Effects of titrated arginine vasopressin on hemodynamic variables and oxygen transport in healthy and endotoxemic sheep

OBJECTIVE: To determine the effects of titrated arginine vasopressin (AVP) alone or in combination with norepinephrine (NE) on hemodynamics and oxygen transport in healthy and endotoxemic sheep. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six adult ewes. INTERVENTIONS: Healthy sheep received AVP as a titrated infusion, initiated with 0.6 units/hr and increased by 0.6 units/hr every 15 mins, either until mean arterial pressure was increased by 20 mm Hg vs. baseline or a maximum of 3.6 units/hr was administered. After 90 mins, AVP infusion was continued with the investigated dosage, and NE (0.2 microg x kg(-1) x min(-1)) was also infused for 90 mins. After a 24-hr period of recovery, endotoxemia was induced and maintained (Salmonella typhosa endotoxin, 10 ng x kg(-1) x min(-1)) in the same sheep for the next 19 hrs. After 16 hrs of endotoxemia, AVP and NE were administered as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamics were obtained at baseline, every 15 mins during the titration period, and 60 and 90 mins after additional NE infusion. Variables of oxygen transport were calculated before and after the titration period. In healthy and endotoxemic sheep, AVP reduced heart rate and cardiac index (p <.001) and compromised oxygen delivery (p <.001) and oxygen consumption (healthy sheep, p =.003; endotoxemic sheep, p <.001). Vasopressin infusion did not alter mean pulmonary arterial pressure but increased pulmonary vascular resistance index in both groups (p <.001). Additional infusion of NE further augmented mean arterial pressure and increased cardiac index during endotoxemia (p <.001). This was accompanied by an increase in oxygen delivery and consumption (p <.05 each). CONCLUSIONS: During ovine endotoxemia, AVP decreased cardiac index, compromised oxygen delivery, and increased pulmonary vascular resistance index. These side effects may limit its use as a sole vasopressor during sepsis. Potentially, a simultaneous infusion of AVP and NE could represent a useful therapeutic option.     

Terlipressin dose response in healthy and endotoxemic sheep: impact on cardiopulmonary performance and global oxygen transport

OBJECTIVE: To determine whether a goal-directed terlipressin infusion increases mean arterial pressure without causing a pulmonary vasopressive effect and whether this response impacts on key parameters of oxygen transport in healthy and endotoxemic sheep. DESIGN AND SETTING: Prospective controlled trial in a university research laboratory. ANIMALS AND INTERVENTIONS: Six conscious adult ewes instrumented for chronic study received terlipressin as titrated infusion started with 10 microg x kg(-1) x h(-1) and increased by 5 microg x kg(-1) x h(-1) every 15 min, either until mean arterial pressure was increased by 15 mmHg from baseline, or a maximum of 40 microg x kg(-1) x h(-1) was given. Following 24 h of recovery sepsis was induced and maintained in the same ewes by a continuous infusion of endotoxin ( Salmonella typhosa, 10 ng x kg(-1) min(-1)). After 16 h of endotoxemia the sheep were again treated with terlipressin. MEASUREMENTS AND RESULTS: Systemic oxygen delivery and consumption were calculated before and after the titration period; hemodynamic parameters were measured every 15 min. The increase in mean arterial pressure was greater during endotoxemia than in healthy controls. In both states terlipressin administration decreased cardiac index and diminished oxygen delivery and consumption. While mean pulmonary arterial pressure remained constant, terlipressin increased the pulmonary vascular resistance index in endotoxemic sheep. CONCLUSIONS: During ovine endotoxemia titrated terlipressin reversed hypotension but impaired the pulmonary circulation. The observed decrease in oxygen delivery may carry the risk of tissue hypoxia especially in sepsis, where oxygen demand is typically increased.     

Somatostatin infusion increases intestinal ischemia and does not improve vasoconstrictor response to norepinephrine in ovine endotoxemia

Hemodynamic support of patients with septic shock is often complicated by a tachyphylaxis against exogenous catecholamines. Because an increase in somatotropic hormones may play a pivotal role in the regulation of the inflammatory response to endotoxin, intravenous supplementation of the neuroendocrine hormone somatostatin (SOMA) may attenuate hemodynamic dysfunction resulting from endotoxemia. The objective of the present study was to assess the short-term effects of SOMA alone and in combination with norepinephrine (NE) on cardiopulmonary hemodynamics, global oxygen transport, plasma nitrate/nitrite levels, and intestinal integrity compared with single NE therapy in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 16) had been performed, Salmonella typhosa endotoxin was centrally infused (10 ng x kg(-1) x min(-1)) to induce a hypotensive-hyperdynamic circulation using an established protocol. Animals surviving 16 h of endotoxemia were randomly assigned to one of the two groups (each n = 6). Sheep allocated to the SOMA + NE group received SOMA as a loading dose of 10.5 microg x kg(-1) x min(-1) for 1 h, followed by a continuous infusion of 3.5 microg x kg(-1) x min(-1) for the next 2 h. After the SOMA loading dose had been given, NE was concurrently infused (0.3 microg x kg(-1) x min(-1)) for 2 h. In the NE group (control), NE (0.3 microg x kg(-1) x min(-1)) was continuously infused for 3 h. Endotoxemia caused a decrease in MAP and systemic vascular resistance index in both groups, but to a greater extent in the NE group. Arterial hypotension persisted despite administration of the study drugs. Infusion of SOMA alone and in combination with NE did not significantly increase systemic vascular resistance index. Neither SOMA nor NE infusion alone affected pulmonary vasoregulation. Plasma nitrate/nitrite levels did not differ between groups. However, combined infusion of SOMA and NE significantly increased arterial lactate concentrations, oxygen consumption index, and oxygen extraction rate (P < 0.05) and aggravated ileal mucosal injury. In conclusion, short-term treatment with SOMA failed to attenuate cardiocirculatory shock resulting from endotoxemia and did not improve vasopressor response to NE. In addition, combined SOMA and NE therapy resulted in intestinal injury. Therefore, SOMA does not seem to represent a therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome.     

Hemodynamic effects of terlipressin (a synthetic analog of vasopressin) in healthy and endotoxemic sheep

OBJECTIVE: Hypotension, vasodilation, and vasoplegia are characteristic signs of septic shock. The vasoconstrictive response to catecholamines typically is reduced. A decreased vasopressive effect of catecholamines can be observed in the late phase of hemorrhagic shock. Interestingly, an unaltered vasopressive response to vasopressin can be demonstrated in hemorrhagic shock. In this study, we investigated the vasoconstrictive response to an agonist of the vasopressin receptor, terlipressin, in healthy sheep as well as in ovine hyperdynamic endotoxemia. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six female adult sheep. INTERVENTIONS: Healthy sheep, instrumented for chronic study, received terlipressin (15 microg/kg) as a bolus; 30 mins later, norepinephrine was continuously given for 30 mins. Three hours later, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng x kg(-1) x min(-1)) was started in the same sheep and given for the next 23 hrs. After 20 hrs of endotoxemia, terlipressin and norepinephrine were given as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were measured before and 30 mins after application of terlipressin and after 30 mins of continuous infusion of norepinephrine. Terlipressin significantly increased systemic vascular resistance index in healthy and endotoxemic sheep (p <.05). The increase was higher in endotoxemic compared with healthy animals (p <.05). Only during endotoxemia, terlipressin increased pulmonary vascular resistance index. This was accompanied by a significant decrease in cardiac index, whereas mean pulmonary arterial pressure did not change after application of terlipressin. Additional treatment with norepinephrine did not further increase systemic vascular resistance index or pulmonary vascular resistance index. CONCLUSIONS: Terlipressin reversed the hemodynamic changes in ovine endotoxemia. However, its pulmonary vasopressive effect might limit its therapeutic use in septic shock.     

Continuous versus bolus infusion of terlipressin in ovine endotoxemia

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng.kg-1.min-1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.     

Continuously infused glipizide reverses the hyperdynamic circulation in ovine endotoxemia

In advanced sepsis, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Although activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, previous studies demonstrated only a transient increase in mean arterial pressure (MAP) after bolus administration of K(ATP) channel inhibitors. We hypothesized that a continuous infusion of the sulfonylurea glipizide, a K(ATP) channel inhibitor, may reverse cardiovascular dysfunctions in sepsis permanently. Eighteen adult sheep were instrumented for chronic study. After a baseline measurement in healthy ewes, endotoxin (Salmonella typhosa, 10 ng kg(-1) min(-1)) was continuously infused for 19 h. After 16 h of endotoxemia, the surviving sheep (n = 14) were randomly assigned to be treated with either glipizide (5 mg/kg, followed by a continuous infusion of 8 mg kg(-1) h(-1)) or placebo (normal saline; each n = 7). Measurements of cardiopulmonary hemodynamics, global oxygen transport, acid-base status, and urine output were performed in the healthy state, after 16 h of endotoxemia, and during 3 h of glipizide infusion. Continuous infusion of glipizide reversed the endotoxin-induced hyperdynamic circulation, as indicated by significant increases in MAP and systemic vascular resistance index, as well as decreases in cardiac index and heart rate (P < 0.001 each). In addition, glipizide increased urine output as compared with untreated controls (P < 0.001). The anticipated decrease in glucose plasma levels was prevented by infusion of glucose 5%. From these results, we conclude that continuous glipizide infusion may represent a useful therapeutic option in the treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.     

Short-term effects of glipizide (an adenosine triphosphate-sensitive potassium channel inhibitor) on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep

In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific K(ATP) channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to elucidate the short-term effects of glipizide, a specific K(ATP) channel inhibitor, on cardiopulmonary hemodynamics and global oxygen transport in healthy sheep and sheep with endotoxemia. Ten adult ewes were anesthetized and operatively instrumented with a pulmonary artery, a femoral artery, and a foley catheter. After 24 h of recovery, healthy sheep received glipizide as a bolus infusion (4 mg/kg over 15 min). After 24 h of recovery, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng.kg.(-1)min) was started in the same sheep and administered for the next 17 h. After 16 h of endotoxemia, glipizide was given as described above. Administration of glipizide was followed by a transient, but significant, increase in mean arterial pressure in both healthy controls (95 +/- 3 mmHg vs. 101 +/- 2 mmHg, P < 0.05) and sheep with endotoxemia (86 +/- 3 mmHg vs. 93 +/- 3 mmHg, P < 0.05). However, the increase in mean arterial pressure was longer lasting in ewes with endotoxemia. Cardiac index, oxygen delivery index, arterial lactate concentrations, and arterial pH were not significantly affected by glipizide. Therefore, administration of glipizide may represent a beneficial therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome. Additional studies are required to determine the effects of continuous infusion of glipizide in the presence of systemic inflammation.     

Dobutamine reverses the vasopressin-associated impairment in cardiac index and systemic oxygen supply in ovine endotoxemia

Introduction

Arginine vasopressin (AVP) is increasingly used to treat sepsis-related vasodilation and to decrease catecholamine requirements. However, AVP infusion may be associated with a marked decrease in systemic blood flow and oxygen transport. The purpose of the present study was to evaluate whether dobutamine may be titrated to reverse the AVP-related decrease in cardiac index (CI) and systemic oxygen delivery index (DO₂I) in an established model of ovine endotoxemia.

Methods

Twenty-four adult ewes were chronically instrumented to determine cardiopulmonary hemodynamics and global oxygen transport. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation and death of five sheep. After 16 hours of endotoxemia, the surviving ewes (n = 19; weight 35.6 ± 1.5 kg (mean ± SEM)) were randomized to receive either AVP (0.04 Umin^-1) and dobutamine (n = 8) or the vehicle (normal saline; n = 6) and compared with a third group treated with AVP infusion alone (n = 5). Dobutamine infusion was started at an initial rate of 2 μg kg^-1min^-1 and was increased to 5 and 10 μg kg^-1 min^-1 after 30 and 60 minutes, respectively.

Results

AVP infusion increased mean arterial pressure (MAP) and systemic vascular resistance index at the expense of a markedly decreased CI (4.1 ± 0.5 versus 8.2 ± 0.3 l min^-1 m^-2), DO₂I (577 ± 68 versus 1,150 ± 50 ml min^-1 m^-2) and mixed-venous oxygen saturation (S_vO₂; 54.5 ± 1.8% versus 69.4 ± 1.0%; all p < 0.001 versus control). Dobutamine dose-dependently reversed the decrease in CI (8.8 ± 0.7 l min^-1 m^-2 versus 4.4 ± 0.5 l min^-1 m^-2), DO₂I (1323 ± 102 versus 633 ± 61 ml min^-1 m^-2) and S_vO₂ (72.2 ± 1.7% versus 56.5 ± 2.0%, all p < 0.001 at dobutamine 10 μg kg^-1 min^-1 versus AVP group) and further increased MAP.

Conclusion

This study provides evidence that dobutamine is a useful agent for reversing the AVP-associated impairment in systemic blood flow and global oxygen transport.     

Employing dobutamine as a useful agent to reverse the terlipressin-linked impairments in cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep

Although arginine vasopressin and terlipressin have been identified as useful nonadrenergic agents to increase systemic blood pressure in catchecholamine-resistant septic shock, the impairments in cardiac index (CI) and global oxygen transport may limit their clinical applicability. The present study was designed as a prospective controlled laboratory experiment to investigate the effects of dobutamine as an adjunct to terlipressin infusion on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. Nine adult ewes were instrumented for chronic study using an established protocol. After a baseline measurement in the healthy state had been performed, 1 mg terlipressin was given as bolus infusion. Thirty minutes later, dobutamine was continuously infused at incremental doses (2 and 5 microg x kg(1) x min(1), each for 1 h). After 24 h of recovery, a hypotensive-hyperdynamic circulation was induced and maintained by a continuous infusion of Salmonella typhosa endotoxin (10 ng x kg(1) x min(1)). After 16 h of endotoxemia, the six surviving sheep received terlipressin and dobutamine according to the same protocol that was used in healthy sheep. Compared with baseline, terlipressin infusion was associated with a significant increase in MAP that, however, occurred at the expense of a compromised CI, oxygen delivery index (DO(2)I), and mixed venous oxygen saturation (SvO(2), each P < 0.05). Dobutamine infusion was followed by a dose-dependent increase in CI, DO(2)I, and SvO(2) in both health and endotoxemia (each P < 0.05). Although the higher dosage of dobutamine exerted favorable effects, such as a decrease in pulmonary vascular resistance index (P < 0.05), the associated onset of tachycardia (P < 0.05) and arterial hypotension (P < 0.05) may limit its therapeutic use under septic conditions. This study provides evidence that dobutamine in a dosage of 2 microg x kg(1) x min(1) is useful to reverse the terlipressin-linked depressions in CI, DO(2)I and SvO(2) in ovine endotoxemia without obvious side effects.     

Arginine vasopressin in 316 patients with advanced vasodilatory shock

OBJECTIVE: To assess the effects of arginine vasopressin (AVP) on hemodynamic, clinical, and laboratory variables and to determine its adverse side effects in advanced vasodilatory shock. DESIGN: Retrospective study. PATIENTS: A total of 316 patients. INTERVENTIONS: AVP infusion (4 units/hr). MEASUREMENTS AND MAIN RESULTS: Cardiocirculatory, laboratory, and clinical variables were evaluated before, 0.5, 1, 4, 12, 24, 48, and 72 hrs after administration of AVP. AVP increased mean arterial pressure, systemic vascular resistance, and stroke volume index. Heart rate, central venous pressure, mean pulmonary arterial pressure, norepinephrine, milrinone, and epinephrine requirements decreased. There was no difference in the hemodynamic response between patients with septic shock, postcardiotomy shock, or systemic inflammatory response syndrome. Cardiac index decreased in 41.1% of patients during AVP treatment. In patients with hyperdynamic circulation before AVP, cardiac index decreased, whereas it remained uncharged or tended to increase in patients with normodynamic or hypodynamic circulation. During the course of AVP treatment, liver enzymes (28.5% of patients) and total bilirubin concentrations (69.3% of patients) increased, whereas platelet count decreased (73.4% of patients). Simultaneous hemofiltration significantly contributed to the decrease in platelet count (p < .001) and increase in bilirubin (p < .001). Whereas patients with an increase in bilirubin were more likely to die, a decrease in cardiac index or platelet count and an increase in liver enzymes did not affect mortality. Systemic inflammatory response syndrome as admission diagnosis, a high degree of multiple organ dysfunction, and norepinephrine requirements of >0.5 microg x kg x min before AVP treatment were independent risk factors for death from advanced vasodilatory shock treated with AVP. If norepinephrine dosages exceeded 0.6 microg x kg x min before AVP treatment, a substantial increase in mortality occurred. CONCLUSIONS: Supplementary AVP infusion improved cardiocirculatory function in advanced vasodilatory shock, but an increase in liver enzymes and bilirubin, and a decrease in platelet count occurred during AVP therapy, particularly during simultaneous hemofiltration. Initiation of AVP infusion before norepinephrine requirements exceeding 0.6 microg x kg x min may improve outcome.     

Vasopressin-mediated forearm vasodilation in normal humans. Evidence for a vascular vasopressin V2 receptor.

Arginine vasopressin (AVP) is a potent vasopressor and antidiuretic neurohormone. However, when administered intravenously to humans, AVP causes forearm vasodilation. This effect has been attributed to sympathetic withdrawal, secondary to AVP-induced sensitization of baroreceptors. The possibility that AVP also causes forearm vasodilation directly has not been examined. Accordingly, the direct effect of AVP was determined by studying the forearm blood flow (FBF) response to intraarterial (IA) AVP infusion (0.01-1.0 ng/kg per min). Infusion of IA AVP increased FBF (96%) in the infused arm, but not the control arm, in a dose-dependent manner. The role of specific AVP V1 receptors in mediating this FBF response was determined before and after pretreatment with a V1 antagonist (AVP-A). AVP-A alone had no effect on FBF, but coadministration of AVP and AVP-A potentiated the vasodilatory response (223%). IA infusion of the V2 agonist, 1-desamino[8-D-arginine] vasopressin, caused a dose-dependent increase in FBF. These findings suggest that AVP causes direct, dose-dependent vasodilation in the human forearm that may be mediated by V2 vasopressinergic receptors. In contrast, AVP infusion caused digital vasoconstriction that was blocked by AVP-A, whereas dDAVP did not affect digital blood flow. Thus, AVP induces regionally selective vascular effects, with concurrent forearm vasodilation and digital vasoconstriction.     

Effects of continuous vasopressin infusion in patients with septic shock

BACKGROUND: Small studies have reported that vasopressin improves hemodynamic instability in patients with septic shock. OBJECTIVE: To determine whether vasopressin infusion increases blood pressure, decreases catecholamine vasopressor use, and improves renal function in a large patient population with septic shock when used in a clinical setting. METHODS: A retrospective chart audit was conducted of critically ill patients who received vasopressin infusion for septic shock from January 2000 through September 2002. Demographic, hemodynamic, laboratory, vasopressor, and adverse event data were collected. Statistical methods included ANOVA with Tukey's test for post hoc analysis. RESULTS: A total of 102 of 353 patients met study criteria. The mean +/- SD vasopressin dosage regimen was 0.11 +/- 0.17 units/min for 53.8 +/- 71.5 hours. Compared with baseline, vasopressin infusion improved mean arterial pressure (MAP) by 15% within one hour (p < 0.05), reduced heart rate by 9% within 4 hours (p < 0.05), and reduced hourly dopamine dosage by 25% within 8 hours (p < 0.05). These effects persisted through 96 hours. Other hemodynamic variables and catecholamine vasopressor usage parameters were not statistically different from baseline. Urine output, serum creatinine, and serum sodium concentrations were not statistically changed from baseline. Adverse events possibly associated with vasopressin infusion included ischemic digits/extremities, myocardial infarction, and hyponatremia. CONCLUSIONS: Vasopressin infusion was effective in increasing MAP and reducing heart rate while decreasing the dopamine dosage in patients with septic shock. Comparative studies with catecholamine vasopressors are needed to define the optimal role of vasopressin in septic shock therapy. In the meantime, vasopressin infusion at 相似文献   

Transient polyuria in pregnancy in diabetes insipidus and gestational diabetes]

Two pregnant women developed overt polyuria (up to 11 l/day) and polydipsia during their second and third trimesters of pregnancy. In one patient hydronephrosis was present. Both patients suffered from mild gestational diabetes mellitus. Plasma sodium was 145 and 162 mmol/l. Polyuria and urinary hypo-osmolality responded well to desmopressin acetate. After delivery, polyuria and polydipsia disappeared in one patient and significantly improved in the other. Infusion of hypertonic saline one and two weeks respectively after delivery led to plasma hyper-osmolality (294 mosmol/kg and 305 mosmol/kg) without detectable stimulation of arginine vasopressin (AVP). Anterior pituitary function was normal. No stimulation of AVP occurred following insulin-induced hypoglycemia. AVP plasma disappearance after i.v. pulse injection of 1 microgram AVP as well as AVP plasma concentration after continuous infusion of 10 ng AVP/min was studied two weeks after delivery in one patient. The results suggested markedly elevated degradation of AVP compared to control subjects, probably due to an increased vasopressin activity. Eight months after delivery, hypertonic saline infusion in one patient led to a plasma-osmolality of 312 mosmol/kg without stimulation of AVP. In the second patient, AVP was not detectable (less than 0.2 pg/ml) six months after delivery when plasma osmolality was 290 mosmol/kg. Our studies demonstrate that a subclinical compensated diabetes insipidus was preexistent in both patients. Exacerbation occurred due to an increased AVP-clearance and presumably due to the hemodynamic and hormonal alterations during pregnancy, including a mild gestational diabetes mellitus.     

Use of Vasopressin in a Canine Model of Severe Verapamil Poisoning: A Preliminary Descriptive Study

OBJECTIVES: The purpose of this preliminary study was to evaluate the effect of arginine vasopressin (AVP) administration in a model of shock induced by calcium channel antagonist overdose and to determine endogenous serum AVP concentrations in calcium channel antagonist-induced shock. METHODS: This was a controlled, randomized laboratory investigation based on a previously described canine model of verapamil toxicity. After induction of verapamil toxicity, animals in both the control and the experimental groups (n = 6 each) received a continuous infusion of verapamil. Experimental animals received an escalating dose of AVP, while control animals received an equal volume of 0.9% saline infusion. The hemodynamic end point was return of mean arterial pressure (MAP) to within 20% of baseline. Surviving animals were killed after 60 minutes. RESULTS: In the treatment group, administration of low-dose AVP (4 mU/kg/min) resulted in further declines in cardiac index and heart rate. No significant change was noted in MAP with low-dose AVP. A slight increase in MAP was noted with both escalating doses of AVP and equivalent volumes of normal saline. By the end of the 60-minute antidote/saline phase, the MAPs of the saline control group and the AVP experimental group were similar. The primary hemodynamic end point was not achieved in either the AVP or the saline control arm. Mean baseline serum AVP concentration in control animals was 5.8 pg/mL, increasing to 225 pg/mL during the toxicity phase. CONCLUSIONS: In an animal model of verapamil-induced shock, endogenous AVP levels increased nearly 40-fold compared with baseline levels. Escalating doses of exogenous AVP worsened cardiac index and failed to return MAP to within 20% of baseline.     

Vascular hyporesponsiveness of the renal circulation during endotoxemia in anesthetized pigs

OBJECTIVE: To compare the vascular reactivity of the renal circulation in control and septic conditions. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Anesthetized pigs (n = 17). INTERVENTIONS: Ten pigs received a continuous intravenous infusion of endotoxin from Escherichia coli (160 ng x kg(-1) x hr(-1)) during 18 hrs, whereas seven control animals received a saline infusion. To test the vascular reactivity, norepinephrine (NE) (1 microg x kg(-1)), acetylcholine (10 microg x kg(-1)), and sodium nitroprusside (10 microg x kg(-1)) were intravenously injected for 20 secs and changes of mean arterial pressure and renal blood flow were observed during the 200 secs after the drug administration. To compare the evolution of the vascular reactivity over time, three tests were performed 5 hrs, 11 hrs, and 17 hrs after initial endotoxin or saline administration. MEASUREMENTS AND MAIN RESULTS: Endotoxin infusion induced a hypotensive and hypokinetic syndrome with renal hypoperfusion. The mean arterial pressure increase after NE injection and the mean arterial pressure decrease after acetylcholine and nitroprusside were lower in endotoxin than in control pigs. In the renal circulation, the increase of resistance after NE injection and the decrease of renal resistance after acetylcholine and nitroprusside injections were lower in endotoxin than in control pigs. CONCLUSIONS: This study shows a hyporesponsiveness of the renal circulation to vasoactive agents during endotoxemia. Vasoconstriction to NE, endothelium-dependent as well as endothelium-independent relaxations are altered during endotoxemia but not abolished, and despite the continuous infusion of endotoxin for 18 hrs, no recovery was observed over time.     

Nicotinamide increases systemic vascular resistance in ovine endotoxemia

OBJECTIVE: The nuclear enzyme Poly(ADP-Ribose)-Polymerase (PARP) has been hypothesized as playing a major role in various forms of inflammation. PARP activation is induced by DNA strand breakage and can result in intracellular energy depletion and, ultimately, cell death. Further, it is thought to influence cardiovascular function and organ failure in endotoxemia. Here, we investigated the effect of the PARP inhibitor nicotinamide on cardiovascular and liver function in healthy and chronically endotoxemic sheep. DESIGN: Prospective controlled trial. SETTING: University research laboratory. Subjects: 12 female adult sheep. INTERVENTIONS: Six healthy sheep, instrumented for chronic study, received nicotinamide intravenously as a bolus of 40 mg/kg followed by a continuous infusion of 10 mg.kg(-1).h(-1); six animals received the vehicle. One hour after bolus application, a continuous infusion of endotoxin ( Salmonella typhosa, 10 ng.kg(-1).min(-1)) was started. Hemodynamic parameters were determined before and during endotoxemia. MEASUREMENTS AND RESULTS: Treatment with nicotinamide resulted in a significantly higher systemic vascular resistance index and lower cardiac index in endotoxemic animals, but not in controls. It also attenuated endotoxin-induced increase in gamma-glutamyl transferase. CONCLUSIONS: The PARP inhibitor nicotinamide attenuates impairment of cardiovascular function during endotoxemia. In addition, PARP activation may be involved in endotoxin-induced liver injury.     

Bench-to-bedside review: Vasopressin in the management of septic shock

This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 μg/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care--or septic shock--and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 μg/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study.     

Intravenous arginine vasopressin in critically ill children: is it beneficial?

Arginine-vasopressin (AVP) may be more effective than epinephrine in shock states and as an end-of-life salvage maneuver. However, there is only limited experience using AVP in children. Our study aim was to evaluate the effect of AVP administration on hemodynamic and ventilatory parameters in critically ill children. Eight critically ill children (1 month to 12 years old) were treated with AVP during the years 2000-2001. Two patients had had head trauma, and six had surgical correction of congenital heart disease. All patients suffered severe septic or cardiogenic shock with a low cardiac output state and were considered to be near death. AVP was administered continuously at a dose of 0.0003-0.002 U/kg/min. Hemodynamic and ventilatory parameters and vasopressor doses were compared before and after AVP initiation. One patient survived with a good neurologic outcome. Seven patients succumbed while receiving AVP. Systolic and diastolic blood pressure increased significantly (P < 0.03) following AVP initiation. The epinephrine requirement decreased from 2.3 to 1.7 microg/kg/min. Blood gases improved with a significant (P < 0.05) increase of PaO2. Oxygenation index and PaO2/FiO2 ratio improved significantly, and ventilatory support requirements and positive inspiratory pressure (PIP) decreased significantly. Despite a significant improvement in hemodynamic and ventilatory support parameters, survival to hospital discharge was not achieved when AVP was used in critically ill pediatric patients. We hypothesize that earlier administration of AVP may be more beneficial.     

Beneficial effects of low-dose prostacyclin on cat intestinal perfusion during endotoxemia as evaluated with microdialysis and oxygen transport variables

OBJECTIVE: To evaluate the effects of low-dose prostacyclin on intestinal perfusion during endotoxemia. DESIGN: A randomized, blinded experimental study. SETTING: A university laboratory. SUBJECTS: Sixteen anesthetized cats. INTERVENTIONS: The animals received endotoxin by continuous intravenous infusion (0.5 mg/kg plus 0.5 mg x kg(-1) x hr(-1)) and a continuous volume replacement throughout the experiment. Four hours after the start of endotoxin, the animals were randomized to receive an infusion of either prostacyclin at a dose of 1 ng x kg(-1) x min(-1) (prostacyclin group) or vehicle (control group) during the next 4 hrs. MEASUREMENTS AND MAIN RESULTS: Intestinal vascular resistance was calculated from systemic arterial pressure, central venous pressure, and superior mesenteric artery blood flow, and intestinal oxygen delivery and uptake were calculated from superior mesenteric artery and vein blood samples and blood flow. Interstitial lactate, pyruvate, glucose, and glycerol in the ileal wall were measured by using microdialysis. There were no differences in baseline values between the groups. Systemic blood pressure decreased initially but recovered and remained stable in both groups. In the control group, intestinal vascular resistance increased from 10.9 +/- 1.0 to 24.7 +/- 5.3 mm Hg x mL x min(-1) x kg(-1) (p <.05) at 8 hrs, and oxygen delivery decreased from 2.6 +/- 0.2 to 1.3 +/- 0.3 mL x min(-1) x kg(-1) (p <.05). Simultaneously, microdialysis lactate increased from 1.6 +/- 0.1 to 3.6 +/- 0.5 mmol/L (p <.05) with concomitant pyruvate increase and unchanged lactate/pyruvate ratio. Blood lactate increased and pH decreased. In the prostacyclin group at 8 hrs, intestinal vascular resistance of 6.9 +/- 0.8 mm Hg x mL x min(-1) x kg(-1) was lower and intestinal oxygen delivery of 3.2 +/- 0.3 was higher (p <.05) than in the control group at 8 hrs. Intestinal oxygen uptake of 0.54 +/- 0.10 mL x min(-1) x kg(-1) was higher than in the control group, in which oxygen uptake was 0.26 +/- 0.04 mL x min(-1) x kg(-1). Lactate, pyruvate, and pH were normalized at 8 hrs in the prostacyclin group. CONCLUSION: Low-dose prostacyclin has beneficial effects on small intestinal perfusion during endotoxemia in this experimental cat model.     

The effect of a thyroid hormone infusion on vasopressor support in critically ill children with cessation of neurologic function

OBJECTIVE: To determine the impact of a thyroid hormone infusion (T4) on the vasopressor requirements in children with cessation of neurologic function (i.e., brain death) during evaluation for organ recovery DESIGN: Retrospective cohort study. SETTING: The 1998-2002 database of a regional organ recovery program. PATIENTS: Children 相似文献