractility and a slight decline in ATP. Most of these events occurred during the first 15 min of reperfusion. We concluded that, in normal hearts which are well protected during hypothermic cardioplegia, reperfusion at optimal coronary pressure results in recovery of the myocardium within 15 min, with the exception of recovery of ATP levels.

Mitral valve replacement via a right mini-thoracotomy in the dog: use of carbon dioxide to reduce intracardiac air.

OBJECTIVE: To develop a clinically applicable method of minimally invasive mitral valve replacement (MVR) with cardioplegia, and examine the ability of carbon dioxide (CO2) to improve de-airing. METHODS: MVR was performed via a 5 x 3-cm right lateral minithoracotomy in eight greyhounds. Peripheral cardiopulmonary bypass and an ascending aortic balloon catheter (endoaortic clamp) were used for cardioplegia and aortic root venting. The endoaortic clamp was inflated in the ascending aorta under fluoroscopy and cardioplegic solution was infused. In four dogs, CO2 at 2 l/min was used to displace air in the chest. A left atriotomy was made, the valve exposed and a mechanical valve implanted. After left atrial closure, retained intracardiac gas was aspirated from the aortic root and collected in a bubble-trap. The endoclamp was deflated and the animal weaned from bypass. RESULTS: A satisfactory MVR was performed in all cases. The clamp time was 64 +/- 13 min and all dogs were stable post-bypass. In the CO2 group, intrathoracic CO2 was maintained above 86% and 0.1 +/- 0.1 ml of gas was collected, compared to 1.3 +/- 0.8 ml in the non-CO2 group (P < 0.05). CONCLUSIONS: Femoro-femoral bypass and use of the endoaortic clamp allow a safe and efficacious MVR via a right minithoracotomy in the dog. A high intrathoracic CO2 concentration reduces the amount of retained intracardiac gas.