Splanchnic Elimination and Systemic Toxicity of Bupivacaine and Etidocaine in Man

Fifteen healthy young volunteers were studied in connection with an intravenous infusion of a local anaesthetic agent. Seven received bupivacaine and eight etidocaine in a dose rate of 2 mg.min-1 over a period of 150 min. The hepatic blood flow and arterial-hepatic venous differences of the two drugs were measured. The estimated hepatic blood flow increased during the infusion of both drugs. While the splanchnic extraction ratio decreased during infusion of bupivacaine to 0.41 +/- 0.13, the same variable did not change (0.76 +/- 0.07) when etidocaine was infused. After 150 min infusion, the splanchnic clearance of bupivacaine and etidocaine was 0.76 +/- 0.27 and 1.32 +/- 0.21 1.min-1, respectively. Slight symptoms of central nervous toxicity were noted towards the end of the bupivacaine infusion, while no such symptoms appeared with etidocaine. A comparison between earlier published data on the blocking properties and the disposition pharmacokinetics of the two drugs shows that etidocaine is likely to confer a clinical advantage over bupivacaine as regards toxicity.     

The effects of vasoactive drugs on hepatic blood flow changes induced by CO2 laparoscopy: an animal study.

Laparoscopic surgery is associated with systemic and splanchnic hemodynamic alterations. Recent data suggest that small-dose dobutamine may attenuate the reduction in splanchnic blood flow associated with increments in intraabdominal pressure. We conducted this study to analyze the effects of dopamine and dobutamine on the hepatic circulation in this setting. Twenty-one pigs were anesthetized and mechanically ventilated. A flow-directed pulmonary artery and carotid artery catheters were inserted. Perivascular flow probes were placed around the main hepatic artery and the portal vein. CO2 was insufflated into the peritoneal cavity to reach an intraabdominal pressure of 15 mm Hg. After 60 min, animals received dopamine (5 microg x kg(-1) x min(-1); n = 8), dobutamine (5 microg x kg(-1) x min(-1); n = 8), or saline (n = 5) for 30 min. Pneumoperitoneum induced significant increases in heart rate, mean arterial pressure, and systemic vascular resistance, with decreases in cardiac output and hepatic artery and portal vein blood flows. Dobutamine infusion, in contrast to dopamine, corrected, at least in part, cardiac output, systemic vascular resistance, and hepatic artery blood flow alterations, but neither drug restored total hepatic blood flow. IMPLICATIONS: Hepatic blood flow decreases during laparoscopic surgery. A small-dose infusion of neither dobutamine nor dopamine corrects the total hepatic blood flow impairment, but the former is able to restore the hepatic arterial blood supply in an animal model mimicking this condition.     

Splanchnic circulation following coeliac plexus block

Both the capacitance vessels and the resistance vessels of the splanchnic area are innervated by the sympathetic nerve fibers. We investigated the effect of abdominal visceral sympathectomy on splanchnic circulation, and the effect of altered splanchnic circulation on systemic circulation in ten mongrel dogs. Abdominal visceral sympathectomy was induced by coeliac plexus block with 1 ml/kg (body weight) of 1 % lidocaine infiltrated around the coeliac artery. Comparison was made with infiltration of physiologic saline of the same volume. The saline infiltration caused no significant changes in the hemodynamic parameters of systemic and splanchnic circulation. Mean arterial pressure decreased significantly from 18.2 ±2.0 to 14.4±1.9 kPa following the coeliac plexus block, with a concomitant decrease in the cardiac index from 2.63 ± 0.46 to 2.30 ± 0.54 1 × min^-1 × m^-2, while systemic vascular resistance was unchanged. Portal vein blood flow, hepatic artery blood flow and, therefore, splanchnic blood flow decreased by 8 to 17%. Portal vascular and hepatic artery resistances were not affected by abdominal sympathectomy. It was concluded that the capacitance vessels in splanchnic circulation are dilated during abdominal sympathetic denervation, causing a blood shift from systemic to splanchnic circulation. On the other hand, the resistance vessels in splanchnic circulation are affected little by abdominal visceral sympathectomy.     

Human Hepatic Blood Flow and its Relation to Systemic Circulation during Intravenous Infusion of Lidocaine

Twelve healthy young volunteers were studied before and during intravenous administration of lidocaine at a dose rate of 2 or 4 mg/min. Five additional volunteers, who did not receive lidocaine solution but were given the same amount of physiological saline, were studied in the same manner. Heart rate, cardiac output, mean arterial blood pressure, mean right atrial blood pressure, estimated hepatic blood flow and plasma concentration of lidocaine were measured repeatedly. The results showed an increase in heart rate, cardiac output and mean arterial blood pressure, the latter two variables in relation to the plasma concentration of lidocaine. The estimated hepatic blood flow increased, partly as a result of the reduction of splanchnic vascular resistance and partly due to the stimulation of cardiac output. The decrease in splanchnic vascular resistance was proportional to the plasma concentration of lidocaine.     

The circulatory effects of intravenously administered ephedrine during epidural blockade.

The changes in central circulation following a small dose of intravenously administered ephedrine were studied in middle-aged and elderly patients during high epidural blockade with bupivacaine 0.5% with adrenaline, etidocaine 1% with adrenaline, and etidocaine 1% plain. Itravenously injected ephedrine restored the mean, systolic and diastolic arterial blood pressures to the preanalgesic value independent of the degree of hypotension, and was not followed by marked hypertension in any case. Although the heart rate did not change, the cardiostimulatory effects were more pronounced than after subcutaneous premedication, resulting in increased stroke volume and cardiac output in all groups. Peripheral vascular resistance increased to the preanalgesic value in the groups receiving bupivacaine adrenaline and etidocaine plain. In the etidocaine adrenaline group, peripheral vascular resistance was little changed, as the cardiostimulatory effects were more pronounced than in the other groups.     

Effects of propranolol on hepatic haemodynamics in the cirrhotic and non-cirrhotic rat

The effects of systemic and intraportal administration of propranolol on hepatic haemodynamics were studied in cirrhotic and non-cirrhotic rats. In the non-cirrhotic rat systemic infusion of 4 micrograms (kg body wt)-1 min-1 propranolol significantly decreased portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow without affecting heart rate. Similar changes were observed in the cirrhotic rat following an infusion of 2 micrograms (kg body wt)-1 min-1 propranolol. Higher rates of propranolol infusion produced greater reductions in portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow in cirrhotic and non-cirrhotic rats but these changes were accompanied by a bradycardia. The reduction in portal pressure effected by propranolol was accompanied by an increased splanchnic vascular resistance. Intraportal injection of propranolol resulted in a rapid but transient fall in portal pressure. The decrease in portal pressure was sustained if propranolol was infused intraportally. The results indicate that propranolol effects a reduction in portal pressure via a combination of increased splanchnic vascular resistance, increased hepatic arterial resistance and reduced cardiac output. The observation that propranolol can significantly reduce portal pressure without affecting heart rate may be clinically important in the long-term management of portal hypertension. Furthermore, the rapid reduction in portal pressure following intravenous administration suggests that propranolol may be of value in the acute control of variceal haemorrhage.     

The Circulatory Effects of Intravenously Administered Ephedrine during Epidural Blockade

The changes in central circulation following a small dose of intravenously administered ephedrine were Ftudicd in middle-aged and elderly patients during high epidural blockade with bupivacainc 0.5% with adrenaline, etidocaine 1% with adrenaline, and etidocaine 1% plain. Intravenously injected ephedrine restored the mean, systolic and diastolic arterial blood pressures to the preanalgesic value independent of the degree of hypotension, and was not followed by marked hypcrtcnsion in any case. Although the heart rate did not change, the cardiostimulatory effects were more pronounced than after subcutaneous premedication, resulting in increased stroke volume and cardiac output in all groups. Peripheral vascular resistance increased to the preanalgesic value in the groups receiving bupivacaine adrenaline and etidocaine plain. In the etidocaine adrenaline group, peripheral vascular resistance was little changed, as the cardiostimulatory effects were more pronounced than in the other groups.     

The effects of bupivacaine on the umbilical circulation and placental gas exchange in the fetal lamb

Seven chronically catheterized fetal sheep at 125-140 days gestation were studied in 12 experiments to determine the direct effects of the local anesthetic bupivacaine (infused intravenously to the fetus) on the umbilical circulation and placental gas exchange. Electrocortical activity, umbilical blood flow, heart rate, and umbilical arterial and venous pressures were continuously monitored in experiments comprising a baseline period, a drug infusion period and a recovery period, each of 2 hr duration. Samples of umbilical arterial and venous blood were taken for blood gas analysis, and for bupivacaine assay using high pressure liquid chromatography technique. Fetal plasma bupivacaine levels were 1.3 +/- 0.3 microgram/ml (mean +/- SEM) between 60-120 min of infusion. Heart rate and umbilical blood flow decreased significantly to 89 and 94% of control, respectively, (P less than 0.05) during the infusion and returned to control levels by 2 hr afterwards. Mean umbilical arterial and venous pressures were not significantly altered, and no significant rise in umbilical vascular resistance occurred. No changes occurred in umbilical arterial or venous pH, PO2, or PCO2. In summary, bupivacaine reversibly depressed fetal heart rate and umbilical blood flow without detrimental changes in fetal blood gas or acid-base status.     

Effects of Ephedrine on Haemodynamics and Oxygen Consumption in the Dog During High Epidural Block with Special Reference to the Splanchnic Region

High lumbar epidural block was induced in seven dogs with 0.5% bupivacaine, causing a fall in mean arterial blood pressure (AP) from 19.2 +/- 3.2 to 10.5 +/- 3.2 kPa, owing to equal reductions in cardiac output (QT) and systemic vascular resistance (SVR). After the administration of ephedrine (a single injection of 200-300 micrograms X kg-1 b.w. followed by a continuous infusion of 10-20 micrograms X kg-1 b.w. X min-1) AP, QT and SVR rose to pre-epidural values. Furthermore, the hypokinetic circulation following the epidural block returned to normokinetic levels. Portal venous blood flow was increased from 16.5 +/- 6.2 to 25.5 +/- 4.3 ml X kg-1 b.w. X min-1 by ephedrine, while the hepatic arterial blood flow was unchanged and remained at its pre-epidural level. In spite of a slight rise in hepatic oxygen consumption from 1.2 +/- 0.4 to 1.6 +/- 0.6 ml X kg-1 b.w. X min-1, the percentages of oxygen extracted from the portal vein and the hepatic artery decreased significantly. It is concluded that ephedrine restores central and splanchnic haemodynamics in a desirable manner during high epidural anaesthesia.     

Splanchnikusperfusion unter Dopexamin bei kardiochirurgischen Eingriffen

The present study investigates the effects of dopexamine on the splanchnic perfusion and the general circulation in patients undergoing coronary artery bypass grafting. METHODS: 34 Patients undergoing elective coronary artery bypass grafting were randomized to receive either dopexamine (1 microg/kg/min) or placebo (0,9% NaCl. ) Cardiac output was measured by thermodilution using a pulmonary artery catheter. Splanchnic blood flow was determined by constant infusion technique of indocyanine green dye (ICG) using a hepatic vein catheter. RESULTS: Under steady state conditions before surgery, dopexamine increased systemic oxygen supply and cardiac output by an increase in heart rate and stroke volume, with no increase in systemic oxygen demand. Before surgery dopexamine increased splanchnic blood flow together with an increase in cardiac output. After cardiopulmonary bypass dopexamine increased splanchnic perfusion without a concomittant rise in cardiac output. CONCLUSION: These results provide evidence that dopexamine improves splanchnic blood flow in patients with coronary artery disease before and after pulmonary bypass without impairment of general hemodynamics.     

Influence of Intravenously Administered Ephedrine on Splanchnic Haemodynamics and Clearance of Lidocaine

The effects of a 20 mg i.v. bolus of ephedrine sulphate on haemodynamics and plasma lidocaine concentrations were evaluated in eight volunteer subjects receiving a constant i.v. infusion of lidocaine HCI (2 or 4 mg min^-1). Injection of ephedrine caused a significant increase in mean arterial blood pressure, which preceded an elevation of heart rate by about 2 min. Cardiac output and hepatic blood flow, measured at 10 and 20 min after injection, were also increased significantly, while there was a decrease in total peripheral resistance and no change in splanchnic vascular resistance. There were no significant circulatory alterations over the same period in a control group of four subjects on receiving the lidocaine infusion. After ephedrine, the mean splanchnic extraction ratio of lidocaine fell from 0.76 to 0.66 at 10 min, then rose again to 0.71 at 20 min, and these changes were accompanied by a 9% increase in its splanchnic clearance. Extraction and clearance remained unchanged in the control group. The implications of these findings are considered in relation to the use of ephedrine to prevent or treat hypotension after peridural block with local anaesthetic agents.     

Effects of celiac plexus block on splanchnic circulation--II: Changes in the systemic hemodynamics and the blood flow of the liver and kidney in dogs

Effects of celiac plexus block (CPB) on systemic and splanchnic circulation, especially of liver and kidney, were investigated in twenty nine mongrel dogs. CPB was performed by an anterior approach through a catheter placed in a paraaortic compartment using 7 mg.kg-1 of 2% mepivacaine. Tissue blood flow measurement was performed by a hydrogen clearance method in eleven dogs, and vascular blood flow was measured in eighteen dogs by an electromagnetic flow meter. Swan-Ganz catheter was inserted to measure mean arterial pressure (ABP), heart rate (HR), central venous pressure (CVP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) and cardiac output (CO). Then stroke volume (SV), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were calculated. Following CPB, ABP, HR, CVP and C.O. were significantly decreased at 7 to 9%. PAP decreased at 5%. PCWP, SV, SVR and PVR were unchanged. The hepatic arterial blood flow increased significantly, and portal venous blood flow decreased after CPB transiently, and then recovered to control value or to a higher level at 60min after CPB. The tissue blood flow of the liver tended to increase, but the change was not significant. In the kidney, both arterial and tissue blood flows increased significantly after CPB. The results suggest that following CPB, hepatic and renal tissue blood flows increased because of the increments of their arterial blood flows, unless a profound systemic hemodynamic depression occurred.     

RELATION OF ETIDOCAINE AND BUPIVACAINE TOXICITY TO RATE OF INFUSION IN RHESUS MONKEYS

The relationship between infusion rate of etidocaine and bupivacaineand central nervous system toxicity was studied in three rhesusmonkeys. Increasing the infusion rate from 0.5 to 2.0 mg/kg.min^-1 decreased the seizure dosage of etidocaine but had noeffect on that of bupivacaine. Arterial plasma concentrationsof etidocaine and bupivacaine that induced electrical seizureactivity increased as the infusion rate was increased from 0.5to 1.0 mg/kg. min^-1. A plasma decay study in a fourth animaldemonstrated that etidocaine decayed more rapidly than did bupivacaine.These results suggest that the rate of administration of theseagents is important in determining central nervous system toxicity.     

Somatostatin and analogs lack splanchnic vasoconstrictive effects in anesthetized pigs

Due to an apparently selective vasoconstrictive effect on the splanchnic circulation, somatostatin (SRIF) has been advocated for the treatment of variceal hemorrhage. The present study was designed to compare and contrast the systemic and splanchnic hemodynamic effects of SRIF and two of its long-acting analogs (SMS 201,995 and L 363,568) with those of Pitressin. Anesthetized pigs were subjected to laparotomy for placement of an electromagnetic flowmeter on the main trunk of the superior mesenteric artery (SMA). Systemic hemodynamic parameters of arterial blood pressure and cardiac output were monitored with thermodilution catheters. Portal venous blood was collected for measurement of plasma levels of SMS 201,995 and L 363,568 and for determination of gastrin levels during infusion of the latter analog. Experimental drugs were administered via an aortic cannula in a range (5-10 mg/kg bolus and 5-10 mg/kg/min continuous infusion) of dosages. At the higher dosages, SRIF, SMS 201,995, and L 363,568 decreased SMA blood flow (mean% +/- SD) 5.6 +/- 2.2, 1.6 +/- 4.4, and 8.0 +/- 3.8 after 10 min. None of the values achieved significance when compared to variation in baseline determinations. Pitressin (0.25 units, intravenously) produced a consistent and highly significant (P less than 0.001) reduction-in SMA flow after 5 min. Pharmacologic levels of SMS 201,995 and L 363,568 were reliably achieved in portal blood and the latter produced significant reduction (P less than 0.05) in portal venous levels of gastrin. SRIF and its long-acting analogs produced no significant splanchnic nor systemic hemodynamic effects in this model.     

Haemodynamic effects of high plasma concentrations of bupivacaine in the dog

The threshold concentrations responsible for circulatory collapse were experimentally investigated by intravenously infusing the drug at high rates (0.2 and 0.3 mg kg-1 min-1 over 20 min, and 0.4 mg kg-1 over 10 min) to 11 anaesthetized and ventilated dogs. Bupivacaine plasma concentrations at the time of haemodynamic measurements were, respectively, 4303 +/- 46, 5829 +/- 615, and 8930 +/- 689 ng ml-1 (means +/- SEM). Cardiac output appeared to be the first and the most affected of the haemodynamic variables studied. Its reduction was already significant with the 0.2 mg kg-1 min-1 bupivacaine infusion, whereas mean systolic blood pressure remained unchanged because of the compensatory increase in vascular resistance. The fall of cardiac output was enhanced by the rise in bupivacaine infusion rate, with simultaneous substantial decreases in left ventricular pressure and LV dP/dt max. At this stage, the increase in systemic vascular resistance was less marked than at low infusion rates, and was not sufficient to prevent hypotension. The variations of mean pulmonary blood pressure and pulmonary capillary wedge pressure did not reach statistical significance, and the absence of significant change in mean pulmonary blood pressure at the time cardiac output was reduced reflected the increase in pulmonary vascular resistance. These results suggest that high plasma concentrations of bupivacaine exert a depressant effect on cardiac contractions earlier than on arteriolar tone.     

Central and Splanchnic Haemodynamics in the Dog During Controlled Hypotension with Sodium Nitroprusside

The effects of controlled hypotension induced by sodium nitroprusside (SNP) on central and splanchnic haemodynamics were studied in ten artificially ventilated dogs under neurolept anaesthesia. SNP was given intravenously as a continuous infusion in order to maintain a mean arterial blood pressure (MABP) of about 50 mmHg. Observations were made before (control) and at 20 and 60 min after the start of the SNP infusion. The mean SNP dosage was 13.7 micrograms X kg-1 X min-1. Systemic vascular resistance (SVR) decreased by 47%. After 20 min there was a 17% decrease in cardiac output, while the hepatic arterial blood flow was diminished by 39%, and portal venous blood flow by 16%. Cardiac output and portal venous blood flow tended to return towards control values at 60 min, while the hepatic arterial blood flow remained depressed. The total oxygen uptake was unaltered after 20 min, but slightly decreased after 60 min. There were no changes in hepatic or preportal tissue oxygen consumption, nor in hepatic lactate uptake. It is concluded that SNP-induced hypotension was achieved primarily by a profound reduction of SVR, and initially also by a slight decrease in cardiac output. Although splanchnic and hepatic blood flows decreased, there were no signs of hypoxia in the preportal tissues or in the liver.     

Blood pressure is maintained despite profound myocardial depression during acute bupivacaine overdose in pigs.

Bupivacaine-induced cardiovascular collapse is a feared complication because of the difficulty in restoring stable circulation (1). Early recognition is important so that the injection of bupivacaine can be discontinued. We used an animal model of near-cardiac arrest from bupivacaine infusion to identify the sequence of hemodynamic events that precedes bupivacaine-induced cardiovascular collapse. Twelve pigs (23-25 kg) were sedated with ketamine and anesthetized with halothane. Arterial blood pressure and cardiac output were measured. Bupivacaine (3.75 mg/mL) was administered at a rate of 5.73 mL/min (approximately 1 mg x kg(-1) x min(-1)) through a central venous catheter until severe ventricular arrhythmia occurred. Blood pressure and heart rate were unchanged, but cardiac output decreased by 40% with increasing doses of bupivacaine. Calculated peripheral resistance increased by 54%. The QRS complex of the surface electrocardiogram widened, and the R-wave amplitude decreased 80%, together with the decrease in cardiac output. T-wave amplitude increased initially but returned toward baseline at the largest bupivacaine doses. The plasma concentration of bupivacaine after the infusion was 16+/-6.8 microg/mL. IMPLICATIONS: The increase in vascular resistance that accompanies acute bupivacaine overdose maintains blood pressure but masks severe myocardial depression.     

Control of gastric vascular resistance in cardiogenic shock

That local splanchnic ischemia is associated with the acute gastric "stress" erosions seen in shock is well established. The hemodynamic mechanism mediating that ischemia is unknown. Pericardial tamponade was produced in anesthetized pigs while hemodynamic parameters were monitored in the systemic circulation as a whole and in the vascular beds of the celiac and left gastric arteries, respectively. Stepwise increases in pericardial pressure produced progressive decreases in arterial pressure and cardiac output (i.e., reproducible, quantitable, and rapidly reversible levels of cardiogenic shock). This produced a profound reduction in blood flow in the celiac and gastric beds that was significantly disproportionate to the reduction in cardiac output. This was due to significant increases in celiac and gastric vascular resistance that were more than twice as great as those seen in the systemic circulation as a whole (i.e., selective splanchnic vasoconstriction). This response was abolished by ablation of the renin-angiotensin axis, whether by bilateral nephrectomy, captopril, or saralasin, and mimicked, without tamponade, by the infusion of angiotensin II. Levels of celiac artery blood flow and resistance correlated significantly with endogenous levels of plasma renin activity. On the other hand, this response was not abolished by confirmed alpha-adrenergic blockade (phenoxybenzamine) or by sympathectomy. In this model, cardiogenic shock produces regional splanchnic ischemia in the celiac and gastric vascular beds by inducing a severe and disproportionate vasospasm that is mediated primarily by the renin-angiotensin axis.     

Effects of Tham, isoprenaline and propranolol on the blood flow and vascular resistance of the liver after clamping of the afferent and efferent vessels. Relation to splanchnic shock]

To determine the roles of portal circulation and the hepatic arteries during states of shock, the authors studied on 38 dogs, the effects of 30 minutes clamping of the sub-diaphragmatic part of the inferior vena cava, the portal vein and the hepatic artery, either together or successively. They measured the pressure in these various vessels, the transhepatic flow, using Xenon133, and calculated the intra-hepatic resistance. The animals were then treated with Tham, isoprenaline and propanolol. Tolerance to clamping was improved significantly when the animals were treated with the association of these drugs. The portal pressure and the systemic arterial pressure, rapidly returned to normal. This was also the case with hepatic, venous or arterial blood flow. There was a remarkable stability between the sinusoidal and biliary resistances, compared with disturbances in control groups. The already well known beneficial effect of Tham was increased by the apparently paradoxical association of isoprenaline and propranolol. In fact, with this dosage, they counter-balanced their reciprocal disadvantages. Finally, a study of blood flow and vascular resistance in the liver, suggests the existence of two components in splanchnic shock, hepatic and visceral.     

Dobutamine compensates deleterious hemodynamic and metabolic effects of vasopressin in the splanchnic region in endotoxin shock

BACKGROUND: Vasopressin is a potent vasopressor in septic shock, but it may impair splanchnic perfusion. We compared the effects of vasopressin alone and in combination with dobutamine on systemic and splanchnic circulation and metabolism in porcine endotoxin shock. METHODS: Twelve pigs were randomized to receive either vasopressin (VASO, n = 6) or vasopressin in combination with dobutamine (DOBU, n = 6) during endotoxin shock (E. coli endotoxin infusion). Endotoxin infusion rate was increased to induce hypotension after which vasoactive drugs were started. We aimed to keep systemic mean arterial pressure (MAP) >70 mmHg by vasopressin; the goal of dobutamine infusion was to prevent decrease in cardiac output often associated with vasopressin infusion. Regional blood flows, oxygen delivery and consumption, arterial and regional lactate concentrations were measured. RESULTS: Mean arterial pressure >70 mmHg was achieved in both the VASO and DOBU groups. After the primary decrease of cardiac output by vasopressin, systemic blood flow remained stable in vasopressin-treated animals. However, vasopressin as a monotherapy decreased portal venous blood flow. This was prevented by dobutamine. Vasopressin also induced splanchnic lactate release and arterial hyperlactatemia, which were not observed when dobutamine was combined with vasopressin. CONCLUSION: Dobutamine prevents adverse hemodynamic and metabolic effects of vasopressin in septic shock.