Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass.

OBJECTIVES: We sought to evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization. RESULTS: Six (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients ( P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group. CONCLUSION: Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.

Comparison of clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery.

BACKGROUND AND OBJECTIVE: We set out to compare the efficacy of clevidipine and sodium nitroprusside infusions in the control of blood pressure and the haemodynamic changes they produce in hypertensive patients after operation for elective coronary bypass grafting. METHODS: Thirty patients were randomly allocated to receive either clevidipine or sodium nitroprusside after their mean arterial pressure (MAP) had reached > 90 mmHg for at least 10 min in the postoperative period. The MAP was continuously measured and related to time. Thus, the efficacy of the drugs in controlling arterial pressure could be inversely related to the total area under the MAP-time curve outside a target MAP range of 70-80 mmHg normalized per hour (AUC(MAP) mmHg min h(-1)). Haemodynamic variables and the number of dose-rate adjustments required to maintain MAP were also studied. RESULTS: There was no statistically significant difference in the efficacy (AUC(MAP) mmHg min h(-1)) of clevidipine (106 +/- 25 mmHg min h(-1)) compared with sodium nitroprusside (101 +/- 28 mmHg min h(-1)). Nor was any significant difference found in the total number of dose adjustments required to control MAP within the target range. The heart rate in patients receiving clevidipine increased less than in those given sodium nitroprusside. Stroke volume, central venous pressure and pulmonary artery pressure were significantly reduced upon administration of sodium nitroprusside but not of clevidipine. CONCLUSIONS: There was no significant difference between clevidipine and sodium nitroprusside in their efficacy in controlling MAP. The haemodynamic changes, including tachycardia, were less pronounced with clevidipine than with sodium nitroprusside.

The action of diaspirin cross-linked haemoglobin blood substitute on human arterial bypass conduits.

BACKGROUND: Immediately available blood substitutes could transform medicine. In coronary artery surgery, vasoconstriction induced by some of these agents could have serious implications. We have examined some of the vasoactive effects of one of these blood substitute, diaspirin cross-linked haemoglobin (DCLHb), on isolated rings of human arterial conduits. METHODS: Sections of human left internal mammary artery (LIMA) and radial artery (RA) were cut into 3-mm rings, mounted in individual organ baths containing aerated (95% O(2)/5% CO(2)) Krebs-Heinseleit solution at 37 degrees C and attached to isometric strain gauge for measurements of tension. All rings were tested for the presence of endothelium by addition of carbachol to rings pre-contracted with phenylephrine. The relative importance of nitric oxide (NO) in contraction mediated by the addition of DCLHb was studied. RESULTS: Carbachol relaxed phenylephrine precontracted LIMA by 72.3+/-1.7% and RA by 97+/-0.7% confirming the presence of a functional endothelium. Sodium nitroprusside (SNP) caused complete relaxation of LIMA with an EC(50) value of 2.0+/-0.1x10(-8) M and RA with an EC(50) value of 1. 9+/-0.1x10(8) M. In the presence of DCLHb (10(-7) M), carbachol-induced relaxation was significantly reduced to 46.3+/-0. 7% (P<0.01) and the BC(50) value for SNP relaxation increased to 1. 2+/-0.1x10(-7) M (P<0.01). DCLHb caused rings to contract in the absence of phenylephrine with EC(50) values of 1.6+/-0.1x10(-7) M (LIMA) and 1.8+/-0.1x10(-7) M (RA). Presence of L-NAME (300 microM) caused no alteration in DCLHb-induced contraction. CONCLUSION: In this study of isolated rings of human vessels, DCLHb causes a significant reduction in relaxation mediated by carbachol and SNP, which is likely to be due to its ability to bind NO. However, it is possible that other mechanisms might contribute to the vasoconstrictor effects of DCLHb and these might be amenable to anti-vasospastic strategies.

Perioperative blood pressure control: a prospective survey of patient management in cardiac surgery.

OBJECTIVE: To conduct a survey of current cardiac anesthetic practice in Europe and the United States, as a first step toward establishing guidelines for the management of perioperative hypertension. DESIGN: Prospective, multicenter study. SETTING: University hospitals. PARTICIPANTS: Unselected patients (n = 1,930) requiring cardiac surgery. INTERVENTIONS: Data extending from the preoperative evaluation to 120 hours or more after surgery were collected from all patients. MEASUREMENTS AND MAIN RESULTS: Only the data from patients undergoing coronary artery bypass surgery, valve surgery, or combined procedures were analyzed, leaving a final total of 1,660 patients from the original 1,930. Of these, 88% were treated at least once perioperatively to lower arterial blood pressure. Deepening of anesthesia was the most commonly used antihypertensive measure (68%), regardless of the ongoing anesthetic regimen, and was usually combined with vasodilator therapy, most frequently nitroglycerin (53%) or sodium nitroprusside (28%). Reported perioperative mean arterial pressure (MAP) was 15 to 20 mmHg lower than MAP before anesthesia induction, regardless of the use of antihypertensive therapy. The MAP at which antihypertensive treatment was initiated varied markedly among the various phases of surgery and showed no clear correlation with preoperative MAP. CONCLUSIONS: The results of this survey show that current anesthetic practice tries to prevent perioperative hypertension wherever possible during cardiac surgery. Blood pressure measurements taken before surgery have little influence on the development of hypertension intraoperatively, and the main determinants of perioperative blood pressure control and the need for therapeutic intervention are factors arising from the surgical procedure itself, such as aortic cross-clamping and activation of adrenergic mechanisms.

Inhibitory effects of glibenclamide on the contraction of human arterial conduits used in coronary artery bypass surgery.

Glibenclamide has been shown to inhibit prostanoid-induced contraction in a number of blood vessel types. In this study, the effects of glibenclamide on the contraction of human peripheral arteries in response to both prostanoid and non-prostanoid agonists were compared and possible mechanisms of action were investigated. Segments of left internal mammary artery (LIMA) and radial artery, taken from patients undergoing coronary artery bypass graft (CABG) surgery, were mounted in organ baths containing physiological saline solution aerated with 95% O2/5% CO2 at 37 degrees C. Contractions were obtained by either the use of a thromboxane analogue (U46619), L-phenylephrine, KCl or CaCl2. The effects of glibenclamide on these contractions were observed and pEC50 values were determined after manipulation of a logistic curve-fitting equation. Concentration-dependent relaxation of U46619-contracted LIMA and radial artery was observed in the presence of glibenclamide, with calculated pEC50 values of 4.2+/-0.17 (n = 7) for LIMA and 3.26+/-0.48 (n = 5) for radial artery. Incubation of both LIMA and radial artery with glibenclamide (50 microM) caused the concentration-response curves for U46619 and L-phenylephrine to shift significantly to the right. Similarly the KCl tension relationship was caused to shift to the right. Finally, glibenclamide (100 microM) also had an inhibitory effect on Ca2+-induced tension in radial artery. These results show that the inhibitory effects of glibenclamide on human peripheral blood vessels are not restricted to prostanoid-induced contractions. Furthermore, evidence has been provided to suggest that these effects might be mediated through an interaction with voltage-sensitive Ca2+ channels.

Cardiovascular pharmacology: new drugs and new indications.

This review presents a brief overview of some of the many exciting developments that are taking place in the field of cardiovascular pharmacology. Research continues to progress at a rapid rate, and we can expect many drugs to enter the clinical arena within the next few years. It must be borne in mind, however, that the pharmaceutical industry and hospital budgetary restrictions sometimes limit drug development and occasionally interrupt clinical trials, even before their results have been obtained.

Increased pre-operative platelet counts are a possible predictor for reduced sensitivity to heparin.

We investigated a possible relationship between pre-operative platelet count and reduced sensitivity to heparin in 87 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Sensitivity to heparin was determined by measuring the slope of the heparin dose response (HDR) before surgery. Pre-operative platelet counts were measured as part of routine analysis of the patients' coagulation status. Patients with an HDR slope of <80 s u. ml(-1), were considered to have a reduced sensitivity to heparin and activated clotting time data were collected from these patients before and after heparin administration before CPB. A significant correlation was determined between pre-operative platelet levels and HDR slope (P<0.001). Platelet counts were significantly greater in heparin-resistant patients compared with those who had the expected response to the anticoagulant (P<0.05). This could be caused by an increased capacity to produce platelet factor 4, which neutralizes heparin.

Effect of aspirin in coronary artery bypass grafting.

OBJECTIVES: To evaluate the effect of aspirin (ASA) therapy on postoperative blood loss, transfusion requirements, reoperation for bleeding, duration of stay in the intensive care unit and in the hospital in a selected population undergoing a first coronary artery bypass grafting (CABG) surgery. DESIGN: Prospective observational study in consecutive patients during a 3-month period. SETTING: A teaching cardiothoracic center. PARTICIPANTS: Two hundred forty consecutive patients undergoing elective coronary artery bypass grafting surgery for the first time. INTERVENTIONS: Two hundred forty consecutive patients admitted for a first CABG the day before surgery were visited. patients with an abnormal routine coagulation screen or taking drugs that might have affected their coagulation mechanisms were prospectively excluded (n = 96). The date of the last dose of ASA was recorded in the 144 remaining patients, and data were acquired prospectively. MEASUREMENTS AND MAIN RESULTS: Total mediastinal blood drainage, blood products usage, reopening, and duration of intensive care unit and hospital stay were recorded. Patients were grouped by days free of ASA. There were no significant differences detected between groups. CONCLUSIONS: In patients undergoing a first CABG and with no known factors affecting their coagulation, ASA therapy did not appear to increase blood loss, reopening for bleeding, or blood products usage requirements during the hospital stay. ASA therapy did not influence the duration of stay in intensive care or in the hospital.

Extraction of nitric oxide and nitrogen dioxide from an oxygen carrier using molecular sieve 5A.

Nitric oxide (NO) is effective in the management of pulmonary hypertension and shunt-related hypoxia. Nitrogen dioxide (NO2) is formed when the gas is delivered with oxygen. Both oxides of nitrogen have well recognized adverse effects. The scavenging properties of several forms of soda lime have been investigated. A gas flow containing NO 70 ppm and NO2 5 ppm in oxygen was introduced into a vertically mounted Waters' canister containing: (i) 125 g of molecular sieve 5A (a calcium aluminosilicate zeolite) and (ii) 135 g of soda lime containing a potassium permanganate marker. NO and NO2 concentrations were measured at hourly intervals at the entry and exit points using an electrochemical analyser. Extraction ratios (gradient/ inlet x 100) were calculated for a 24-h period. High extraction ratios (in excess of 90%) of NO and NO2 were observed with both compounds for up to 1 h but these declined rapidly after this time with soda lime. In contrast, the molecular sieve produced extraction ratios in excess of 98% for both gases over the 24-h period. We conclude that the molecular seive 5A is a highly effective scavenger of NO and NO2.

Somatostatin-induced contraction of human isolated saphenous vein involves sst2 receptor-mediated activation of L-type calcium channels.

A range of somatostatin (SRIF) analogues have been used to characterize the SRIF receptor-mediating contraction of the human saphenous vein. SRIF produced concentration-dependent contractions with an EC50 value of approximately 20 nM. The peptidase inhibitors phosphoramidon and amastatin did not alter the potency of SRIF. The sst2 receptor-selective peptide BIM-23027 was approximately three times more potent than SRIF in contracting the vein, whereas the sst5 receptor-selective peptide L-362855 was approximately 50 times weaker. The sst3 receptor-selective peptide BIM-23056 did not contract the saphenous vein. Contractions to SRIF were not antagonised by the putative SRIF receptor blocker cyclo(7-aminoheptanoyl-Phe-D Trp-Lys-Thr[Bzl]) (CPP), phentolamine, or indomethacin. Decreasing the external calcium concentration reduced the maximum contraction to SRIF in a concentration-dependent manner without altering the EC50 value. Nifedipine and verapamil also markedly reduced the SRIF-induced contraction. SRIF and several SRIF analogues caused contraction of the human saphenous vein by what appeared to be a direct effect on the smooth muscle. Their relative potencies suggest that their effects were mediated by a somatostatin receptor that is like the recombinant sst2 receptor. The receptor transduction mechanism appears to involve activation of L-type calcium channels and entry of extracellular calcium.

Treatment of perioperative low cardiac output syndrome.

New approaches to the treatment of perioperative low cardiac output are considered. In particular, use of the phosphodiesterase III inhibitors and their cardiovascular actions are reviewed and contrasted with those of conventional inotropic agents. The increasing recognition of right-sided dysfunction is highlighted, and appropriate therapeutic strategies are considered. The increasing role of pulmonary-specific vasodilators such as inhaled nitric oxide is emphasized. Strategies to preserve right heart perfusion while producing pulmonary vasodilatation are discussed.

The role of soda lime during administration of inhaled nitric oxide.

We have studied the ability of three commercially available preparations of soda lime to act as nitrogen dioxide scavengers during administration of inhaled nitric oxide. Soda lime, with a green to brown colour change (indicator = potassium permanganate), markedly reduced concentrations of nitrogen dioxide, but also markedly reduced inhaled concentrations of nitric oxide. The other varieties of soda lime, with colour changes from pink to white (indicator = kenazol yellow) or white to violet (indicator = ethyl violet), produced little effect on concentrations of nitrogen dioxide. None of the above soda limes can be recommended for use as a nitrogen dioxide scavenger during administration of inhaled nitric oxide.

Inhaled nitric oxide in patients with normal and increased pulmonary vascular resistance after cardiac surgery.

We studied the haemodynamic effects of inhaled nitric oxide 40 p.p.m. in two groups of patients after cardiac surgery (mitral valve surgery or coronary artery bypass grafting). Nitric oxide caused a significant reduction in pulmonary vascular resistance after mitral valve surgery in patients who had pre-existing pulmonary hypertension, but no change in haemodynamic state in the coronary artery bypass group of patients, who had normal pulmonary arterial pressures.