Effects of inhaled aerosolized iloprost and inhaled NO on pulmonary circulation and edema formation in ovine lung injury.

Although inhaled NO (iNO) has been shown to lower pulmonary pressures and edema accumulation in experimental acute lung injury, its clinical use has been questioned because of a lack of improvement in outcome, rebound phenomena, and potential toxicity. We investigated the effects of aerosolized iloprost, a stable prostacyclin analogue, compared with iNO on pulmonary pressures and lung edema in 20 female sheep with oleic acid lung injury. The most effective dose of iloprost was determined in healthy animals before the experiment. Anesthetized and ventilated sheep received a central venous oleic acid infusion and were continuously infused with Ringer lactate to achieve a positive fluid balance (5 mL.kg(-1).h(-1)). In the iNO group (n = 6), iNO (20 ppm) was administered continuously for 8 h. Animals in the iloprost group (n = 6) received aerosolized iloprost (40 microg 2 h(-1)). Animals in the control group (n = 6) had no further intervention. Oleic acid infusion was associated with impaired oxygenation, pulmonary hypertension, and lung edema in all groups. Although iNO significantly decreased pulmonary vascular resistance index, effective pulmonary capillary pressure, and extravascular lung water index, these parameters were unaffected by iloprost. Oxygenation index (Pao2/Fio2) increased significantly both during NO and iloprost inhalation but also tended to improve in the control group over time. In contrast to iNO, the investigated dose of iloprost was ineffective to attenuate acute lung injury-induced changes in pulmonary hemodynamics and lung edema in this experimental model.

Hemodynamic effects of titrated norepinephrine in healthy versus endotoxemic sheep.

In patients with sepsis and systemic inflammatory response syndrome, hemodynamic support is often complicated by a vascular hyporesponsiveness to exogenously administered norepinephrine. Although norepinephrine tachyphylaxis represents a significant clinical problem, the relationship between norepinephrine dosages and mean arterial pressure (MAP) in the presence of systemic inflammation is still not fully understood. This study was, therefore, designed as a prospective, controlled laboratory trial to elucidate the hemodynamic response to incremental norepinephrine doses in healthy and endotoxemic sheep. ANOVA demonstrated that a significantly higher mean infusion rate of norepinephrine was needed to increase MAP by 20 mmHg in endotoxemic versus healthy control sheep (P = 0.007). Whereas the goal-MAP was reached in 100% of healthy controls, it was achieved in only 80% during endotoxemia. Cardiac index increased significantly in healthy, but not in endotoxemic, sheep. Our findings confirm the presence of vascular hyporesponsiveness to norepinephrine in endotoxemia. In addition, this study demonstrates that the presence of systemic inflammation leads to an early hyporesponsiveness against norepinephrine which was caused by a drug-independent mechanism rather than a tachyphylaxis due to long-term administration of norepinephrine.

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.

Admission hyperglycemia is associated with poor outcome after emergent coronary bypass grafting surgery.

PURPOSE: Hyperglycemia during or after cardiac surgery is a common finding that is associated with poor outcome. Very few data, however, are available regarding a correlation between admission blood glucose and outcomes after coronary artery bypass grafting (CABG). Thus, the goal of the current study was to examine the relationship between admission blood glucose and outcome after emergency CABG surgery. MATERIALS AND METHODS: A retrospective analysis to evaluate whether admission hyperglycemia associated with increased morbidity or mortality was performed in patients after emergency CABG surgery. The records of all the patients undergoing emergency CABG surgery between January 1999 and December 2010 at the University of Virginia Health System were reviewed. Postoperative in-hospital mortality and complications were considered as study end points. RESULTS: A total of 240 patients met the final inclusion criteria. Overall mortality was 14.1%. The median admission blood glucose in patients who died 7.4 (interquartile range, 5.9-10.1) mmol/L was significantly higher compared with survivors 6.1 (interquartile range, 5.4-7.2; P<.01). Furthermore, 59% of the patients who died had admission blood glucose levels higher than 6.6 mmol/L, whereas only 35% of the patients who survived had similar blood glucose levels (P=.01). On multivariable analysis, admission blood glucose was identified as an independent risk factor for death after emergency CABG (P=.01; odds ratio, 1.16; 95% confidence interval, 1.04-1.29). Admission blood glucose was further identified as independently associated with increased risk for a composite outcome of death, postoperative renal failure or stroke (P=.01; odds ratio, 1.14; 95% confidence interval, 1.03-1.27). CONCLUSIONS: Our study shows for the first time that admission blood glucose is correlated with increased morbidity and mortality among patients undergoing emergency CABG surgery.

Inhaled nitric oxide reduces lung edema during fluid resuscitation in ovine acute lung injury.

OBJECTIVE: Fluid resuscitation in sepsis-related lung injury is limited by aggravation of pulmonary edema. Hypovolemia, however, may compromise tissue perfusion and contribute to organ dysfunction. We hypothesized that inhaled nitric oxide would reduce edema formation during fluid therapy. DESIGN AND SETTING: Prospective laboratory investigation in a university research laboratory. PARTICIPANTS: Eighteen chronically instrumented sheep. INTERVENTIONS: The animals were randomly assigned to one of three groups and received endotoxin (S. typhi, 10 ng kg(-1) min(-1)) for 30 h. After 24 h the sheep were anesthetized (ketamine/midazolam), mechanically ventilated with oxygen, and received 0.1 ml kg(-1) oleic acid: oxy group (n=6), an infusion of Ringer's lactate was restricted to 1 ml kg(-1) h(-1); fluid/oxy group (n=6), a bolus of 10 ml kg(-1) Ringer's lactate plus 10 ml kg(-1) h(-1) was given; fluid/NO group (n=6), the sheep were treated as in the fluid/oxy group, except that they inhaled nitric oxide (20 ppm). MEASUREMENTS AND RESULTS: The extravascular lung water index was measured using thermodye dilution. Oleic acid increased extravascular lung water, impaired oxygenation, and reduced cardiac index at 26 h in all groups. After 30 h the extravascular lung water in the fluid/NO group was not higher than in the oxy group and significantly than in the fluid/oxy group. While cardiac index returned to the level of sepsis baseline in fluid/NO and fluid/oxy, it was reduced in the oxy group after 30 h. There were no significant differences in cardiac index between groups. CONCLUSIONS: Inhaled nitric oxide may be an option for reducing edema formation secondary to fluid resuscitation in acute lung injury.

Isoflurane impairs immature astroglia development in vitro: the role of actin cytoskeleton.

General anesthetics, either alone or in combination, can be detrimental to the developing mammalian brain and induce extensive apoptotic degeneration of immature neurons when they are administered at the peak of synaptogenesis. Because neuron development and normal functions depend on the integrity of astroglia, we sought to determine whether general anesthesia also causes disturbances in the early development of astroglia. Using isoflurane, an inhaled anesthetic that is highly toxic to immature neurons, we studied primary astroglia cultures, focusing on very early development (Day-In-Vitro 4 treatment). Exposure to 3% isoflurane for 24 hours delayed morphological differentiation and impaired the growth of immature astrocytes. The timing of delayed astroglia maturation and growth coincided with a major disturbance in actin cytoskeleton sculpting that was manifest as impaired actin stress fiber formation and cytoskeletal organization and downregulation of the focal adhesion protein, paxillin. Isoflurane-induced actin cytoskeletal changes were accompanied by a significant decrease in protein levels of the endogenous GTPase RhoA that regulates the phosphorylation of myosin light chain protein, suggesting that isoflurane-induced impairment in glial growth and morphological development is, in part, mediated by the RhoA/myosin light chain protein signaling pathway.

Intraoperative factors and the risk of respiratory complications after pneumonectomy.

BACKGROUND: The potential effect of intraoperative factors on respiratory complications after pneumonectomy is still unclear. METHODS: We conducted a retrospective cohort study; charts of 129 patients who underwent elective pneumonectomy at the University of Virginia were reviewed. Logistic regression was used to estimate the effect of anesthetic factors on the odds of at least one respiratory complication. Linear regression models were fit to assess the impact of these outcomes on length of stay (LOS). RESULTS: The incidence of respiratory complications in this cohort was 21%. In univariate analysis total nonblood fluids (p = 0.001), and the blood products packed red blood cells (p < 0.001), plasma (p < 0.001), and platelets (p = 0.044) were significantly associated with respiratory complications. In a multivariable logistic regression analysis, single unit transfusion of any blood product (packed red blood cells, plasma, or platelets) was identified as a major risk factor for respiratory complications after controlling for covariates (odds ratio = 1.47, 95% confidence interval 1.06 to 2.05). Respiratory failure and complications were closely related to LOS, increasing the LOS by a factor of 4.7 (95% confidence interval 3.51 to 6.18) and 3.5 (95% confidence interval 2.69 to 4.41), respectively. CONCLUSIONS: Blood product transfusion affects respiratory function and is an independent risk factor for respiratory complications after pneumonectomy.