Novel bioartificial liver support system: preclinical evaluation.

Preclinical safety and efficacy evaluation of a novel bioartificial liver support system (BLSS) was conducted using a D-galactosamine canine liver failure model. The BLSS houses a suspension of porcine hepatocytes in a hollow fiber cartridge with the hepatocytes on one side of the membrane and whole blood flowing on the other. Porcine hepatocytes harvested by a collagenase digestion technique were infused into the hollow fiber cartridge and incubated for 16 to 24 hours prior to use. Fifteen purpose-bred male hounds, 1-3 years old, 25-30 kg, were administered a lethal dose, 1.5 g/kg, of D-galactosamine. The animals were divided into three treatment groups: (1b) no BLSS treatment (n = 6); (2b) BLSS treatment starting at 24-26 h post D-galactosamine (n = 5); and (2c) BLSS treatment starting at 16-18 h post D-galactosamine (n = 4). While maintained under isoflurane anesthesia, canine supportive care was guided by electrolyte and invasive physiologic monitoring consisting of arterial pressure, central venous pressure, extradural intracranial pressure (ICP), pulmonary artery pressure, urinary catheter, and end-tidal CO2. All animals were treated until death or death-equivalent (inability to sustain systolic blood pressure > 80 mmHg for 20 minutes despite massive fluid resuscitation and/or dopamine administration), or euthanized at 60 hours. All animals developed evidence of liver failure at 12-24 hours as evidenced by blood pressure lability, elevated ICP, marked hepatocellular enzyme elevation with microscopic massive hepatocyte necrosis and cerebral edema, elevated prothrombin time, and metabolic acidosis. Groups 2b and 2c marginally prolong survival compared with Group 1b (pairwise log rank censored survival time analysis, p = 0.096 and p = 0.064, respectively). Since survival times for Groups 2b and 2c are not significantly different (p = 0.694), the groups were combined for further statistical analysis. Survival times for the combined active treatment Groups 2b and 2c are significantly prolonged versus Group 1b (p = 0.047). These results suggest the novel BLSS reported here can have a significant impact on the course of liver failure in the D-galactosamine canine liver failure model. The BLSS is ready for Phase I safety evaluation in a clinical setting.

Selective positive end-expiratory pressure and right ventricular function in dogs.

Differential ventilation with selective positive end-expiratory pressure (PEEP) has been shown to reduce cardiac output less than general PEEP. In previous studies we have demonstrated that during selective PEEP left ventricular preload is better maintained than during general PEEP. The present study was designed to determine whether the different haemodynamic responses to selective and general PEEP also might be due to different effects on RV preload. The study was performed on nine acutely instrumented dogs, in which extraventricular pressure was measured by pericardial balloon transducers. Measures of RV preload were obtained by the use of ultrasonic segment length transducers as well as end-diastolic transmural pressure (RVEDP). The study showed reductions in RVEDP during general and selective right (R) PEEP, accompanied by moderate reductions in RV inflow tract segment lengths. These changes were most marked with general PEEP. Selective LPEEP did not change RV preload significantly. Therefore, better maintained cardiac output with selective PEEP than with general PEEP is partly due to less impairment of right ventricular filling.

Changes in pulmonary vein flow pattern during volume loading.

OBJECTIVE: The aim was to investigate the effect of increased left ventricular filling pressure on the pulmonary vein flow (PVQ) pattern. METHODS: Pulmonary vein flow was recorded using an ultrasonic transit time flow meter in six anaesthetised dogs. Mean left atrial pressure was increased by stepwise volume loading from 7.8(SEM 1.3) to 18.9(1.9) mm Hg (p < 0.01). RESULTS: With loading the PVQ signal developed several characteristic positive and negative waves which corresponded to directionally opposite pressure waves in the left atrium. There was a marked increase in the amplitude of the PVQ signal: peak flow increased from 165(50) to 310(38) ml.min-1 (p < 0.01), while minimum flow decreased from 49(37) to -61(23) ml.min-1 (p < 0.01). The minimum value of PVQ occurred during early ventricular systole, corresponding to the left atrial C wave. With progressive loading there was an increasing deceleration of flow during atrial contraction. To quantify the effect of atrial contraction and the C wave on the flow pattern a ratio was calculated between the integrated flow from the start of atrial contraction to the nadir of the x descent and the integrated flow during the rest of the cardiac cycle. This ratio decreased from 0.40(0.06) to 0.11(0.07) with loading (p < 0.01). In each experiment this flow ratio varied inversely with mean left atrial pressure (regression coefficients between 0.66 and 0.97). CONCLUSIONS: Volume loading caused marked changes in the pulmonary vein flow pattern. The PVQ waves reflected the pressure waves in the left atrium. The relative flow during atrial contraction varied inversely with mean left atrial pressure. Further studies should be done to determine whether this index reflects left ventricular filling pressure under different conditions.

Effect of the pericardium on atrial systolic function.

The effect of pericardial constraint on atrial systolic function was investigated in nine acutely instrumented anesthetized dogs. Left and right atrial pressures were recorded by high-fidelity catheters; auricular diameters and free wall segment lengths were measured by sonomicrometry. Atrial function curves were constructed by relating atrial systolic dimensional shortening to atrial end-diastolic pressure during progressive volume loading. With the pericardium closed, the function curves were shifted markedly downward and rightward, such that atrial systolic shortening was reduced at any given pressure. There was a concomitant leftward and upward shift of the atrial end-diastolic pressure-dimension relationship. The relationship between atrial systolic shortening and atrial end-diastolic dimension was not shifted. These results suggest that the apparent depression of atrial systolic function with the pericardium closed is due to a restrictive effect of the pericardium on atrial filling. In conclusion, in the acutely dilated heart, the pericardium restricts atrial filling and thus causes a reduction in atrial systolic contribution to ventricular filling.

Hormonal changes in patients with severe chronic congestive heart failure treated by ultrafiltration.

Plasma atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), plasma renin activity (PRA), and circulatory haemodynamics were studied in five patients with chronic congestive heart failure undergoing ultrafiltration on two consecutive days. The patients were in the New York Heart Association class IV, and were considered candidates for heart transplantation. A mean of 3.3 +/- 0.5 litres of fluid was removed during each ultrafiltration. Plasma ANP concentration remained unchanged during ultrafiltration: 369 +/- 151 pg/ml at start and 316 +/- 116 pg/ml at the end, while plasma ADH concentration and PRA increased from 5.1 +/- 2.1 to 7.5 +/- 3.4 pg/ml (P less than 0.02), and 5.9 +/- 3.0 to 7.7 +/- 3.2 ng/ml (P less than 0.03) respectively (n = 10). After treatment, plasma ADH and PRA declined to baseline values within 1 h. Pulmonary artery, pulmonary capillary wedge, and right atrial pressures decreased significantly, while blood pressure and heart rate remained constant during ultrafiltration. A volume of 3.3 +/- 0.5 litres of fluid was removed, and caused an increase in colloid osmotic pressure from 22.0 +/- 3.0 to 33.7 +/- 3.9 mmHg (P less than 0.02). It was unexpected that plasma ANP concentration did not decline. Due to long-standing severe heart failure the atrial wall may have lost some of its elastic properties, resulting in less ability to adapt to reduced filling pressures. Accordingly, atrial wall stretch remained unchanged, explaining the constant ANP levels. Ultrafiltration treatment caused an increased responsiveness to diuretic therapy, and four patients survived long enough to receive heart transplants.

The relationship between atrial pressure, atrial dimensions and atrial natriuretic factor during pacing tachycardia in dogs.

Acute supraventricular tachycardia is known to increase the plasma level of atrial natriuretic factor (ANF). The purpose of these experiments was to investigate if such an increase in plasma-ANF could be ascribed to changes in atrial pressure and atrial dimensions. Eight anaesthetized dogs were instrumented with atrial pressure catheters and sonomicrometers to measure left and right auricular and atrial free wall dimensions. An acute increase in atrial rate from 150 to 200 min-1 for 10 min did not change plasma-ANF or atrial haemodynamic variables. A further increase in atrial rate to 250 or 300 min-1 increased right and left atrial intracavitary pressures (P less than 0.01), both auricular diameters and right atrial free wall segment length (P less than 0.05). Left atrial free wall segment length remained unchanged. Plasma-ANF increased in all dogs (P less than 0.01). The change in plasma-ANF correlated well with changes in atrial pressures as well as with changes in atrial dimensions. These results support the hypothesis that release of ANF during acute atrial tachycardia may in part be attributed to atrial dilatation.

The effect of positive end-expiratory pressure ventilation on atrial filling.

As a measure of atrial filling, left and right auricular diameter and free wall segment length were recorded by sonomicrometry during incremental positive end-expiratory pressure (PEEP) in eight acutely instrumented closed chest dogs. The effect of PEEP was assessed with the pericardium open (n = 6) and closed (n = 8). On both occasions, PEEP decreased left auricular diameter (P less than 0.05). PEEP also caused a reduction in right auricular diameter with the pericardium open (P less than 0.05), while the variable was unchanged with the pericardium closed. PEEP did not cause any changes in either left or right free wall segment lengths. Both left and right auricular pressure-diameter relationships were progressively shifted leftwards with incremental PEEP. These observations suggest that PEEP may reduce left ventricular output not only by interfering with passive ventricular filling, but also by reducing atrial dimensions.

Rate-induced increase in plasma atrial natriuretic factor can occur independently of changes in atrial wall stretch.

Tachycardia is known to increase the plasma level of atrial natriuretic factor (ANF). The aim of the study was to determine whether such release of ANF can occur independently of increased atrial wall stretch. Seven anesthetized dogs were instrumented with pressure catheters and sonomicrometer crystals to measure left and right auricular and atrial free wall dimensions. During atrial pacing, the measured atrial dimensions were kept constant by adjusting vascular constrictors placed around the great vessel trunks. When atrial rate was increased progressively by pacing at 150, 200, and 250 min-1, plasma ANF increased from 40.8 +/- 5.4 to 43.0 +/- 6.0 (P = NS) and 103.1 +/- 17.6 (SE) pmol/l (P less than 0.05), respectively. Repeating the pacing sequence at two different levels of elevated left atrial pressure caused at each level a similar increase in plasma ANF at 250 min-1. The relationship between plasma ANF and atrial dimensions was shifted upward by pacing, such that ANF was higher for any given atrial dimension. In conclusion, pacing tachycardia elevates plasma ANF in the presence of constant atrial dimensions. These results support the hypothesis that chronotropic stimulation can cause release of ANF by a mechanism that is independent of atrial stretch.

Endocrine responses to positive end-expiratory pressure ventilation in patients who have recently undergone heart surgery.

The effect of positive end-expiratory pressure ventilation (PEEP) on angiotensin II and atrial natriuretic factor (ANF) was studied postoperatively following heart surgery. In nine patients pressures were recorded in the radial artery, pulmonary artery and the right atrium. PEEP of 5 cmH2O (0.5 kPa) and 10 cmH2O (1 kPa) increased angiotensin II from 38.8 +/- 20.3 (mean +/- s.e.mean) to 56.7 +/- 29.6 (n.s.) and 66.7 +/- 28.7 (P less than 0.05) pmol/l, respectively. Plasma-ANF showed no significant changes during PEEP. Pulmonary artery wedge pressure increased from 12.9 +/- 2.0 to 14.1 +/- 2.0 (n.s.) and 18.5 +/- 2.1 (P less than 0.01) mmHg, and right atrial pressure from 8.3 +/- 1.7 to 9.8 +/- 1.7 (n.s.) and 12.9 +/- 1.7 (P less than 0.01) mmHg with 5 and 10 cmH2O (0.5 and 1.0 kPa) of PEEP, respectively. Systemic blood pressure tended to decrease (n.s.) with PEEP. In conclusion, PEEP markedly increased angiotensin II. This may represent an important compensatory mechanism, helping to prevent reduction in aortic pressure during PEEP. ANF, however, did not change with PEEP of 5 or 10 cmH2O (0.5 and 1.0 kPa).

[Treatment of unstable angina pectoris]. / Behandling av ustabil angina pectoris.

We present the results of an acute revascularisation program for unstable angina. Of the 63 consecutive patients included in the program 61 had significant coronary artery disease. Coronary bypass grafting was performed in 39 and percutaneous transluminal angioplasty in 9. There were two perioperative myocardial infarctions and one death in hospital. 13 patients were found unsuitable for revascularisation. At follow-up (14-26 months) 60 patients were still alive (95%). In the revascularised group 30 patients (65%) were free of angina pectoris. Accordingly, in patients who do not respond to medical therapy, acute revascularisation may be performed with low operative mortality, low incidence of perioperative myocardial infarctions, and good long term results.

Unstable angina pectoris. Experience with an acute revascularization program.

One year's experience of an acute revascularization program for unstable angina pectoris is presented. In the total material of 63 patients, significant coronary artery stenosis was found in 61 and normal coronary arteries in two. Coronary artery bypass grafting was performed in 39 patients (62%) and percutaneous transluminal angioplasty in nine (14%). There were two perioperative myocardial infarctions and one hospital death. Thirteen patients were not eligible for revascularization. At follow-up (14-26 months) 60 patients were still alive (95%). In the revascularization group, one patient had died, but of the remaining 46 patients, 30 (65%) were free of angina pectoris, and in addition six had only minor symptoms.

Plasma atrial natriuretic peptide in cardiac transplant recipients. A prospective study.

Cardiac transplantation in 10 patients with congestive heart failure resulted in reduction of high plasma concentrations of atrial natriuretic peptide (ANP), preoperatively five-fold above normal, to a level two-fold above normal, which was maintained throughout a 12-week follow-up period. Cardiac function was normalized in all patients. Transient increases in plasma ANP, in four cardiac recipients 3-10-fold their basal levels, could neither be related to rejection episodes nor to cardiac dysfunction, but rather to signs of fluid and sodium retention. High plasma ANP levels in cardiac transplant recipients suggest that the capacity to secrete ANP is preserved in the transplanted heart.