Henning D. Stubbe

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

ObjectiveTo 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. DesignProspective controlled trial. SettingUniversity research laboratory. SubjectsSix adult ewes. InterventionsHealthy 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 &mgr;g·kg−1·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·kg−1·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 ResultsHemodynamics 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). ConclusionsDuring 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.

Early multiple organ failure after recurrent endotoxemia in the presence of vasoconstrictor-masked hypovolemia.

ObjectiveCritically ill patients who develop multiple organ failure during systemic inflammatory states are often predisposed to hypovolemia and vasoconstrictor therapy. Although numerous investigations have evaluated the sequelae of systemic inflammation, no data are available on the contribution of chronic vasoconstrictor-masked hypovolemia to organ dysfunction and morphology. DesignProspective, randomized laboratory investigation. SettingUniversity research laboratory. SubjectsEighteen adult chronically instrumented sheep. InterventionsThe animals were randomly assigned to one of three groups. In the norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) group, mean arterial pressures of 80 mm Hg were maintained by using the &agr;1-adrenergic catecholamine norfenefrine for 52 hrs during hypovolemia. Hypovolemia was induced by hemorrhage (about 23 mL·kg−1) until mean arterial pressures reached 40 mm Hg. Endotoxin (0.5 &mgr;g·kg−1) was then injected after 4, 16, 28, and 40 hrs. The NMH group received norfenefrine-masked hypovolemia but no endotoxin. In the ENDO group, recurrent endotoxemia was induced during normovolemia. Measurements and Main ResultsDespite profound differences in fluid management, cardiovascular filling pressures were not statistically different between groups. Endotoxemia induced norfenefrine-refractory shock (p < .05 vs. the other groups) and contributed to renal dysfunction only during vasoconstrictor-masked hypovolemia. Norfenefrine-masked hypovolemia caused disseminated cardiac cell necrosis independent of endotoxemia (p < .05 vs. ENDO). ConclusionsHypovolemia can be masked when volume status is monitored by filling pressures. In this new model of endotoxemia-associated multiple organ failure, chronic vasoconstrictor-masked hypovolemia turned systemic inflammation into a life-threatening condition with renal and cardiovascular failure. Cardiomyocyte necroses were caused by vasoconstrictor-masked hypovolemia but were unrelated to cardiovascular failure.

Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep.

Adrenomedullin (AM) is a vasodilatory peptide hormone, playing a key role in the regulation of cardiovascular homeostasis. In view of the circulatory failure in sepsis, it is still debated as to whether the occurrence of vascular hyporeactivity against AM plays a causative or protective role. This study was designed as a prospective, controlled trial to elucidate the hemodynamic response following a titrating infusion of human AM in healthy and endotoxemic sheep. ANOVA demonstrated that AM infusion produced hypotension and tachycardia, and increased cardiac index in a dose-dependent manner, both in healthy and endotoxemic sheep. In addition, AM application reduced pulmonary vascular resistance index in ovine endotoxemia (P=0.02). These findings confirm that AM produces a hyperdynamic circulation, in the presence and absence of systemic inflammation. Further, exogenous AM could possibly be a useful adjunct in the common setting of sepsis-associated pulmonary hypertension.

Continuous thoracic epidural anesthesia improves gut mucosal microcirculation in rats with sepsis.

Microcirculatory dysfunction contributes significantly to tissue hypoxia and multiple organ failure in sepsis. Ischemia of the gut and intestinal hypoxia are especially relevant for the evolution of sepsis because the mucosal barrier function may be impaired, leading to translocation of bacteria and toxins. Because sympathetic blockade enhances intestinal perfusion under physiologic conditions, we hypothesized that thoracic epidural anesthesia (TEA) may attenuate microcirculatory perturbations during sepsis. The present study was designed as a prospective and controlled laboratory experiment to assess the effects of continuous TEA on the mucosal microcirculation in a cecal ligation and perforation model of sepsis in rats. Anesthetized Sprague-Dawley rats underwent laparotomy and cecal ligation and perforation to induce sepsis. Subsequently, either bupivacaine 0.125% (n = 10) or isotonic sodium chloride solution (n = 9) was continuously infused via the thoracic epidural catheter for 24 h. In addition, a sham laparotomy was carried out in eight animals. Intravital videomicroscopy was then performed on six to ten villi of ileum mucosa. The capillary density was measured as areas encircled by perfused capillaries, that is, intercapillary areas. The TEA accomplished recruitment of microcirculatory units in the intestinal mucosa by decreasing total intercapillary areas (1,317 ± 403 vs. 1,001 ± 236 μm2) and continuously perfused intercapillary areas (1,937 ± 512 vs. 1,311 ± 678 μm2, each P < 0.05). Notably, TEA did not impair systemic hemodynamic variables beyond the changes caused by sepsis itself. Therefore, sympathetic blockade may represent a therapeutic option to treat impaired microcirculation in the gut mucosa resulting from sepsis. Additional studies are warranted to assess the microcirculatory effects of sympathetic blockade on other splanchnic organs in systemic inflammation.

Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia

Since arginine vasopressin (AVP)may reduce cardiacout-put and, in proportion, oxygen delivery, we studied the efficacy of dopexamine (DPX) as an adjunct to AVP infusion. After1 h of continuous AVP infusion (0.04U/min)in healthy sheep(n = 7),DPX was additionally administered in incremental doses (1, 5, and 10 μg · kg−1 · min−1; each dose for 30 min). After a 24-h period of recovery, endotoxin was continuously infused in the same sheep to induce and maintain a hypotensive/hyperdynamic circulation. After 16 h of endotoxemia, AVP and DPX were given as described previously. AVP infusion increase dsystemic vascular resistance index and decreased cardiac index in both healthy and endotoxemic conditions (P < 0.001 each). This was accompanied by an augmented pulmonary vascular resistance index in endotoxemia (159 ± 13 dynes · cm−5 · m−2 versus 202 ± 16 dynes · cm−5 · m−2) and a decrease in oxygen delivery index (health: 842 ± 66 mL · min−2 · m−2 versus 475 ± 38 mL · min−2 · m−2; endotoxemia: 1073 ± 49 mL · min−2 · m−2 versus 613 ± 44 mL · min−2 · m−2) and mixed venous oxygen content (health: 63% ±2% versus 47% ± 2%; endotoxemia: 68% ± 2% versus 51% ± 3%; P < 0.001 each). Small doses of DPX (1 and 5 μg · kg−1 · min−1) improved not only the AVP-associated depressions in cardiac index, oxygen delivery index, and mixed venous oxygen content, but also the pulmonary vasopressive effect in both groups. While large-dose DPX (10 μg · kg−1 · min−1) also reduced mean pulmonary arterial pressure in endotoxemia (27 ± 1 mm Hg versus 23 ± 1 mm Hg; P < 0.05 versus baseline), mean arterial blood pressure decreased (105 ± 4 mm Hg versus 80 ± 3 mm Hg) and heart rate increased (84 ± 4 bpm versus 136 ± 9 bpm; P < 0.001 versus AVP alone), thereby limiting its therapeutic use.

Effects of thoracic epidural anesthesia on hemodynamics and global oxygen transport in ovine endotoxemia.

ABSTRACT Besides providing effective analgesia, thoracic epidural anesthesia (TEA) has been shown to decrease perioperative morbidity and mortality. Because of its vasodilatory properties in association with the sympathetic blockade, however, TEA may potentially aggravate cardiovascular dysfunctions resulting from sepsis and systemic inflammatory response syndrome. The objective of the present study was to assess the effects of TEA on hemodynamics, global oxygen transport, and renal function in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 18), Salmonella typhosa endotoxin was centrally infused at incremental doses to induce and maintain a hypotensive-hypodynamic circulation using an established protocol. The animals were then randomly assigned to one of two groups. In the treatment group, continuous TEA was initiated with 0.1 mL·kg−1 of 0.125% bupivacaine at the onset of endotoxemia and maintained with 0.1 mL·kg−1·h−1. In the control group, the same amount of isotonic sodium chloride solution was injected through the epidural catheter. In the animals surviving the entire experiment (n = 7 per group), cardiac index and mean arterial pressure decreased in a dose-dependent manner during endotoxin infusion. In the TEA group, neither systemic hemodynamics nor global oxygen transport were impaired beyond the changes caused by endotoxemia itself. Urinary output was increased in the TEA group as compared with the control group (P < 0.05). In this model of endotoxic shock, TEA improved renal perfusion without affecting cardiopulmonary hemodynamics and global oxygen transport.

Cerebral response to norepinephrine compared with fluid resuscitation in ovine traumatic brain injury and systemic inflammation.

Objective:Traumatic brain injury is frequently accompanied by a systemic inflammatory response. Systemic inflammation was associated with cerebral hyperperfusion uncoupled to global oxygen metabolism in ovine head trauma. The present study investigated the cerebral effects of cerebral perfusion pressure (CPP) management performed by either fluid resuscitation or vasopressor treatment of low CPP induced by systemic inflammation. Design:Nonrandomized experimental study. Setting:University hospital laboratory. Subjects:A total of 12 adult sheep. Interventions, Measurements, and Main Results:Sheep were anesthetized and ventilated throughout the experimental period (13 hrs). After baseline measurements (hour 0), blunt head trauma was induced by a nonpenetrating stunner. After postinjury measurements (hour 2), all animals received continuous endotoxin infusion. At hour 10, one group (n = 6) was infused with hydroxyethyl starch until CPP reached 60–70 mm Hg. A second group (n = 6) received norepinephrine for CPP elevation. In the norepinephrine group, blood was isovolemically exchanged by hydroxyethyl starch to achieve comparable hematocrit levels. Head trauma increased intracranial pressure and decreased brain tissue oxygen tension. Endotoxemia induced a hyperdynamic cardiovascular response with increased internal carotid blood flow in the presence of systemic hypotension and decreased CPP. Hydroxyethyl starch infusion further increased internal carotid blood flow from (mean ± sd) 247 ± 26 (hour 10) to 342 ± 42 mL/min (hour 13) and intracranial pressure from 20 ± 4 (hour 10) to a maximum of 25 ± 3 mm Hg (hour 12) but did not significantly affect brain tissue oxygen tension, sinus venous oxygen saturation and oxygen extraction fraction. Norepinephrine increased internal carotid blood flow from 268 ± 19 to 342 ± 58 mL/min and intracranial pressure from 22 ± 11 to 24 ± 11 mm Hg (hour 10 vs. hour 13) but significantly increased sinus venous oxygen saturation from 49 ± 4 (hour 10) to a maximum of 59 ± 6 mm Hg (hour 12) and decreased oxygen extraction fraction. The increase in brain tissue oxygen tension during norepinephrine treatment was not significant. Conclusion:We conclude that despite identical carotid blood flows, only CPP management with norepinephrine reduced the cerebral oxygen deficit in this model.

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

IntroductionArginine 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.MethodsTwenty-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.ResultsAVP 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 (SvO2; 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 SvO2 (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.ConclusionThis study provides evidence that dobutamine is a useful agent for reversing the AVP-associated impairment in systemic blood flow and global oxygen transport.

Cerebral vascular and metabolic response to sustained systemic inflammation in ovine traumatic brain injury.

Traumatic brain injury (TBI) is frequently accompanied by a systemic inflammatory response secondary to multiple trauma, shock, or infections. This study investigated the impact of sustained systemic inflammation on cerebral hemodynamics and metabolism in ovine traumatic brain injury. Fifteen sheep were investigated for 14 hours. Head injury was induced with a nonpenetrating stunner in anesthetized, ventilated animals. One group (TBI/Endo, n = 6) subsequently received a continuous endotoxin infusion for 12 hours, whereas a second group (TBI, n = 6) received the carrier. Three instrumented animals served as sham controls. Head impact significantly increased intracranial pressure from 9 ± 4 mm Hg to 21 ± 15 mm Hg (TBI/Endo) and from 10 ± 3 mm Hg to 24 ± 19 mm Hg (TBI) (means ± SD). Internal carotid blood flow increased and cerebral vascular resistance decreased (P < 0.05) during the hyperdynamic inflammatory response between 10 and 14 hours in the TBI/Endo group, whereas these parameters were at baseline level in the TBI group. Intracranial pressure remained unchanged during this period, but increased during hypercapnia. The CMRO2, PaCO2, and arterial hematocrit values were identical among the groups between 10 and 14 hours. It is concluded that chronic endotoxemia in ovine traumatic brain injury was associated with cerebral vasodilation uncoupled from global brain metabolism. Different mechanisms appear to induce cerebral vasodilation in response to inflammation and hypercapnia.

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 (KATP) 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 KATP channel inhibitors. We hypothesized that a continuous infusion of the sulfonylurea glipizide, a KATP 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.