Global Oxygen Transport Research Articles

Comparison Between Two Pharmacologic Strategies to Alleviate Rewarming Shock: Vasodilation vs. Inodilation.

Rewarming from hypothermia is often challenged by coexisting cardiac dysfunction, depressed organ blood flow (OBF), and increased systemic vascular resistance. Previous research shows cardiovascular inotropic support and vasodilation during rewarming to elevate cardiac output (CO). The present study aims to compare the effects of inodilatation by levosimendan (LS) and vasodilation by nitroprusside (SNP) on OBF and global oxygen transport during rewarming from hypothermia. We used an in vivo experimental rat model of 4 h 15°C hypothermia and rewarming. A stable isotope-labeled microsphere technique was used to determine OBF. Cardiac and arterial pressures were monitored with fluid-filled pressure catheters, and CO was measured by thermodilution. Two groups were treated with either LS (n = 7) or SNP (n = 7) during the last hour of hypothermia and throughout rewarming. Two groups served as hypothermic (n = 7) and normothermic (n = 6) controls. All hypothermia groups had significantly reduced CO, oxygen delivery, and OBF after rewarming compared to their baseline values. After rewarming, LS had elevated CO significantly more than SNP (66.57 ± 5.6/+30% vs. 54.48 ± 5.2/+14%) compared to the control group (47.22 ± 3.9), but their ability to cause elevation of brain blood flow (BBF) was the same (0.554 ± 0.180/+81 vs. 0.535 ± 0.208/+75%) compared to the control group (0.305 ± 0.101). We interpret the vasodilator properties of LS and SNP to be the primary source to increase organ blood flow, superior to the increase in CO.

Study of the Effects of 3 h of Continuous Cardiopulmonary Resuscitation at 27°C on Global Oxygen Transport and Organ Blood Flow.

AimsComplete restitution of neurologic function after 6 h of pre-hospital resuscitation and in-hospital rewarming has been reported in accidental hypothermia patients with cardiac arrest (CA). However, the level of restitution of circulatory function during long-lasting hypothermic cardiopulmonary resuscitation (CPR) remains largely unknown. We compared the effects of CPR in replacing spontaneous circulation during 3 h at 27°C vs. 45 min at normothermia by determining hemodynamics, global oxygen transport (DO2), oxygen uptake (VO2), and organ blood flow.MethodsAnesthetized pigs (n = 7) were immersion cooled to CA at 27°C. Predetermined variables were compared: (1) Before cooling, during cooling to 27°C with spontaneous circulation, after CA and subsequent continuous CPR (n = 7), vs. (2) before CA and during 45 min CPR in normothermic pigs (n = 4).ResultsWhen compared to corresponding values during spontaneous circulation at 38°C: (1) After 15 min of CPR at 27°C, cardiac output (CO) was reduced by 74%, mean arterial pressure (MAP) by 63%, DO2 by 47%, but organ blood flow was unaltered. Continuous CPR for 3 h maintained these variables largely unaltered except for significant reduction in blood flow to the heart and brain after 3 h, to the kidneys after 1 h, to the liver after 2 h, and to the stomach and small intestine after 3 h. (2) After normothermic CPR for 15 min, CO was reduced by 71%, MAP by 54%, and DO2 by 63%. After 45 min, hemodynamic function had deteriorated significantly, organ blood flow was undetectable, serum lactate increased by a factor of 12, and mixed venous O2 content was reduced to 18%.ConclusionThe level to which CPR can replace CO and MAP during spontaneous circulation at normothermia was not affected by reduction in core temperature in our setting. Compared to spontaneous circulation at normothermia, 3 h of continuous resuscitation at 27°C provided limited but sufficient O2 delivery to maintain aerobic metabolism. This fundamental new knowledge is important in that it encourages early and continuous CPR in accidental hypothermia victims during evacuation and transport.

Cystathionine-γ-lyase (CSE) deficiency increases erythropoiesis and promotes mitochondrial electron transport via the upregulation of coproporphyrinogen III oxidase and consequent stimulation of heme biosynthesis

BackgroundHydrogen sulfide (H2S) is an endogenous gasotransmitter produced by mammalian cells. The current study investigated the potential role of H2S in the regulation of heme biosynthesis using mice deficient in cystathionine gamma-lyase (CSE), one of the three major mammalian H2S-producing enzymes. MethodsWild-type and global CSE−/− mice, as well as mitochondria prepared from their liver were used. In vivo, arterial and venous blood gases were measured, and survival of the mice to severe global hypoxia was monitored. Ex vivo, expression of various heme biosynthetic enzymes including coproporphyrinogen oxidase (CPOX) was measured, and mitochondrial function was evaluated using Extracellular Flux Analysis. Urine samples were collected to measure the oxidized porphyrinogen intermediates. The in vivo/ex vivo studies were complemented with mitochondrial bioenergetic studies in hepatocytes in vitro. Moreover, the potential effect of H2S on the CPOX promoter was studied in cells expressing a CPOX promoter construct system. ResultsThe main findings are as follows: (1) CSE−/− mice exhibit elevated red blood cell counts and red blood cell mean corpuscular volumes compared to wild-type mice; (2) these changes are associated with elevated plasma and liver heme levels and (3) these alterations are likely due to an induction of CPOX (the sixth enzyme involved in heme biosynthesis) in CSE−/− mice. (4) Based on in vitro promoter data the promoter activation of CPOX is directly influenced by H2S, the product of CSE. With respect to the potential functional relevance of these findings, (5) the increased circulating red blood cell numbers do not correspond to any detectable alterations in blood gas parameters under resting conditions, (6) nor do they affect the hypoxia tolerance of the animals in an acute severe hypoxia model. However, there may be a functional interaction between the CSE system and the CPOX system in terms of mitochondrial bioenergetics: (7) CSE−/− hepatocytes and mitochondria isolated from them exhibit increased oxidative phosphorylation parameters, and (8) this increase is partially blunted after CPOX silencing. Although heme is essential for the biosynthesis of mitochondrial electron chain complexes, and CPOX is required for heme biosynthesis, (9) the observed functional mitochondrial alterations are not associated with detectable changes in mitochondrial electron transport chain protein expression. ConclusionsThe CSE system regulates the expression of CPOX and consequent heme synthesis. These effects in turn, do not influence global oxygen transport parameters, but may regulate mitochondrial electron transport.

A pseudo-three-dimensional model for quantification of oxygen diffusion from preglomerular arteries to renal tissue and renal venous blood.

To assess the physiological significance of arterial-to-venous (AV) oxygen shunting, we generated a new pseudo-three-dimensional computational model of oxygen diffusion from intrarenal arteries to cortical tissue and veins. The model combines the 11 branching levels (known as "Strahler" orders) of the preglomerular renal vasculature in the rat, with an analysis of an extensive data set obtained using light microscopy to estimate oxygen mass transfer coefficients for each Strahler order. Furthermore, the AV shunting model is now set within a global oxygen transport model that includes transport from arteries, glomeruli, peritubular capillaries, and veins to tissue. While a number of lines of evidence suggest AV shunting is significant, most importantly, our AV oxygen shunting model predicts AV shunting is small under normal physiological conditions (~0.9% of total renal oxygen delivery; range 0.4-1.4%), but increases during renal ischemia, glomerular hyperfiltration (~2.1% of total renal oxygen delivery; range 0.84-3.36%), and some cardiovascular disease states (~3.0% of total renal oxygen delivery; range 1.2-4.8%). Under normal physiological conditions, blood Po2 is predicted to fall by ~16 mmHg from the root of the renal artery to glomerular entry, with AV oxygen shunting contributing ~40% and oxygen diffusion from arteries to tissue contributing ~60% of this decline. Arterial Po2 is predicted to fall most rapidly from Strahler order 4, under normal physiological conditions. We conclude that AV oxygen shunting normally has only a small impact on renal oxygenation, but may exacerbate renal hypoxia during renal ischemia, hyperfiltration, and some cardiovascular disease states.

Moderate-dose Vasopressin Therapy May Impair Gastric Mucosal Perfusion in Severe Sepsis

The effects of moderate-dose vasopressin on gastric mucosal perfusion and its relation to global and hepatosplanchnic hemodynamic and oxygen transport variables were investigated in patients with severe sepsis. Vasopressin was administered at a dose of 0.04 IU · kg⁻¹ · h⁻¹ over 4 h in 12 patients with severe sepsis who were receiving norepinephrine. During the study period, the norepinephrine infusion rate was reduced to keep mean arterial blood pressure constant. Hepatosplanchnic blood flow, oxygen delivery, and oxygen consumption (via hepatic venous catheterization using the Fick principle and continuous indocyanine green infusion technique), global hemodynamics (transpulmonary thermodilution method), and the difference between the gastric mucosal and arterial carbon dioxide tension (Pco₂-gap) were measured at baseline and 4 h after the start of the vasopressin infusion. The administration of 0.04 IU · kg⁻¹ · h⁻¹ vasopressin over 4 h was associated with minimal changes in global hemodynamics. Heart rate decreased slightly from 99 [81-115] (median [interquartile range]) to 96 [74-109] beats/min (P = 0.016) and cardiac index from 3.7 [2.8-4.7] to 3.5 [2.7-3.6] L · min⁻¹ · m⁻² (P = 0.003). Global oxygen delivery index decreased significantly from 461 [375-637] to 419 [352-551] ml · min⁻¹ · m⁻² (P = 0.002), whereas hepatosplanchnic blood flow and oxygen uptake remained unchanged. Gastric mucosal Pco₂-gap increased significantly from 13.3 [8.0-16.7] to 17.1 [10.3-28.7] mmHg (P = 0.002), suggesting that blood flow may have been redistributed away from the gut mucosa. Vasopressin at a dosage of 0.04 IU · kg⁻¹ · h⁻¹ may impair gastric mucosal perfusion with minimal global hemodynamic effects.

Role of selective V1a receptor agonism in ovine septic shock*

The vasopressor effect of arginine vasopressin, a mixed V1a/V2 receptor (V1aR/V2R) agonist, is mediated through the V1aR. Because V2R stimulation may aggravate sepsis-induced vasodilation, fluid accumulation, and microvascular thrombosis, a higher V1aR vs. V2R selectivity might be advantageous. The objective of this study was to elucidate the effects of a first-line therapy with the selective V1aR agonist Phe2-Orn8-Vasotocin vs. arginine vasopressin or norepinephrine on cardiopulmonary hemodynamics and organ function in ovine septic shock. Randomized controlled laboratory experiment. University animal research facility. : Twenty-four chronically instrumented sheep. After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with Phe2-Orn8-Vasotocin (0.05 μg·kg·h), arginine vasopressin (0.05 μg·kg·h), or normal saline (each n = 8). In all groups, open-label norepinephrine was additionally titrated up to 1 μg·kg·min to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary. Compared with single norepinephrine therapy, the selective V1aR agonist Phe2-Orn8-Vasotocin reduced norepinephrine requirements (2-6 hrs: p < .05 each) and fluid accumulation (p = .043). In addition, mean arterial pressure (6-10 hrs: p < .05 each), pulmonary gas exchange (8-10 hrs: p < .05 each), and global oxygen transport (10 hrs: p < .05 each) were improved by Phe2-Orn8-Vasotocin vs. both other groups. Despite similar preload left ventricular stroke work index was higher in Phe2-Orn8-Vasotocin- than in arginine vasopressin-treated animals (10 hrs: p = .02). Metabolic dysfunction (base excess, lactate concentrations) and renal dysfunction (urinary output, creatinine clearance) were attenuated by Phe2-Orn8-Vasotocin infusion when compared with arginine vasopressin and single norepinephrine therapy. Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 and lower 3-nitrotyrosine concentrations in Phe2-Orn8-Vasotocin-treated animals vs. both other groups (p < .05 each). In addition, the selective V1aR agonist Phe2-Orn8-Vasotocin slightly prolonged survival when compared with arginine vasopressin (p = .01) and standard treatment with norepinephrine (p = .003). Selective V1aR agonism appears to be superior to the V1aR/V2R agonist arginine vasopressin and single norepinephrine infusion for hemodynamic support in septic shock.

The Effects of 6% Hydroxyethyl Starch–Hypertonic Saline in Resuscitation of Dogs with Hemorrhagic Shock

Hemodynamic and global oxygen transport variables have failed to reflect splanchnic hypoperfusion, resulting in a failure to recognize inadequately treated hemorrhagic shock. Volemic expansion after fluid resuscitation is essential to improve global and regional oxygen in hemorrhagic shock. We hypothesized that, in contrast to conventional plasma expanders, the smaller volemic expansion from 7.5 NaCl/6% hydroxyethyl starch (HHES) solution administration in hemorrhagic shock may provide lesser systemic oxygen delivery and gastric perfusion. We used hemorrhaged dogs to compare intravascular volume expansion and the early systemic oxygenation and gastric perfusion effects of fixed fluid bolus administration, which are usually used in clinical situations with severe hemorrhage, of HHES, lactated Ringer (LR), and 6% hydroxyethyl starch (HES) solutions. Thirty dogs were bled (30 mL · kg(-1)) to hold mean arterial blood pressure at 40 to 50 mm Hg over 45 minutes and were resuscitated in 3 groups: LR (n = 10) at 3:1 ratio to shed blood; HES (mean molecular weight 130 kDa, degree of substitution 0.4) (n = 10) at 1:1 to shed blood; and HHES (n = 10), 4 mL · kg(-1). Intravascular volume expansion (Evans blue and hemoglobin dilution), hemodynamic, systemic oxygenation, venous-to-arterial CO(2) gradient (Pv-aCO(2)), and gastric intramucosal-arterial PCO(2) gradient (PCO(2) gap) variables were measured at baseline, after 45 minutes of hemorrhage, and 5, 45, and 90 minutes after fluid resuscitation. HHES increased blood volume because of the high volume expansion efficiency, but intravascular volume expansion with this solution was the smallest of the solutions (P < 0.05). All 3 solutions induced a similar hemodynamic performance but HHES showed lower mixed venous PO(2) and higher systemic oxygenation extraction, Pv-aCO(2), and PCO(2) gap than LR and HES (P < 0.05). In dogs submitted to pressure-guided hemorrhagic shock and fixed-volume resuscitation, the smaller intravascular volume expansion from HHES solutions provides worse recovery of systemic oxygenation and gastric perfusion compared with LR and HES solutions despite its high volume expansion efficiency, which was limited by low infused volume.

Arginine-vasopressin attenuates beneficial norepinephrine effect on jejunal mucosal tissue oxygenation during endotoxinaemia

The objective of the present study was to investigate the effects of increasing doses of norepinephrine (NE) with or without arginine-vasopressin (AVP) on intestinal oxygen supply and jejunal mucosal tissue oxygen tension in an acute endotoxic pig model. In this prospective, randomized, experimental study on 24 domestic pigs, jejunal mucosal tissue PO2 (PO2muc) was measured using two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular haemoglobin (HbO2j) was determined by tissue reflectance spectrophotometry. Systemic haemodynamic variables, mesenteric-venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline, after Escherichia coli lipopolysaccharide (LPS) administration, and at 20 min intervals during incremental NE infusion (0.05, 0.1, 0.5, 1.0, and 2 microg kg(-1) min(-1), respectively) with 57 mU kg(-1) h(-1) AVP (n=8; NE+AVP group) or without (n=8; NE group); or infusion of an equal amount of normal saline (n=8; CON group). LPS infusion led to a significant (P<0.05) decrease of PO2muc and HbO2j. Both NE and NE+AVP increased arterial pressure, cardiac output, and mesenteric artery blood flow. Concomitant to an increase in systemic oxygen delivery, NE improved PO2muc and HbO2j. NE alone was superior in restoration of PO2muc when compared with NE+AVP. Both NE and NE+AVP improved global haemodynamics and systemic oxygen transport variables when compared with control animals in an acute endotoxic pig model. NE improved jejunal PO2muc at all dosages. NE effects were significantly blunted by simultaneous administration of AVP.

Comparison between central venous oxygen saturation and tissue oxygenation and perfusion: a case report

Comparison between central venous oxygen saturation and tissue oxygenation and perfusion: a case report

Mathematical Modeling/Problem Solving in Global Oxygen Transport

A simplified approach to mathematical modeling/problem solving in global oxygen transport is presented. In addition to standard oxygen transport formulae, it uses the S-Factor and a mathematical relationship relating SvO(2) to the ratio DO(2)/VO(2). This method allows the determination or specification of SvO(2), PvO(2), P(50), and systemic shunting in the context of this simplified approach. Heretofore this has not been possible. With this approach, essentially all clinical problems in global oxygen transport can be dealt with. This is illustrated by the broad scope of the five problems presented.

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.

Role of levosimendan in sepsis and septic shock

To present the pharmacologic and biologic profile of levosimendan and discuss potential indications in the treatment of sepsis and septic shock, with a special focus on myocardial and pulmonary dysfunction. In animal models of endotoxic shock, levosimendan improved both left ventricular systolic and diastolic dysfunction, as well as ventriculovascular coupling. In addition, positive effects have been reported on right ventricular performance and pulmonary circulation. Two randomized, controlled trials in patients with septic shock revealed levosimendan provided consistent beneficial effects on cardiopulmonary performance, global oxygen transport, splanchnic perfusion and renal function. These effects have been reported as superior to placebo and the classic inotropic agent dobutamine. Due to its vasodilatory effects, combination with vasoconstrictor agents may be crucial in the presence of arterial hypotension. There is increasing evidence that levosimendan exerts beneficial effects in the treatment of sepsis-induced myocardial and pulmonary dysfunction. Future large-scale multicenter clinical trials are now needed to clarify whether levosimendan improves the overall outcome of patients with sepsis and septic shock.

SHORT-TERM EFFECTS OF PHENYLEPHRINE ON SYSTEMIC AND REGIONAL HEMODYNAMICS IN PATIENTS WITH SEPTIC SHOCK

Clinical studies evaluating the use of phenylephrine in septic shock are lacking. The present study was designed as a prospective, crossover pilot study to compare the effects of norepinephrine (NE) and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock. In 15 septic shock patients, NE (0.82 +/- 0.689 microg x kg(-1) x min(-1)) was replaced with phenylephrine (4.39 +/- 5.23 microg x kg(-1) x min(-1)) titrated to maintain MAP between 65 and 75 mmHg. After 8 h of phenylephrine infusion treatment was switched back to NE. Data from right heart catheterization, acid-base balance, thermo-dye dilution catheter, gastric tonometry, and renal function were obtained before, during, and after replacing NE with phenylephrine. Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE with phenylephrine except for a significant decrease in heart rate (phenylephrine, 89 +/- 18 vs. NE, 93 +/- 18 bpm; P < 0.05). However, plasma disappearance rate (phenylephrine, 13.5 +/- 7.1 vs. NE, 16.4 +/- 8.7% x min(-1)) and clearance of indocyanine green (phenylephrine, 330 +/- 197 vs. NE, 380 +/- 227 mL x min(-1) x m(-2)), as well as creatinine clearance (phenylephrine, 81.3 +/- 78.4 vs. NE, 94.3 +/- 93.5 mL x min(-1)) were significantly decreased by phenylephrine infusion (each P < 0.05). In addition, phenylephrine increased arterial lactate concentrations as compared with NE infusion (1.7 +/- 1.0 vs. 1.4 +/- 1.1 mM; P < 0.05). After switching back to NE, all variables returned to values obtained before phenylephrine infusion except creatinine clearance and gastric tonometry values. Our results suggest that for the same MAP, phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction as compared with NE.

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.

Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial

IntroductionPrevious findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. Nevertheless, a direct comparison between the two study drugs has not yet been performed. The aim of the present study was, therefore, to investigate the effects of a first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock.MethodsWe performed a prospective, randomized, controlled trial in a multidisciplinary intensive care unit in a university hospital. We enrolled septic shock patients (n = 32) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion (n = 16 each) titrated to achieve a mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization, a thermodye dilution catheter, gastric tonometry, acid-base homeostasis, as well as creatinine clearance and cardiac troponin were obtained at baseline and after 12 hours. Differences within and between groups were analyzed using a two-way analysis of variance for repeated measurements with group and time as factors. Time-independent variables were compared with one-way analysis of variance.ResultsNo differences were found in any of the investigated parameters.ConclusionsThe present study suggests there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock.Trial registrationClinicalTrial.gov NCT00639015

GLIBENCLAMIDE DOSE RESPONSE IN PATIENTS WITH SEPTIC SHOCK

Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 microg.kg-1.min-1 or greater to maintain MAP between 65 and 75 mmHg. In addition to standard therapy, patients were randomized to receive either 10, 20, or 30 mg of enteral glibenclamide. Systemic hemodynamics, global oxygen transport including arterial lactate concentrations, gas exchange, plasma glucose concentrations, and electrolytes were determined at baseline and after 3, 6, and 12 h after administration of the study drug. Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.

Microvascular response to red blood cell transfusion in patients with severe sepsis*

Microvascular alterations may play a role in the development of multiple organ failure in severe sepsis. The effects of red blood cell transfusions on microvascular perfusion are not well defined. We investigated the effects of red blood cell transfusion on sublingual microvascular perfusion in patients with sepsis. Prospective, observational study. A 31-bed, medical-surgical intensive care unit of a university hospital. Thirty-five patients with severe sepsis requiring red blood cell transfusions. Transfusion of one to two units of leukocyte-reduced red blood cells. The sublingual microcirculation was assessed with an Orthogonal Polarization Spectral device before and 1 hr after red blood cell transfusion. Red blood cell transfusions increased hemoglobin concentration from 7.1 (25th-75th percentile, 6.7-7.6) to 8.1 (7.5-8.6) g/dL (p < .01), mean arterial pressure from 75 (69-89) to 82 (75-90) mm Hg (p < .01), and oxygen delivery from 349 (278-392) to 391 (273-473) mL/min.M (p < .001). Microvascular perfusion was not significantly altered by transfusion, but there was considerable interindividual variation. The change in capillary perfusion after transfusion correlated with baseline capillary perfusion (Spearman-rho = -.49; p = .003). Capillary perfusion was significantly lower at baseline in patients who increased their capillary perfusion by >8% compared with those who did not (57 [52-64] vs. 75 [70-79]; p < .01), while hemodynamic and global oxygen transport variables were similar in the two groups. Red blood cell storage time had no influence on the microvascular response to red blood cell transfusion. The sublingual microcirculation is globally unaltered by red blood cell transfusion in septic patients; however, it can improve in patients with altered capillary perfusion at baseline.

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.

EFFECTS OF THORACIC EPIDURAL ANESTHESIA ON HEMODYNAMICS AND GLOBAL OXYGEN TRANSPORT IN OVINE ENDOTOXEMIA

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 of 0.125% bupivacaine at the onset of endotoxemia and maintained with 0.1 mL.kg.h. 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.

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.