Mechanism of the Hypotension Produced Protamine Sulfate in Dogs / 대한마취과학회지

INTRODUCTION: Protamine reversal of heparin anticoagulation often produces profound hypotension. However, the precise mechanisms of its hypotensive effect have not been fully elucidated. Using a canine model, we explored the effects of cyclo-oxygenase inhibitor, indomethacin (INDO), and nitric oxide synthetase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) either alone or both on the cardiopulmonary responses to protamine. METHODS: Fifty-four mongrel dogs in five groups were studied during 1.5% halothane anesthesia. GroupI (n=17) received heparin (300 IU/kg iv) followed by protamine (3 mg/kg iv over 30 s) 5 min after the heparin. The same protocol were used in groups II (n=11), III (n=12), and IV (n=7), except that L-NAME (20 mg/kg), INDO (10 mg/kg), and INDO (10 mg/kg) plus L-NAME (10 mg/kg) were infused over 10 min beginning 30 min before the protamine injection, respectively. Animals in group V (n=7) were given protamine (3 mg/kg) alone. Mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular end-diastolic pressure (LVEDP), LVdP/dt and cardiac output and left circumflex coronary flow (LCX flow) via Doppler flowmeter and heart rate were continuously recorded in baseline conditions and up to 15 min. Plasma NOx (NO2-, NO3-) levels were also measured before (baseline) and 3, 5, 10, and 15 min after protamine injection. RESULTS: In group I, protamine caused immediate but transient decreases of MAP (41%), cardiac index (CI, 58%), dP/dt (28%), and LVEDP (62%) and increases of MPAP (38%) and systemic and pulmonary vascular resistance indices (SVRI, 30%; PVRI, 316%). INDO significantly attenuated the hemodynamic responses to protamine, whereas L-NAME did not affect them at all. INDO plus L-NAME prevented protamine-induced hypotension, but CI (-24%) and LVEDP (-30%) showed similar changes as those in group II. Protamine increased MPAP but inconsistently, meanwhile no correlation was found between the magnitude of increase of MPAP and decrease of MAP at peak responses in groups I-IV. LCX flow increased significantly (124~188%) immediately after protamine infusion without any changes in plasma NOx levels in groups I-IV. Neither significant hemodynamic effects nor NOx release was found in animals given protamine alone. CONCLUSION: Protamine in the presence of heparin induces profound hypotension which may be mediated by a prostanoid and other potent vasodilators. In addition, increase of PAP and NO release may not play a significant role in the protamine-induced hypotension.

Influence of Acute Pulmonary Hypertension on the Protamine-induced Systemic Hypotension in the Heparinized Dog / 대한마취과학회지

INTRODUCTION: The present study was aimed to investigate the hemodynamic effects of protamine and to determine whether the increases of pulmonary arterial pressure (deltaPAP) after protamine is related to development of systemic hypotension in heparinized dogs. METHODS: Nineteen mongrel dogs were acutely instrumented during 1.5% halothane anesthesia. All dogs then received protamine 3 mg.kg (-1) over a period of 30 s given through right atrium 5 minutes after heparin (300 IU.kg (-1), iv). Animals were retrospectively assigned into two groups, control (deltaPAP<6 mmHg, n=9) and pulmonary hypertensive (PHT, deltaPAP<6 mmHg, n=10) groups. Mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular pressure, heart rate (HR), and cardiac output and left circumflex coronary flow (LCX flow) via Doppler flowmeter were continuously recorded throughout the experiments. Changes in MPAP were related to changes in MAP using standard regression analysis. RESULTS: MPAP (66% in PHT vs 7% in control group) and pulmonary vascular resistance index (5.1- vs 3.0-fold) increased more markedly immediately after protamine administration in PHT group than in control group. However, protamine caused similar reductions of MAP (-40 vs -46%), cardiac index (-60 vs -59%), and left ventricular end- diastolic pressure (-47 vs -53%) in both groups. No correlation was found between deltaPAP and deltaMAP in either group. LCX flow increased significantly but similarly immediately after protamine in both groups (183 vs 238%), indicating rapid release of potent vasodilator. CONCLUSIONS: These results suggest that, in heparinized dogs, protamine produces transient severe hypotension but does not consistently elevate pulmonary arterial pressure and, that acute pulmonary vasoconstriction does not play a major role in protamine-induced hypotension.

Effects of Pretreatment with a Small Dose of Protamine on Protamine-induced Systemic Hypotension in the Heparinized Dog / 대한마취과학회지

INTRODUCTION: Protamine reversal of heparin anticoagulation in patients often produces profound hypotension. The present study was aimed to investigate the effectiveness of pretreatment with a small dose (0.5 mg.kg (-1)) of protamine in attenuating protamine-induced systemic hypotension in heparinized dogs. METHODS: Forty mongrel dogs were pretreated with either intravenous saline (control group, n=19) or protamine 0.5 mg.kg (-1) (protamine group, n=11) 5 minutes after heparin (300 IU.kg (-1), iv) during 1.5% halothane anesthesia. All dogs were then given protamine 3 mg.kg (-1) over a period of 30 s through right atrium 10 minutes after the pretreatment. Mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular end-diastolic pressure (LVEDP), heart rate (HR), and cardiac output and left circumflex coronary flow (LCX flow) via Doppler flowmeter were continuously recorded in baseline conditions and up to 20 minutes. Calculated parameters included cardiac index (CI), systemic and pulmonary vascular resistance indices (SVRI and PVRI), and LV dp/dt. RESULTS: In the control group, protamine infusion caused immediate but transient decreases of MAP (-42%), CI (-58%), LVEDP (-53%) and dP/dt (-25%), and increases of MPAP (39%), SVRI (38%) and PVRI (4.0 fold). Protamine pretreatment significantly attenuated but not completely blocked the hemodynamic responses to protamine. LCX flow increased significantly (213~258%) immediately after protamine infusion in both groups. CONCLUSIONS: These results suggest that, in the heparinized dog, pretreatment with a small dose of protamine attenuates the degree of hypotension that may follow the rapid administration of protamine.

Activated Coagulation Time (ACT) Differences between Arterial and Venous Blood Samples in Patients with Open Heart Surgery / 대한마취과학회지

BACKGROUND: Activated coagulation time (ACT) is commonly used to guide heparin and protamine dosing during cardiovascular surgery. There are many factors that influence the ACT such as time of test, hemodilution, temperature, aprotinin and etc. We considered the other factor that influence the ACT, the route of blood sample. METHODS: This study included 40 patients who were scheduled for cardiac surgery. Whole blood was sampled through arterial and central venous line at 10 minutes after surgical incision and heparin administration. The ACT was measured with Hemochron 801 blood coagulation timer with 12 mg of celite surface activator. RESULTS: At 10 minutes after surgical incision and heparin administration, arterial blood and venous blood ACTs were 127 20, 537 214 seconds and 118 18, 496 145 seconds respectively (p<0.05). CONCLUSIONS: We conclude that the venous blood ACT is more less than arterial blood ACT during cardiovascular surgery.