Comparison of two protocols for heparin neutralization by protamine after cardiopulmonary bypass

Twenty patients undergoing cardiac operations were randomly assigned to two protocols for heparin neutralization by protamine after cardiopulmonary bypass. In all patients protamine chloride was given at a ratio of 1 unit of protamine to 1 unit of injected heparin. In Group I (10 patients) all protamine was infused within 10 minutes after termination of cardiopulmonary bypass. Group II (10 patients) received 75% of the calculated protamine dose within 10 minutes after termination of bypass and the remainder after transfusion of all blood in the heart-lung machine. Plasma heparin levels were significantly lower in Group II 5 minutes after transfusion of all blood in the heart-lung machine and were 0.13 units/ml (standard deviation 0.04) in Group I and 0.06 units/ml (standard deviation 0.05) in Group II (p less than 0.001) 60 minutes after bypass. Activated partial thromboplastin time mirrored the changes in plasma heparin, whereas activated clotting time (Hemochron) was too insensitive to detect these low plasma heparin levels. We conclude that the two-dose protocol resulted in more complete heparin neutralization than the one-dose protocol.     

Renal vasoconstriction and transient declamp hypotension after infrarenal aortic occlusion: role of plasma purine degradation products

To better understand renal and systemic hemodynamics associated with hindquarter ischemia produced by aortic compression, chloralose-anesthetized dogs were given phentolamine while an external clamp maintained infrarenal aortic pressure below 25 mm Hg for 45 minutes. In four sham-operated dogs, infrarenal pressure was maintained; reinforced cannulas, capable of resisting clamp compression, were placed within the aorta and the inferior vena cava. Suprarenal and infrarenal arterial pressure and renal blood flow were continuously monitored. Blood samples taken before clamp application and at 1, 3, 5, and 10 minutes after clamp removal were assayed for adenosine, inosine, xanthine, and hypoxanthine. On clamp removal suprarenal pressure immediately dropped from a preclamp pressure of 114 to 82 mm Hg but returned to preclamp values within 1 minute. Renal blood flow was significantly reduced after clamp release, reaching a nadir of 39% of preclamp flow. This reduction persisted despite a normalization of arterial pressure. Summed plasma purines were significantly elevated 1 minute after clamp removal. Sham-operated dogs showed no significant alterations in arterial pressure, renal blood flow, or plasma purine levels. This study demonstrates a significant non-alpha-adrenergic receptor-mediated reduction in renal blood flow and a coincident increase in purine degradation products after removal of an infrarenal aortic cross-clamp.     

The effect of renin-angiotensin system blockade on visceral blood flow during and after thoracic aortic cross-clamping

Surgical procedures necessitating clamping of the thoracic aorta are associated with a high incidence of postoperative renal dysfunction. Plasma renin activity is elevated during and after thoracic aortic occlusion in animals. The pathophysiology of the renal dysfunction may involve the renin-angiotensin system. Blockade of the renin-angiotensin system was studied in a canine model during occlusion of the thoracic aorta. Saralasin, a competitive blocker of angiotensin II, and the converting enzyme inhibitor MK422 were studied. Sixteen animals were separated into three treatment groups: control (five animals), saralasin (five), and MK422 (six). All dogs underwent clamping of the thoracic aorta for 60 minutes. In control animals, plasma renin activity increased from 0.16 +/- 0.04 to 6.41 +/- 1.57 ng/ml/hr at 30 minutes after thoracic aortic occlusion (p less than 0.05). Thirty minutes after cross-clamp release, plasma renin activity remained 10 times greater than baseline, 1.47 +/- 0.20 ng/ml/hr (p less than 0.05). Renal blood flow was measured with 15 micron microspheres before, during, and after thoracic clamping. In control animals, renal cortical blood flow decreased during cross-clamping and remained below baseline after clamp release: baseline, 7.05 +/- 0.98 ml/gm/min (standard error of the mean); 30 min after clamp release, 3.77 +/- 0.43 ml/gm/min (standard error of the mean) (p less than 0.05). In the MK422 group, renal cortical blood flows returned to baseline after cross-clamp release: baseline, 6.38 +/- 0.49 ml/gm/min; 30 minutes after clamp release, 7.30 +/- 1.6 ml/gm/min. Infusion of MK422 after placement of the thoracic aortic cross-clamp resulted in normal renal blood flow after clamp release. This protective effect was not seen with saralasin. The resumption of normal renal cortical blood flow after the administration of the converting enzyme inhibitor MK422 suggests that elevated plasma renin activity may contribute to renal dysfunction after thoracic aortic occlusion.     

Prediction of excessive bleeding after coronary artery bypass graft surgery: the influence of timing and heparinase on thromboelastography

OBJECTIVE: To compare the ability of thromboelastography, when done at either 10 or 60 minutes after protamine reversal of heparin, to predict excessive bleeding after coronary artery bypass graft (CABG) surgery and to investigate, with the use of heparinase, whether heparin contamination was responsible for the difference, if any. DESIGN: Prospective study. SETTING: University hospital, single institution. PARTICIPANTS: Patients undergoing elective CABG surgery (n = 40). INTERVENTIONS: Blood samples for thromboelastography and routine coagulation tests were collected before induction of anesthesia and at 10 and 60 minutes after protamine reversal of heparin. Blood loss and blood product use were recorded postoperatively. MEASUREMENTS AND MAIN RESULTS: Of 40 patients undergoing elective CABG surgery, 10 fulfilled the criteria for excessive postoperative bleeding. The sensitivity of thromboelastography to identify patients who bled was better at 60 minutes than at 10 minutes after protamine reversal of heparin (100% v 70%). There was greater specificity (83% v 40% at 10 minutes; 73% v 20% at 60 minutes) and positive predictive value (58% v 28% at 10 minutes; 55% v 29% at 60 minutes) when heparinase was added. At both times, thromboelastography showed only moderate correlation with total blood loss and the use of fresh frozen plasma or platelets or both. Conventional coagulation tests did not predict excessive postoperative bleeding. CONCLUSION: This study suggests that timing and the use of heparinase influence the predictive ability of thromboelastography, but its usefulness as a sole predictor of post-CABG surgery bleeding is limited.     

Beneficial effect of cyclooxygenase inhibition on adverse hemodynamic responses after protamine

The hypothesis that adverse effects observed when heparin is antagonized by protamine are mediated by metabolites of the arachidonic acid cascade was tested during general anesthesia (enflurane, fentanyl) in 16 pigs classified into two groups. In the first group (n = 9), effects of intravenously administered protamine on systemic hemodynamics, blood/gas tensions, and arterial and mixed-venous prostanoid levels were studied. The second group (n = 7) was pretreated with indomethacin 10 mg/kg, and the same measurements were made. All pigs received heparin 150 units/kg. When protamine 1.1 +/- 0.1 mg/kg was administered over 3 minutes, marked hemodynamic alterations were observed in group 1: pulmonary artery pressure and pulmonary vascular resistance increased, and left ventricular end-diastolic and systemic arterial pressures decreased. Arterial and mixed-venous PO2 values deteriorated in all pigs in group 1 at the end of protamine infusion. These alterations were accompanied by significantly elevated prostanoid levels in arterial and mixed-venous plasma samples: Thromboxane A2, prostaglandin F2 alpha, KH2-PGF2 alpha (a metabolite of prostaglandin F2 alpha), and prostacyclin were maximally elevated at completion of protamine and remained significantly above control values at 5 minutes but were not significantly different from control after 10 minutes. Blocking the cyclooxygenase cascade by pretreatment of the pigs with indomethacin (group 2) prevented hemodynamic and blood gas alterations. It is concluded that in pigs the detrimental side effects associated with the use of protamine to reverse heparin are mediated by metabolites of the cyclooxygenase cascade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protamine pretreatment attenuation of hemodynamic and hematologic effects of heparin-protamine interaction. A prospective randomized study in human beings undergoing aortic reconstructive surgery

Hemodynamic and hematologic responses to protamine sulfate reversal of heparin's anticoagulant effects were studied in 15 consecutive randomized patients undergoing aortic reconstructive surgery. In a double-blinded manner, patients were pretreated with either normal saline solution (n = 8) or protamine (0.75 mg/kg/3 min, n = 7) 5 minutes before heparinization (150 IU/kg). After aortic grafts were placed, protamine (1.5 mg/kg/3 min) was administered intravenously to reverse the heparin. Arterial blood pressure, heart rate, pulmonary artery and capillary wedge pressure, central venous pressure, and cardiac output were monitored, as were platelet count, white blood cell count, activated clotting time, total hemolytic complement levels, and C3a levels. Calculated parameters included systemic vascular resistance and pulmonary vascular resistance. Pretreatment with protamine compared with saline solution prevented the hypotension (+6 vs. -16 mm Hg, p less than 0.05) and declining pulmonary artery pressure (+1 vs. -7 mm Hg, p less than 0.01) observed with protamine reversal of heparin. Significant differences between the two groups in central venous pressure and pulmonary vascular resistance were of less clinical relevance. Protamine pretreatment lessened the thrombocytopenia found during reversal compared with saline-pretreated patients although the difference was not statistically significant. Minimal hypotension occurring after protamine pretreatment alone was not accompanied by hemodynamic or hematologic changes, other than decreased heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monitoring of heparin in vascular surgery

In patients heparinized for surgery on the infrarenal aorta, the degree of anticoagulation by heparin of stasis blood (taken from below the aortic clamp) was compared with that obtained in circulating blood taken from a forearm artery. A measurement of activated partial thromboplastin time (APTT) was made on a venous blood sample taken from each patient before 5000 units of heparin was administered intravenously. Further measurements of APTT from static blood and from circulating arterial blood were made at 3, 15, 30, and 60 minutes after heparinization. Samples taken below the aortic clamp showed measurements of APTT lower than those from circulating arterial blood at 15, 30, and 60 minutes (p less than 0.05 paired Wilcoxon rank sum test). Current methods for administering and monitoring heparin may not provide an adequate degree of anticoagulation in static blood during vascular surgery. The consequences, if any, of inadequate anticoagulation in vascular surgery need further study.     

The effect of mannitol and dopamine on the renal response to thoracic aortic cross-clamping

Postoperative renal failure and insufficiency are important complications of operations that require thoracic aortic cross-clamping. Successful application of pharmacologic methods to protect renal function would be clinically useful. The ability of mannitol and dopamine to prevent renal dysfunction in a canine model of thoracic aortic cross-clamping was studied. Twenty animals were divided into four equal groups, and all underwent thoracic aortic cross-clamping for 60 minutes. An intra-aortic infusion of saline (control), mannitol, dopamine, or mannitol plus dopamine was started before, and continued during, the period of aortic occlusion. Glomerular filtration rate was significantly depressed 60 minutes after clamp release, and although there was some recovery in treated animals 150 minutes after clamp release, it remained significantly decreased (52% to 73% of baseline values, p less than 0.01). Renal blood flow was significantly reduced 60 minutes after clamp release, and there was no recovery in any group at 150 minutes (38% to 56% of baseline values, p less than 0.01). No significant differences in osmolar clearance or fractional excretion of sodium were evident between groups. These data reveal that the profound reductions in glomerular filtration and renal blood flow induced by thoracic aortic cross-clamping were not attenuated by mannitol or dopamine and suggest that efforts to protect renal function should be directed toward improving renal blood flow in the post-clamp period.     

Heparin Monitoring and Neutralization during Cardiopulmonary Bypass Using a Rapid Plasma Separator and a Fluorometric Assay

Avoidance of over- or underheparinization during cardiopulmonary bypass (CPB) is crucial in preventing bleeding or clotting. Currently no completely satisfactory method is available for measuring heparin levels—a method that would be rapid, inexpensive, specific, and reproducible. We combined the use of two devices, a rapid plasma separator and a fluorometric heparin assay system, in an attempt to satisfy these requirements in 15 patients having CPB during cardiac surgical procedures. The first instrument separates plasma from whole blood using a pneumatic filtration principle, while the heparin assay system measures the effect of heparin on thrombin conversion of a synthetic fluorogenic substrate. Accurate plasma heparin levels can be generated in less than five minutes, and the assays are inexpensive and easy to perform. Performing heparin assays at critical intervals during CPB allowed desired heparin levels to be maintained and the protamine dose for heparin neutralization to be reduced to a minimum. In addition, studies for heparin rebound revealed negligible rebound up to six hours postoperatively despite the reduced doses of protamine. There were no hemorrhagic or clotting complications in the series.     

Repeated administration of protamine does not attenuate circulatory changes caused by protamine reversal of heparin in dogs.

OBJECTIVE: To determine whether repeated administration of protamine attenuates circulatory changes caused by protamine reversal of heparin and to evaluate the significance of nitric oxide generation. DESIGN: Prospective, randomized, controlled, animal study. SETTING: University research laboratory. PARTICIPANTS: Twenty-seven adult mongrel dogs. INTERVENTIONS: The animals were randomly assigned to 3 groups (n = 9 in each) according to the pretreatment. The control group was pretreated with normal saline, and the 2 other groups were given 2 different doses of protamine: protamine 0.1 (protamine, 0.1 mg/kg) and protamine 1.0 (protamine, 1.0 mg/kg). Under general anesthesia, all animals were anticoagulated with intravenous heparin, 200 IU/kg. Five minutes after heparin injection, preadministered saline (control) or protamine in saline was infused during 60 seconds. Five minutes after the pretreatment, protamine, 2.0 mg/kg in control, 1.9 mg/kg in protamine 0.1, or 1.0 mg/kg in protamine 1.0, was administered intravenously during 10 seconds. MEASUREMENTS AND MAIN RESULTS: Percent changes in mean arterial blood pressure among the 3 groups at each period were not significantly different except 60 minutes after protamine infusion. Mean pulmonary arterial pressure in the protamine 1.0 group at 5, 15, 20, and 60 minutes was higher than in the control group. Serum nitrate concentration was not significantly different among the 3 groups at baseline and 10 minutes after protamine injection. CONCLUSION: Repeated administration of protamine does not attenuate circulatory changes caused by protamine reversal of heparin in dogs. Nitric oxide generation does not appear to be responsible for the phenomenon.     

Heparin rebound: a comparative study of protamine chloride and protamine sulfate in patients undergoing coronary artery bypass surgery

Heparin rebound has been suggested to occur when protamine sulfate, but not protamine chloride, is used to neutralize heparin. This study was undertaken to compare these two protamine salts in 32 patients undergoing coronary artery bypass surgery. Initial heparin and subsequent protamine doses were determined by constructing a heparin-activated coagulation time response curve. Heparin was neutralized either with protamine sulfate or protamine chloride. The total protamine/heparin dose ratio was 0.71 +/- 0.05 for protamine sulfate and 0.77 +/- 0.07 (mg/100 U) for protamine chloride. The initial neutralization effect, the subsequent behavior of the plasma heparin level, and the various coagulation parameters did not differ significantly between the groups. Two hours after neutralization, a small and temporary increase of plasma heparin level was observed in both groups. The postoperative blood losses were comparable in both groups. Thus, protamine chloride was not a clinically superior antidote to heparin than protamine sulfate. The observed heparin rebound levels were low and clinically insignificant in terms of blood loss, but they were associated with slight changes in coagulation monitoring.     

Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery?

OBJECTIVES: Heparin rebound, the reappearance of anticoagulant activity after adequate neutralization with protamine, is thought to contribute to excessive postoperative bleeding after cardiac surgery. We have previously demonstrated that a significant amount of heparin is bound nonspecifically to plasma proteins and is incompletely neutralized by protamine. The aim of this study was to investigate whether clinically important bleeding attributable to heparin rebound can be eliminated by infusion of small amounts of additional protamine for 6 hours postoperatively and whether this treatment can reduce mediastinal blood loss. METHODS: Three hundred patients undergoing elective cardiac surgery were randomized to receive either a continuous infusion of protamine sulphate (25 mg/h for 6 hours) postoperatively or saline placebo. Serial blood samples were obtained to measure thrombin clotting time and anti-factor Xa activity. Heparin bound nonspecifically to plasma proteins was measured after displacement with a chemically altered heparin with low affinity to antithrombin. Mediastinal blood loss and transfusion requirements were recorded. RESULTS: Heparin rebound was demonstrated in every patient in the placebo group as reflected by increased thrombin clotting time, anti-factor Xa activity, and protein-bound heparin between 1 and 6 hours after surgery. In contrast, heparin rebound was eliminated in the protamine infusion group. The thrombin clotting time was normalized and both heparin concentration and protein-bound heparin were almost undetectable (P <.001). There was a modest 13% reduction in postoperative bleeding but this did not reduce blood transfusions. No adverse events were attributable to the extra protamine. CONCLUSIONS: Postoperative protamine infusion was able to almost totally abolish heparin rebound. In the context of this study, protamine infusion resulted in reduced postoperative bleeding but the magnitude was insufficient to alter transfusion requirements.     

Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass

BACKGROUND: Despite long use of protamine in cardiac operations, neither protamine concentrations nor pharmacokinetics have been reported in patients. METHODS: Twenty-eight patients (age, 26 to 80 years) undergoing various cardiac surgical procedures gave their consent to receive 250 mg of protamine sulfate administered intravenously by an infusion pump during 5 minutes. Protamine was administered at the usual intraoperative time after separation from cardiopulmonary bypass for reversal of heparin. Timed arterial blood samples were obtained after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. Total (free + heparin-bound) protamine concentration versus time data were subjected to pharmacokinetic modeling. RESULTS: Twenty-six patients completed the study. Total plasma protamine concentrations declined rapidly. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution, 5.4 L (0.82 to 34 L); clearance, 1.4 L/min (0.61 to 3.8 L/min); and half-life, 4.5 min (1.9 to 18 min). Schwarz-Bayesian criterion identified a two-compartment exponential model with adjustment for weight in the central compartment volume of distribution as performing better than other compartmental or Michaelis-Menten models. CONCLUSIONS: Protamine has a very short (approximately 5 minutes) half-life after a single 250-mg dose in adult patients. This short half-life could underlie recurrent anticoagulation after initial apparent reversal of heparin.     

Heparin concentration and hemostatic alterations with low systemic heparinization during CPB using heparin-coated circuits

Extracorporeal circulation with heparin coated circuits allows reduction of systemic heparin. The authors investigated the effects of this method on the hemostatic and fibrinolytic systems and heparin concentration simultaneously. Ten patients undergoing coronary artery bypass surgery were studied. The dose of heparin was 100 IU.kg-1, and the target activated clotting time (ACT) was more than 300 seconds. Blood samples were obtained at the following times; before and after giving heparin, 10 and 40 minutes after the start of extracorporeal circulation, after cross-clamp release, and after giving protamine, and heparin concentration, ACT, thrombin-antithrombin complex (TAT), plasmin alpha 2 plasmin inhibition complex (PIC), and D-dimer were measured. ACT was kept over 300 seconds without additional heparin administration. Heparin concentration was maintained at 1.0 IU.ml-1. However, after release of the aortic cross-clamp, TAT, PIC, D-dimer increased significantly. Despite reduced systemic heparinization, heparin concentration was maintained adequately. Thrombin generation and fibrinolytic activity showed no significant increase until the release of the aortic cross-clamp.     

Aortic clamping during elective operations for infrarenal disease: The influence of clamping time on renal function

OBJECTIVE: Aortic clamping proximal to the renal arteries is sometimes necessitated during infrarenal and juxtarenal aortic surgery and may be associated with an increased risk of renal ischemia and its consequences. The aim of the study was to estimate this risk and possibly identify a "safe" duration of renal ischemia. METHODS: Medical records were retrospectively reviewed for 60 consecutive patients (from 1987 to 1994) with abdominal aortic aneurysm (n = 43) and occlusive disease (n = 17) confined to the infrarenal or juxtarenal aorta who underwent infrarenal aortic reconstruction with temporary suprarenal clamping. The data obtained included risk factors, preoperative and postoperative serum creatinine level, blood urea nitrogen (BUN) value, proteinuria before surgery, and suprarenal clamping times. RESULTS: The mean age of the patients was 64.4 years (+/- 11.4 years), and 74% were men. Concomitant cardiac disease was present in 41% of the patients, and 9% had diabetes. The preoperative creatinine level was 1.21 mg/dL (+/- 0.54 mg/dL), and the BUN value was 16.6 mg/dL (+/- 7.8 mg/dL). During surgery, blood flow to the renal arteries was interrupted for 32.0 minutes (+/- 17 minutes). None of the surviving patients needed dialysis or had signs of acute renal failure after the operations, but transient azotemia (rise in creatinine level) occurred in 23% of the patients. Risk factors for this condition were high preoperative creatinine values and hypotension during surgery, but the main determinant was total renal ischemia time. Odds ratios for such transient renal dysfunction showed as much as a 10-fold risk when suprarenal aortic clamping was greater than 50 minutes as compared with 30 minutes or less. CONCLUSION: Postoperative renal function impairment is rare in this group of patients. If suprarenal clamp duration (renal ischemia time) is brief, patients with normal preoperative creatinine levels exhibit no increase or a marginal increase in BUN or creatinine levels after surgery. Accordingly, suprarenal aortic clamping less than 50 minutes in this patient group appears safe and well tolerated.     

Effects of a thromboxane receptor antagonist (NT-126) and a thromboxane synthase inhibitor (OKY-O46) on protamine-induced circulatory changes in dogs

OBJECTIVE: To examine whether a thromboxane receptor antagonist, NT-126, or a thromboxane synthase inhibitor, OKY-046, prevents circulatory changes caused by protamine reversal of heparin and to evaluate the significance of thromboxane generation in the phenomena. DESIGN: Prospective, randomized, controlled, animal study. SETTING: A university research laboratory. PARTICIPANTS: Twenty-four adult mongrel dogs. INTERVENTIONS: According to the pretreatments, the animals were divided into 3 groups (n = 8 in each): (1) control (normal saline); (2) NT-126, 0.01 mg/kg; and (3) OKY-046, 1 mg/kg. Under general anesthesia, all animals were anticoagulated with intravenous heparin, 200 IU/kg, 5 minutes before the pretreatment. Five minutes after the pretreatment, protamine sulfate, 2 mg/kg, was administered intravenously over 10 seconds. Hemodynamic variables were recorded repeatedly until 60 minutes after the protamine. Plasma thromboxane B2 level was determined at baseline and 10 minutes after protamine injection. MEASUREMENTS AND MAIN RESULTS: The average values of mean arterial blood pressure and mean pulmonary artery pressure among the 3 groups in each period and values in each group over the study period were not significantly different. There was weak correlation between maximum percent increases in systolic pulmonary artery pressure or maximum percent decreases in systolic arterial blood pressure for 5 minutes after the protamine versus percent increases in plasma thromboxane B2 level. CONCLUSION: Neither NT-126 nor OKY-046 appears to be effective in preventing protamine-induced circulatory changes in this dog model, suggesting that thromboxane generation alone is not responsible for the phenomena.     

Response to heparinization in adults and children undergoing cardiac operations.

The activated clotting time is an unreliable index of anticoagulation status during cardiopulmonary bypass procedures. However, modern instrumentation (Hemotec Hepcon HMS) now allows the monitoring of free heparin levels via automated protamine titration. In the present study, the standard procedure of anticoagulation at Killingbeck Hospital, Leeds, was investigated. Twenty-two pediatric patients and 20 adult patients undergoing open heart procedures involving cardiopulmonary bypass were given empirical doses of heparin (3 mg/kg body weight bolus), and activated clotting time was maintained at a level greater than 450 seconds using the Hemochron Timer. Heparin neutralization was performed at the termination of the bypass period using an empirical equivalent (3 mg/kg) of protamine sulfate. Mean free heparin concentration (+/- standard deviation) fell from 2.26 (+/- 0.45) mg/kg to 1.39 (+/- 0.34) mg/kg over the period 10 to 40 minutes on bypass in children. In adults, free heparin level declined from 2.56 (+/- 0.58) mg/kg to 1.81 (+/- 0.58) mg/kg over the same period. The biological half-life for heparin was 60 minutes in adults and 35 minutes in pediatric patients. Empirical protamine dosing resulted in excess protamine administration when compared with Hepcon titrated dose requirements: for children: median (range), 80 (12 to 350) versus 33 (12 to 97) mg, p less than 0.001; and for adults: 350 (200 to 500) versus 130 (61 to 237) mg, p less than 0.001. In conclusion, empirical heparin administration (3 mg/kg) does not result in "steady-state" anticoagulation during cardiopulmonary bypass, and empirical administration of protamine takes no account of interindividual differences in heparin sensitivity and biological half-life, which may be assessed using the Hepcon HMS.     

THE EFFECT OF INFRARENAL AORTIC CROSS CLAMPING AND DECLAMPING ON RENAL FUNCTION IN THE PIG

Renal insufficiency following periods of infrarenal aortic cross clamping has been reported by some investigators but not by others, and conflicting views have been expressed concerning the ability of renal autoregulation to overcome the adverse circulatory effects of cross clamping. The object of this study was to examine the blood flow distribution to four layers within the renal cortex (subcapsular to juxtamedullary) and measure global renal function following application and release of an aortic cross clamp after 90 min. Nine juvenile female pigs weighing 25 to 50 kg were anaesthetized and subjected to intensive physiological monitoring. Throughout the study the blood pressure and cardiac output were maintained as close as possible to control levels by fluid administration and varying the depth of anaesthesia. Renal cortical blood flow was estimated by means of radionuclide labelled microspheres and global renal function was determined by the measurement of creatinine clearance. The aortic cross clamp was applied for 90 min immediately distal to the renal arteries and proximal to the inferior mesenteric artery. Cardiovascular and renal parameters were recorded on four occasions during each experiment, prior to, 10 and 60 min after cross clamping, and 30 min after clamp release. No significant changes in cardiac output, systemic blood pressure or global renal function were recorded during the study. There was. however, a significant fall in renal blood flow following release of the aortic cross clamp but this was not associated with any significant redistribution of blood flow within the renal cortex. In the pigs studied, the application of an infrarenal aortic cross clamp did not have any adverse effects on the cardiovascular system or on global renal function. Following release of the clamp, however, there was a significant fall in renal cortical blood flow to which, presumably, could predispose postoperative renal insufficiency. It is proposed that intensive cardiovascular monitoring coupled with appropriate corrective therapy would substantially reduce the risk of this complication.     

Activated clotting time for control of anticoagulation during surgery

Two groups of patients undergoing extracorporeal bypass were compared for heparin activity and for heparin and protamine dosage. In group I (18 patients), a uniform dosage pattern was neutralized at the end to a normal clotting time. In group II (43 patients), heparin and terminal protamine doses were regulated by activated clotting times (ACT) using a Hemochron (International Technidyne Corp., Metuchen, NJ). In group II there was a 39 per cent reduction of total heparin dose per case, protamine was reduced 76 per cent, and if the initial heparin doses were excluded, maintenance heparin was reduced 73 per cent. No pattern of heparin administration could be applied to all patients. Heparin half-life varied from 43 to 220 minutes. Other factors that alter heparin activity during bypass revealed no statistical differences. Plasma Hgb was significantly higher in group I, and platelet counts the day following operation were higher in group II. ACT allows tailoring heparin and protamine without the unnecessary dangers of variations in patient response and drug potency.     

Thromboxane mediation of pulmonary hemodynamic responses after neutralization of heparin by protamine in pigs

Protamine neutralization of heparin is often associated with severe hemodynamic side-effects, including pulmonary hypertension and systemic hypotension. Because prostanoids may be involved, the authors studied the role of arachidonic acid metabolites, especially thromboxane A2, in this process. During anesthesia with enflurane and fentanyl, four groups of pigs were studied: Group 1 (n = 10) received heparin (250 IU/kg), followed by protamine (100 mg) after 15 minutes to neutralize the heparin. The same protocol was used in group 2 (n = 11), except that the thromboxane A2 receptor antagonist BM 13.177 (10 mg/kg) was infused 5 minutes before the protamine. The protocol for group 1 was also used for group 3 (n = 7) except that these animals were pretreated with indomethacin (10 mg/kg). Animals in group 4 (n = 10) were given protamine only (100 mg). Pulmonary artery pressure and pulmonary vascular resistance increased significantly in group 1 after protamine neutralization of heparin. This was accompanied by significant increases in plasma concentrations of the cyclooxygenase products thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin F2 alpha. Cyclooxygenase products increased to comparable degrees in group 2, but without hemodynamic effects. Leukocyte counts decreased comparably in both groups. Hemodynamic reactions, as well as changes in plasma prostanoid levels were absent in group 3, and group 4, but leukocyte counts were less affected in animals that received protamine alone. The results indicate that the hemodynamic side-effects of protamine are mediated by prostanoids and that thromboxane A2 release is the pivotal step, because side effects were effectively prevented by pretreatment with a thromboxane receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)