Cardiac release of prostacyclin and thromboxane A2 during coronary revascularization

Cardiac surgery stimulates the systemic synthesis of prostacyclin and thromboxane A2, but the cardiac release of these prostanoids has been reported infrequently. Fifty-four patients undergoing elective coronary artery bypass had coronary sinus catheters inserted to evaluate the cardiac release of the stable metabolites of prostacyclin (6-keto-prostaglandin F1 alpha) and thromboxane A2 (thromboxane B2). Arterial concentrations of 6-keto-prostaglandin F1 alpha and thromboxane B2 were elevated after cardiac cannulation and during cardiopulmonary bypass. The cardiac release of 6-keto-prostaglandin F1 alpha was observed after cannulation and during, but not after, cardiopulmonary bypass. Cardiac thromboxane B2 release was detected after cross-clamp release and persisted during the early postoperative period when cardiac 6-keto-prostaglandin F1 alpha release was no longer detectable. Cardiopulmonary bypass stimulated the systemic production of thromboxane and prostacyclin. The cardiac release of thromboxane was unopposed by cardiac prostacyclin production in the early postoperative period and may contribute to reperfusion injury.     

Prostaglandin E2, prostacyclin, and thromboxane changes during nonpulsatile cardiopulmonary bypass in humans

To study the effect of lung bypass on the production of prostaglandin E2, prostacyclin, and thromboxane A2, we measured simultaneously arterial and venous plasma concentrations of prostaglandin E2, 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin), and thromboxane B2 (stable metabolite of thromboxane A2) before, during, and after cardiopulmonary bypass. Seventeen patients (age range 46 to 69 years) undergoing aorta-coronary bypass grafts were investigated. The prostaglandin E2 production rose sharply immediately after the onset of bypass (baseline: 9.7 +/- 2.9 pg/ml to 85 +/- 16.6 pg/ml in venous and 87 +/- 12 pg/ml in arterial plasma, p less than 0.03) and rapidly decreased after pulmonary reperfusion (53 +/- 6.4 and 57 +/- 20 pg/ml, respectively, in venous and arterial plasma at the end of bypass). The increase in prostaglandin E2 was influenced by the heart-lung machine itself (as demonstrated by a closed "bypass" circuit) and by lung bypass. Pulmonary metabolism of prostaglandin E2 was maintained after bypass. The prostacyclin production rose significantly at the beginning of bypass (154 +/- 26 pg/ml venous prebypass level to 361 +/- 94 pg/ml after aortic clamping, p less than 0.03). Prostacyclin decreased progressively during rewarming of the patient, pulmonary reperfusion, and discontinuation of bypass. When prostacyclin decreased, thromboxane B2 production rose significantly and reached peak arterial levels when the lungs were reperfused (112 +/- 33 pg/ml prebypass levels to 402 +/- 101 pg/ml, p less than 0.01). Except for prostaglandin E2, there were no significant differences between arterial and venous plasma levels of these substances. The same prostanoids were also measured in five patients undergoing major orthopedic operations, and no significant changes in prostanoids were observed. Our data demonstrate significant production of prostaglandin E2 in the systemic circulation during cardiopulmonary bypass in humans. They further indicate that lung bypass disturbs the plasma prostaglandin/thromboxane balance.     

Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass.

Thirty-seven patients undergoing cardiopulmonary bypass operations were studied to assess the effect of skin temperature on platelet function. Differences in skin temperature between the two arms were created during bypass, at the completion of bypass, and at 2 and 24 hours after the completion of bypass. In each of 37 patients the temperature of one arm was increased with a water-filled blanket set at 40 degrees C. In 11 of these patients the other arm was allowed to equilibrate with the environment, and in the other 26 patients the arm was cooled with ice. Except for the differences in local skin temperature between the two arms, all factors known to affect the patient's bleeding time were similar. Measurements were made of bleeding times and the levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha in shed blood obtained at the template bleeding time site. In the 33 patients not treated with aspirin, local hypothermia produced an increased bleeding time and a significant reduction in the thromboxane B2 level at the bleeding time site, but no reduction in 6-keto-prostaglandin F1 alpha level. Local rewarming produced a significant increase in the shed blood thromboxane B2 level. In the four patients treated with aspirin, local hypothermia produced no differences in bleeding times or shed blood levels of thromboxane B2 or 6-keto-prostaglandin F1 alpha. These data show the benefits of rewarming patients with hypothermia who have nonsurgical blood loss to restore to normal both core and peripheral temperatures before resorting to the transfusion of homologous blood products.     

Antioxidant therapy with Salvia miltiorrhiza decreases plasma endothelin-1 and thromboxane B2 after cardiopulmonary bypass in patients with congenital heart disease

OBJECTIVE: The endothelium-derived vasoconstrictor endothelin-1 is increased after cardiopulmonary bypass in children with congenital heart defects. This study determines whether antioxidant therapy with Salvia miltiorrhiza injection, an herb extract containing phenolic compounds, prevents the postoperative increase of endothelin-1. The relationship between endothelin-1 and the endothelium-derived prostacyclin (prostaglandin I2) and thromboxane A2 postoperatively is also investigated. METHODS: Twenty children with congenital heart defects and pulmonary hypertension were randomly assigned to group A (placebo control, n=10) or B (200 mg/kg Salvia miltiorrhiza intravenously after anesthesia induction and at the time of rewarming, respectively; n =10) before cardiac surgery. Central venous blood samples were taken before operation (T(0)), 10 (T(1)) and 30 minutes (T(2)) after starting cardiopulmonary bypass, 10 (T(3)) and 30 minutes (T(4)) after aortic declamping, and 30 minutes (T(5)) and 24 hours (T(6)) after termination of cardiopulmonary bypass. Plasma lipid peroxidation product malondialdehyde, myocardial specific creatine kinase-MB activity, thromboxane B2, and 6-keto-prostaglandin F(1 alpha) (stable metabolites of thromboxane A2 and prostaglandin I2) were measured. RESULTS: Malondialdehyde increased significantly at T(1) in group A and remained significantly higher than in group B thereafter (P <.05). Malondialdehyde in group B did not significantly increase over time. At T(5), plasma creatine kinase-MB, thromboxane B2, and endothelin-1 in group B were lower than in group A (P <.05); malondialdehyde correlated significantly with creatine kinase-MB (r = 0.71, P =.0005). At T(6), endothelin-1 negatively correlated with the 6-keto-prostaglandin F(1 alpha)/thromboxane B2 ratio (r = -0.64, P =.0025). CONCLUSION: Antioxidant therapy reduces myocardial damage and attenuates postoperative vasoactive mediator imbalance.     

Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.

Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.     

Effect of experimental cardiopulmonary bypass on systemic and transcardiac thromboxane B2 levels

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.     

Pharmacological, hematological, and physiological effects of a new thromboxane synthetase inhibitor (CGS-13080) during cardiopulmonary bypass in dogs

The hematological and pharmacological effects of a new thromboxane synthetase inhibitor, CGS-13080 (imidazo[1,5-alpha]pyridine-5-hexanoic acid), were investigated during cardiopulmonary bypass in a blinded, randomized manner in dogs. Compared with placebo, CGS-13080 suppressed thrombin-stimulated platelet thromboxane B2 production by 90% during cardiopulmonary bypass (p less than .001), an effect that persisted for two hours after stopping the infusion. In the CGS-13080-treated group, plasma 6-keto-prostaglandin F1 alpha levels significantly increased over time (p less than .03) and were somewhat higher when compared with those in the placebo-treated group. This observation suggests that an "endoperoxide shunt" may have occurred. In the control group, an inverse correlation between platelet count and level of thromboxane B2 per platelet following in vitro thrombin stimulation (r = .5, p less than .001) was apparent, but there was no correlation between these two variables (r = .18, p less than .10) in the CGS-13080-treated group. No adverse hemodynamic or other effects attributable to CGS-13080 occurred during or immediately following cardiopulmonary bypass. These results suggest that CGS-13080 is an effective inhibitor of thromboxane B2 production during cardiopulmonary bypass in dogs and has no adverse physiological effects.     

Changes in arterial thromboxane B2 and 6-keto-prostaglandin-F1 alpha levels in cirrhotic and non-cirrhotic patients after hepatectomy

Following hepatectomy, arterial concentrations of thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), which are stable metabolites of thromboxane A2(TXA2) and prostaglandin I2(PGI2), were measured by radioimmunoassay in 17 cirrhotic and 9 non-cirrhotic patients to assess the role of TXB2 and PGI2 in patients with liver dysfunction during hepatectomy. In both cirrhotic and non-cirrhotic patients, arterial TXB2 and 6-keto-PGF1 alpha levels significantly increased during hepatectomy and decreased to preoperative levels at the 1st postoperative day (1-POD). The TXB2/6-keto-PGF1 alpha ratio significantly decreased during hepatectomy and at 1-POD. There were no significant differences in changes of TXB2 and PGI2 levels between cirrhotic and non-cirrhotic patients. In cirrhotic patients with poor hepatic reserve, whose ICG K values were less than 0.08, arterial 6-keto-PGF1 alpha levels were significantly higher and the ratio were significantly lower than in cirrhotic patients with good hepatic reserve and non-cirrhotic patients before and after operation. Based on these results, it is concluded that the TXA2/PGI2 ratio becomes low after hepatectomy and the ratio is lower in cirrhotic patients with poor hepatic reserve.     

Evidence of organ damage after cardiopulmonary bypass. The role of elastase and vasoactive mediators.

In this study the causes of organ damage after cardiopulmonary bypass were multifactorial. The concentration of the proteolytic enzyme elastase, which was released from activated granulocytes in the milieu of significantly reduced levels of alpha 1-protease inhibitor (p less than 0.01), increased during cardiopulmonary bypass (p less than 0.01). In addition, bypass initiated platelet aggregation, which both altered the eicosanoid metabolism and caused the level of thromboxane A2 to increase and surpass the level of prostaglandin I2. Because thromboxane A2 dominance subsided immediately after cardiopulmonary bypass, the effect of thromboxane A2 (vasoconstriction) on the development of organ damage may have been influential only during bypass. Both during and after bypass, the increase in endothelin excretion (p less than 0.01 to 0.05) was believed to induce a further vasoconstriction in the microvasculature. On completion of the cardiopulmonary bypass, the elevation of the lysosomal enzyme beta-glucuronidase, which is a sensitive indicator of cellular damage, was influenced by the concentrations of elastase (r = 0.8) and endothelin (r = 0.52). As evidenced by leuko-sequestration in the lung after cardiopulmonary bypass, the increase in the alveolar-arterial oxygen tension difference correlated with the elastase concentration (r = 0.68). Renal damage, which was detected by an increase in renal tubular enzymes (N-acetyl-beta-D-glucosaminidase and gamma-glutamyltranspeptidase) was affected by the endothelin (r = 0.68, 0.56) and elastase levels (r = 0.58, 0.68), respectively, but not by the ratio of thromboxane B2 to prostaglandin F1 alpha. The elastase level influenced the pulmonary vascular resistance (r = 0.56). However, neither the cardiac index nor the systemic and pulmonary vascular resistances were influenced by the endothelin level and the ratio of thromboxane B2 to prostaglandin F1 alpha.     

Effects of cardiopulmonary bypass on eicosanoid metabolism during pediatric cardiovascular surgery

Cardiopulmonary bypass in children with congenital heart disease is associated with significant morbidity manifested by increased complement degradation products, heightened pulmonary vascular activity, and coagulopathy. In adults with cardiac disease, the prostaglandins (eicosanoids) have been shown to contribute to the pathophysiologic response to extracorporeal circulation. This study assessed the effect of cardiopulmonary bypass in infants and children on two potent eicosanoids: thromboxane, a vasoconstrictor and platelet aggregating agent, and prostacyclin, a vasodilator and platelet disaggregating agent. The biochemical profiles of thromboxane and prostacyclin were evaluated in temporal relationship to selected parameters of platelet loss and pulmonary vascular hemodynamics during and after cardiopulmonary bypass. Twenty-one children, aged 3 days to 9 years, with congenital heart defects who were undergoing repair with cardiopulmonary bypass were studied. Nine pediatric patients undergoing palliative heart operations with no cardiopulmonary bypass served as the control group. In the group having cardiopulmonary bypass, the thromboxane concentration significantly increased during bypass (195 +/- 10 to 910 +/- 240 pg/ml, +/- standard error of the mean, p less than 0.005), whereas the control group demonstrated no significant change in thromboxane concentration. The highest thromboxane values were seen in the youngest patients (p less than 0.002). There was no significant correlation between thromboxane changes with alterations in pulmonary vascular resistance, platelet loss, duration of cardiopulmonary bypass or aortic cross-clamping. Prostacyclin levels rose significantly in both the bypass group (100 +/- 20 to 570 +/- 80 pg/ml, p less than 0.01) and in the control group (109 +/- 44 to 589 +/- 222 pg/ml, p less than 0.01), which apparently is due to surgical manipulation of vascular endothelium. These data show that eicosanoid production is significantly altered in children during cardiopulmonary bypass. Although thromboxane, a potent vasoconstrictor, is produced in significant amounts during and after cardiopulmonary bypass, our data show that thromboxane does not directly mediate changes in pulmonary artery hypertension and is not quantitatively related to platelet loss during pediatric cardiovascular operations.     

Aprotinin reduces operative closure time and blood product use after pediatric bypass

BACKGROUND: The use of aprotinin in children undergoing cardiopulmonary bypass is controversial. We hypothesized that aprotinin would reduce blood product use and operative closure time in selected pediatric patients. METHODS: For a 6-month period starting in October 1999, consecutive cardiopulmonary bypass patients 6 months of age or less (n = 18) or having a repeat sternotomy (n = 18) received aprotinin. Similar consecutive patients from the preceding 6 months served as controls (n = 35 and 41, respectively). Data extracted from medical records included preoperative clinical characteristics, operative and postoperative procedures, and total blood product use. RESULTS: Patients in the aprotinin and control groups were well matched with regard to preoperative and intraoperative variables. Patients 6 months of age or less who received aprotinin required less operative closure time when compared with controls (median, 93 vs 127 minutes, p = 0.004), and trended toward requiring fewer red blood cell unit exposures (median, three vs five exposures, p = 0.07). Patients undergoing repeat sternotomy who received aprotinin required less operative closure time when compared with controls (mean, 126 vs 159 minutes, p = 0.007), fewer red blood cell unit exposures (median three vs four exposures, p = 0.002), and fewer fresh-frozen plasma unit exposures (median, zero vs one exposure, p = 0.007). CONCLUSIONS: Aprotinin reduced operative closure time and blood product exposure in pediatric patients undergoing cardiopulmonary bypass who were 6 months of age or less or underwent a repeat sternotomy.     

Intraoperative versus routine hemodialysis in end-stage renal disease patients undergoing open-heart surgery.

Of 13 chronic hemodialysis end-stage renal disease (ESRD) patients undergoing open-heart surgery, 7 received intraoperative hemodialysis (IHD) during cardiopulmonary bypass and 6 received hemodialysis on a routine basis (RHD). Within the groups, IHD patients had significantly lower post-operative mean serum potassium and mean plasma creatinine concentrations compared to mean preoperative values. Postoperative mean BUN tended to decrease and mean serum bicarbonate concentration was unchanged as compared to mean preoperative values. In the RHD group, however, post-operative mean serum potassium concentration tended to increase, mean serum bicarbonate concentration significantly declined and mean BUN was unchanged as compared to mean preoperative values. An average of 2.1 +/- 0.5 liters of fluid was removed from the IHD patients during cardiopulmonary bypass. Post-operatively, 0 of 7 IHD patients versus 4 of 6 RHD patients required parenteral sodium bicarbonate therapy (chi 2, p less than 0.01). On average, RHD patients required hemodialysis 1 day after surgery, whereas IHD patients were hemodialyzed 2 days after surgery (p = 0.009). We conclude that IHD lessened postoperative hyperkalemia and metabolic acidosis and delayed postoperative hemodialysis by an additional day. IHD should be considered as an adjunct to RHD therapy in the management of ESRD patients undergoing open-heart surgery.     

Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass.

The use of aprotinin to reduce blood loss after cardiopulmonary bypass is under debate. Concern has been raised about the renal effects of aprotinin. We administered a mean aprotinin dose of 4.2 x 10(6) kallikrein-inhibiting units to 13 patients with coronary disease undergoing cardiopulmonary bypass for 74 +/- 5 minutes (mean +/- standard error of the mean); 13 comparable patients having cardiopulmonary bypass served as control subjects, and all were studied postoperatively for 24 hours. Aprotinin reduced postoperative blood loss by 50% (p = 0.0082). Two of the 13 patients who received aprotinin needed one red cell unit each versus a total of 18 units in eight of 13 control patients (p = 0.0096). Blood pressure, hemoglobin value and serum protein concentration were higher after operation in the aprotinin group (p less than 0.05 to p less than 0.01). Platelet counts did not differ, but plasma thromboxane was lower in aprotinin recipients (p less than 0.001). In control patients fibrinogen degradation products (D dimer) doubled, and alpha 2-antiplasmin activity was halved during and after cardiopulmonary bypass (p less than 0.01 to p less than 0.001), whereas aprotinin patients showed no changes. The complement breakdown products C4a, C3a, and C3dg as well as C9 neoantigen increased from prebypass baseline in both groups (p less than 0.001); the increment of C3a and C3dg was greater in the aprotinin than in the control patients (p less than 0.001). Serum electrolytes, osmolality, and creatinine remained normal in both groups of patients. Creatinine clearance was normal or above normal and virtually identical in both groups. Osmolar clearance and fractional sodium excretion were higher in the aprotinin group than in the control group shortly after cardiopulmonary bypass (p less than 0.05 to p less than 0.01); renal function was unremarkable the next morning. No adverse clinical effects attributable to aprotinin were seen. In summary, aprotinin offers advantages for cardiopulmonary bypass.     

Deferoxamine reduces neutrophil-mediated free radical production during cardiopulmonary bypass in man

We assessed the effects of the iron chelator deferoxamine in 24 adult patients (12 controls, 12 treated) undergoing cardiopulmonary bypass for various cardiac operations. Deferoxamine was given both intravenously (30 mg/kg of body weight, starting 30 minutes before and ending 30 minutes after bypass) and as an additive to the cardioplegic solution (250 mg/L). Right atrial blood samples were taken before, during, and after bypass, and isolated polymorphonuclear neutrophils were evaluated for their capacity to generate superoxide radicals after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FLMP, 10(-7) mol) and phorbol myristate acetate (100 ng/ml). At the same sampling times, measurement of the plasma levels of 6-keto-prostaglandin F1 alpha, the stable derivative of prostacyclin, was used as an index of membrane phospholipid breakdown. The two groups were not significantly different with regard to age, duration of bypass, and quantitative changes in polymorphonuclear neutrophil counts during the operation. Before bypass, the superoxide production of FMLP-stimulated polymorphonuclear neutrophils was comparable in the two groups. Conversely, after bypass, polymorphonuclear neutrophils harvested from deferoxamine-treated patients produced significantly fewer superoxide radicals than those of control patients (1.9 +/- 0.3 versus 3.7 +/- 0.2 nmol/10(6) polymorphonuclear neutrophils per minute, p less than 0.05). Stimulation of polymorphonuclear neutrophils by phorbol myristate acetate yielded similar changes, as the postbypass superoxide production was 12.6 +/- 2.5 nmol/10(6)/min in control patients and 7.1 +/- 0.9 nmol/10(6)/min in those receiving deferoxamine (p less than 0.05). In contrast, plasma levels of 6-keto-prostaglandin F1 alpha were not significantly different between the two groups. We conclude that deferoxamine-exposed polymorphonuclear neutrophils have a decreased oxidative responsiveness, compatible with the fact that they may have been less "primed" by secretagogues released during bypass, as compared with cells of untreated patients. Our results are consistent with the hypothesis that deferoxamine, by inhibiting iron-catalyzed free radical production, may limit the free radical-mediated amplification of the inflammatory response to bypass and as such could be effective in reducing the harmful effects of extracorporeal circulation.     

Changes in urinary prostaglandins during cardiopulmonary bypass in man

We measured urinary and plasma levels of thromboxane B2 (TXB2), 6-keto PGF1 alpha and urinary NAG during cardiopulmonary bypass (CPB) and studied their clinical significance. Subjects studied were 10 patients undergoing coronary artery bypass graft. Urinary and plasma levels of TXB2 and 6-keto PGF1 alpha increased during CPB. However, predictive plasma levels of TXB2 and 6-keto PGF1 alpha, calculated by urinary excretion, were higher than actual plasma levels. This result suggests that the kidney produces TXA2 and PGI2. Significant correlation (r = 0.87, P less than 0.01) was observed between NAG and TXB2 during CPB. The results suggest that TXA2 impairs the function of the renal urinary tubules.     

Prostacyclin and prostaglandin E2 mediate reduction of increased mean arterial pressure during cardiopulmonary bypass by aspiration of shed pulmonary venous blood

Increased mean arterial pressure during the aortic crossclamp period while on cardiopulmonary bypass was usually treated by us with hypotensive drugs. We noticed, however, that aspirating shed excess pulmonary venous blood from the open pleural cavities causes an immediate reduction in mean arterial pressure, obviating the need for any further pharmaceutical intervention. In this study we investigated the relationship between the reduction in mean arterial pressure and the levels of prostacyclin and prostaglandin E2 in the peripheral and pulmonary venous blood. Ten men undergoing coronary bypass operations had 21 episodes of increased mean arterial pressure (106.9 +/- 11.4 mm Hg) during aortic crossclamping, which was reduced to 67.4 +/- 11.4 mm Hg (p less than 0.001) only by aspirating a mean of 490 ml (range 150 to 1100 ml) of pulmonary venous blood from the pleurae back into the circulation. Mean peripheral prostacyclin level, measured as 6-keto-prostaglandin F1 alpha, and prostaglandin E2 level, both measured by radioimmunoassay technique, were significantly lower at peak mean arterial pressure (419 +/- 180 and 59.5 +/- 21.2 pg/ml) than at lowest mean arterial pressure (632 +/- 271 and 96.7 +/- 52.4 pg/ml for 6-keto-prostaglandin F1 alpha and prostaglandin E2, respectively; p less than 0.001). Prostaglandin F1 alpha and prostaglandin E2 levels in the aspirated pulmonary venous blood were 2309 +/- 3098 pg/ml and 749 +/- 909 pg/ml, respectively. The hypotensive effect of shed pulmonary venous blood that is aspirated back from the pleurae into the circulation seems to be mediated by the high levels of prostacyclin and prostaglandin E2, both powerful vasodilators.     

Plasma prostanoids in neonatal extracorporeal membrane oxygenation. Influence of meconium aspiration

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.     

The role of neural and vasoactive mediators in the regulation of the pulmonary circulation during cardiopulmonary preservation

The autoperfused working heart-lung preparation has been used for extended cardiopulmonary preservation for transplantation. However, acute lung injury and failure of the preparation can result from pulmonary hypertension, which previous investigators have linked to denervation. We studied the neural and vasoactive mediators of pulmonary vasoconstriction during normothermic autoperfusion of the heart and lungs from 13 calves. Pulmonary vascular resistance was quantitated by multipoint pulmonary artery pressure/flow plots generated by incremental reduction in venous return at three times: A, after sternotomy but before autoperfusion (control); B, during in situ autoperfusion (innervated heart-lung preparation); and C, after explanation (denervated heart-lung preparation). During hemodynamic measurements, left atrial blood samples were obtained for measurement of thromboxane B2, 6-keto-prostaglandin-F1 alpha, and complement activation products C3a and C5a. Results show that pulmonary hypertension in the autoperfused working heart-lung preparation begins during autoperfusion before denervation and may be related to complement activation and to increased levels of circulating thromboxane B2 and 6-keto-prostaglandin F1 alpha (both the absolute levels and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha). After denervation, both prostaglandin intermediates were markedly increased, but their ratio was not significantly affected. These data suggest that there is an initial stage of pulmonary vasoconstriction at the onset of autoperfusion that is accompanied by increased circulating levels of vasoactive mediators and that denervation further contributes to this response.     

Arachidonic acid metabolism following aneurysm rupture. Evaluation of cerebrospinal fluid and serum concentration of 6-keto-prostaglandin F1 alpha and thromboxane B2 in patients with subarachnoid hemorrhage

Experimental investigations have suggested an important role of arachidonic acid metabolites in the genesis of cerebral vasospasm following subarachnoid hemorrhage. In this clinical study the cerebrospinal fluid (CSF) and serum levels of the two main arachidonic acid metabolites prostacyclin and thromboxane A2 are evaluated by measuring their stable degradation products 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) using radioimmunoassay methods during the pre- and postoperative course in patients after aneurysm rupture. Although the serum levels of both substances do not seem to be important for the clinical course of the patients, the CSF concentrations of 6-keto-PGF1 alpha and TXB2 provide important data. A close correlation between the initial TXB2 level of the individual patient and the amount of blood in the basal cisterns as detected by computed tomography scan can be demonstrated. The predictive value of this additional information for the occurrence of cerebral angiospasm is discussed. Comparing the CSF levels of both metabolites the slight preoperative elevation of 6-keto-PGF1 alpha is significantly surmounted by an extraordinary rise in TXB2 concentration. Postoperatively, after cleavage of the basal cisterns there is a decline in the CSF levels of both substances. The pre- and postoperative clinical course in comparison to the CSF levels of 6-keto-PGF1 alpha and TXB2 is demonstrated in four patients. A nearly normal course of TXB2 and 6-keto-PGF1 alpha seems to be associated with an uneventful clinical course, whereas a high TXB2 level--whether occurring preoperatively or, even more important, as a secondary postoperative rise--seems to be associated with ischemic complications and neurological deterioration. It is suggested that pre- and postoperative monitoring of CSF levels of 6-keto-PGF1 alpha and especially TXB2 may serve as a possible indicator for the detection of patients at risk of developing cerebral vasospasm.     

Effects of autologous mesothelial cell seeding on prostacyclin production within Dacron arterial prostheses

Canine abdominal aortas have been replaced with Dacron arterial prostheses to assess the effects of mesothelial cell seeding on graft prostacyclin and thromboxane A2 release. At both 2 weeks and 6 weeks after surgery, three seeded and two unseeded control grafts were examined for prostacyclin release. In addition, thromboxane release was assessed in one seeded and one unseeded graft. Sections of aorta and graft were removed and incubated in PBS containing either 10 microM calcium ionophore A23187 or 20 microM arachidonic acid. The incubation mixture was sub-sampled at 5 min intervals over a 20 min period to assess the progressive release of prostacyclin and thromboxane A2 using a radioimmunoassay for 6-keto-prostaglandin F1 alpha and thromboxane B2 respectively. In seeded grafts, 6-keto-prostaglandin F1 alpha release averaged 15 per cent compared with aorta at 2 weeks and 45 per cent compared with aorta at 6 weeks. By contrast, release from unseeded grafts was undetectable at 2 weeks; however, by 6 weeks there was some release amounting to 15 per cent compared with aorta. There was a statistically significant increase in the release of 6-keto-prostaglandin F1 alpha from mesothelial cell seeded grafts at 6 weeks compared with unseeded grafts (P less than 0.01). Thromboxane release from the graft sections was variable and unrelated to whether the grafts had been seeded or not. These preliminary results, showing that grafts seeded with autologous peritoneal mesothelial cells release more prostacyclin than unseeded grafts, further highlight the role of the mesothelial cell as an alternative to the endothelial cell for improving the patency of arterial Dacron prostheses in the early postoperative days.