J. Hobbhahn

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 cyclooxygen-ase products thromboxane B2, 6-keto-prostaglandin F1α, and prostaglandin F2α. 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. Leukocyte or platelet counts were not directly related to the severity of hemodynamic alterations.

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 levelsin arterial and mixed-venous plasma samples: Thromboxane A2, prostaglandin F2α, KH2-PGF2α (a metabolite of prostaglandin F2α), 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. This was evidenced in the present study by 1) elevated prostanoid levels in pigs in group 1 and 2) by the absence of side effects after protamine in the cyclooxygenase-inhibited pigs in group 2.

Myocardial oxygenation and transmural lactate metabolism during experimental acute coronary stenosis in pigs.

SummaryMeasurement of surface tissue pO2 (ptO2) with surface electrodes is increasingly applied in experimental medicine. Its use on the beating heart may seem to be problematic because transmural gradients of tissue pO2 would reduce the validity of pO2 determinations in the epicardial layers. This study attempted to determine whether ptO2 may be a valid and sensitive indicator of transmural myocardial oxygenation.In order to measure ptO2, two eight-channel Clark-type electrodes were placed on a beating porcine left ventricle (n=13). Measurements were made at different degrees of acute stenosis of the left anterior descending artery (LAD). A 24-F cannula was inserted into the great cardiac vein, draining the poststenotic myocardium to obtain coronary venous blood samples. Transmural metabolic changes were detected simultaneously by coronary venous blood gas parameters and lactate levels. Epicardial tissue pO2 was 49±2 mm Hg (mean±SEM) before stenosis and decreased to a mean value of 25±2 mm Hg during stenosis. Different degrees of LAD stenosis (ptO2 range: 12–35 mm Hg) were substantial enough to alter arterio-coronary venous lactate difference (avd lactate) from +0.31±0.07 mmol/l (control) to −0.62±0.15 mmol/l (stenosis). A significant linear correlation between changes of ptO2 (Δ ptO2) and changes of avd lactate (Δ avd lactate) resulted (y=0.59+0.62x; r=0.86; p≤0.001). However, linear regression analysis between ΔptO2 correlated with the corresponding data from coronary venous pO2 (ΔpO2cv) oxygen content (ΔO2contcv), and oxygen saturation (ΔO2satcv) showed no significant correlations.We conclude that measurement of ptO2 is a sensitive and valuable indicator of transmural oxygenation in ischemic myocardium, whereas pO2cv, O2contcv and O2satcv do not seem to be valid predictors of ischemia in myocardial oxygenation.

Left ventricular oxygen tensions in dogs during coronary vasodilation by enflurane, isoflurane and dipyridamole.

The purpose of this study was to investigate the effects of the anesthetics enflurane and isoflurane and of the coronary vasodilator dipyridamole on myocardial oxygen balance and myocardial tissue oxygen tensions. The studies were performed in 24 open-chest dogs during basal anesthesia with a narcotic. Myocardial blood flow (MBF) was measured using radioactive microspheres, myocardial surface tissue PO2 by means of a platinum multiwire surface electrode. One control group and three experimental groups were studied: enflurane (1.1 vol%), isoflurane (0.7 vol%, both end-tidal concentrations), and dipyridamole (0.4 mg/kg). Mean arterial pressure significantly decreased to an average of 70 mm Hg in all three experimental groups. Although MBF was unchanged during enflurane (−18%) and isoflurane (+20%), it increased during dipyridamole (+304% p < 0.05 vs baseline and control, enflurane, and isoflurane groups). Myocardial oxygen consumption decreased significantly during enflurane and isoflurane but remained unchanged during dipyridamole. Thus, the ratio between myocardial oxygen delivery and consumption increased 6% with enflurane (p < 0.05 vs baseline), 47% with isoflurane (p < 0.05 vs baseline and control group) and 280% with dipyridamole (p < 0.05 vs baseline and control, enflurane, and isoflurane groups). Coronary venous PO2 remained unchanged during enflurane but increased significantly during isoflurane and dipyridamole. Left ventricular surface tissue PO2 was unchanged in enflurane and isoflurane animals and decreased slightly, yet significantly, during dipyridamole. All variables remained unchanged in the control group. Thus, isoflurane and dipyridamole interfered with MBF autoregulation and increased myocardial oxygen delivery out of proportion to myocardial demands. The lack of simultaneous increase in tissue oxygen pressures may reflect occurance of functional shunting on a cardiac microvascular level. These results also suggest that coronary vasodilating agents may not necessarily be beneficial for oxygenation of the intact myocardium.

Perioperative Changes in Cardiac Autonomic Control in Patients Receiving Either General or Local Anesthesia for Ophthalmic Surgery

To investigate whether local (LA) or general anesthesia (GA) provides more perioperative stability in cardiac autonomic tone, we analyzed heart rate variability (HRV) by means of spectral analysis, intraoperatively and up to 3 h postoperatively, in otherwise healthy patients scheduled for cataract surgery.Fourteen patients received GA (premedication: clorazepate; anesthetic induction: propofol, alfentanil, atracurium; anesthetic maintainance: isoflurane, alfentanil; airway management: laryngeal mask airway), and 14 patients received LA (retrobulbar block with bupivacaine/mepivacaine). In the GA group, total power, as an indicator of cardiac autonomic activity, was significantly reduced intraoperatively and increased slowly during the postoperative period. The ratio of low frequency/high frequency (LF/HF) power, indicating cardiac sympathovagal balance, did not change significantly intraoperatively and remained stable in the postoperative period. The LA group showed no significant changes in total power intraoperatively. Postoperatively, heart rate and the LF/HF power ratio were significantly increased in the LA group compared to the GA group. GA as described above was associated with intra- or postoperative stability of the cardiac sympathovagal balance. Thus GA had no disadvantageous effects on the perioperative cardiac autonomic tone during ophthalmic surgical procedures compared to LA in otherwise healthy patients. (Anesth Analg 1996;82:113-8)

Myocardial contractility, blood flow, and oxygen consumption in healthy dogs during anesthesia with isoflurane or enflurane

Left ventricular contractility (Vmax), myocardial blood flow (MBF), and oxygen consumption (O2C) were determined together with systemic hemodynamic parameters in a total of 21 mongrel dogs. Baseline recordings were obtained under basal anesthetic conditions with a narcotic (piritramid, IV). In the control group (n = 7), recordings were obtained during a three-hour observation period with infusion of piritramid. In experimental groups measurements were repeated with equi-anesthetic concentrations of isoflurane (0.7 and 1.4 vol%; n = 8) and enflurane (1.1 and 2.2 vol%; n = 6). Dose-dependent reductions of arterial pressure, cardiac output (CO) and peripheral vascular resistance were observed with isoflurane and enflurane. CO at the higher anesthetic level was depressed significantly more with enflurane. This difference was obviously due to a more severe depression of myocardial contractility with enflurane; Vmax was decreased by 18% and 26% with enflurane, but only by 10% and 17% with isoflurane (P less than 0.01). MBF and the fraction of CO received by the heart were increased above their baseline values with both concentrations of isoflurane. In contrast, the fraction of CO remained constant with enflurane while MBF decreased. O2C was reduced due to decreases of afterload and left ventricular contractility. The reduction was greater with enflurane than with isoflurane. All parameters remained unchanged in the control group. The results of this study indicate that the most striking difference in the actions of isoflurane and enflurane on cardiac parameters is on myocardial vascular resistance; MBF is increased with isoflurane, but is decreased with enflurane although myocardial perfusion pressure is reduced by almost identical amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary hypertension after heparin-protamine : roles of left-sided infusion, histamine, and platelet-activating factor

Severe pulmonary hypertension after protamine neutralization of heparin is an infrequent but life-threatening event following cardiopulmonary bypass. The effect of left ventricular infusion of protamine on pulmonary hypertension as well as a possible role of platelet-activating factor (PAF) or histamine in the heparin-protamine reaction was investigated in 30 pigs in four different groups during general anesthesia. Group 1 animals received 250 lU/kg heparin, followed by 100 mg protamine intravenously after 15 min. In group 2 protamine was infused into the left ventricle. Group 3 animals received the histamine H1− and H2− antagonists clemastine and ranitidine 5 min before protamine infusion. In group 4 the PAF receptor blocker WEB 2086 was given 5 min before protamine. Platelet-activating factor was measured by a bioassay in serum samples of group 1 and group 4 animals. In all four groups protamine caused severe pulmonary hypertension, thromboxane A2 release, and a transient decrease in leukocyte counts. No PAF release was detected after protamine infusion. Neither left ventricular infusion of protamine nor histamine or PAF antagonists prevented or attenuated the reactions after protamine infusion. The authors conclude that left ventricular infusion of protamine provides no protection from pulmonary hypertension, and that histamine and PAF are not involved in the acute pulmonary vasoconstriction after protamine neutralization of heparin.