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Biomedical subjects

Y Gundersen

Publications and source records attributed to Y Gundersen.

16 recordsLinked to original sources
PubMed2005

Response of circulating immune cells to major gunshot injury, haemorrhage, and acute surgery.

PURPOSE: The purpose of this study was to use an established porcine model to investigate the effects on immune function of severe gunshot injury. METHODS: Twelve pigs sustained two standardised rounds, one through right femur and one through left upper abdomen. First aid treatment and acute surgery was started immediately. Blood samples were drawn before shooting and after 75 min. Circulating neutrophils were isolated and reactive oxygen species (ROS) measured. Serum levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-10 were determined at 0, 75 min, as well as 2h after incubation with 1 microg/ml endotoxin in an ex vivo whole blood model. RESULTS: TNF-alpha, IL-1beta, and IL-6 significantly increased at 75 min. ROS in circulating granulocytes tended to increase (NS). Incubation with endotoxin led to a more than 100-fold increase of TNF-alpha pre-trauma, compared to a three-fold increase post-trauma (p<0.0001 between groups). A similar pattern was obtained for IL-1beta, and IL-6. IL-10 was below detection in all samples. The granulocytes maintained their ability to react to the protein kinase C activator phorbol myristate acetate (PMA) after trauma. CONCLUSION: Severe gunshot injury and peritraumatic stress rapidly activate circulating immune cells, but reduce their capacity to react to a subsequent challenge to endotoxin.

Abdominal Injuries↗
PubMed2003

Modest protection of early hydrocortisone treatment in a rat model of volume-controlled haemorrhage.

BACKGROUND: Major insults may trigger generalized inflammatory responses that contribute to progressive multiple organ dysfunction. The present study was performed to test the potential of early hydrocortisone treatment to influence these responses as well as organ function following an episode of rapid and profound blood loss. METHODS: In isoflurane anaesthesia, 35 spontaneously breathing male Sprague-Dawley rats were bled 2.5 ml 100 g-1 body weight over 10 min. Immediately following withdrawal of blood, one group (n = 17) was given 2 mg of hydrocortisone, and the other (n = 18) had the same amount of normal saline. Seventy-five minutes after initiation of bleeding, two-thirds of the blood was retransfused, together with a new injection of hydrocortisone or saline. Thereafter the rats were observed for 2 h. Key mediators of systemic inflammation and plasma markers of organ function and integrity were measured. Internal organs were weighed and scored for visible pathology. Leukocyte infiltration of the liver was counted in a light microscope. RESULTS: Hydrocortisone reduced the plasma levels of IL-6 (P < 0.05); non-significant reductions of TNF-alpha (P = 0.12) and IL-10 (P = 0.44) were noted. The synthesis of reactive oxygen species in peritoneal cells was unaffected. Relative organ weights and organ injury scores tended to be reduced, but only wet organ weight for the lungs reached statistical significance. Leukocyte infiltration of the liver was equal in both groups. Plasma levels of ALT, AST, alpha-GST and creatinine did not differ significantly between groups. Two of the hydrocortisone treated rats died compared with four controls. CONCLUSION: Early treatment with hydrocortisone had a limited organ protective effect in this model of controlled haemorrhagic shock. Although a general tendency for better outcome in the hydrocortisone group was noted, clear-cut and significant advantages of the treatment were not obtained.

Animals↗
PubMed2001

[Steroid treatment of shock lung--tune for re-evaluation?].

BACKGROUND: The acute respiratory distress syndrome (ARDS) is one consequence of the body's systemic inflammatory response to a variety of powerful external stimuli. Glucocorticosteroids are highly effective anti-inflammatory drugs. During the last few years, the molecular mechanisms for their mode of action have been revealed; this has prompted a new wave of interest in corticosteroid treatment of systemic inflammatory states. Several clinical studies have been launched; the results have so far been promising. MATERIAL AND METHODS: We briefly discuss how new knowledge in this field may influence the use of corticosteroids in the treatment of ARDS. The presentation is illustrated by a case study. RESULTS: The patient was a 15-year-old boy with life-threatening and therapy-resistant ARDS. He was treated in a respirator in an intensive care unit (ICU). Two weeks after admission to the ICU, his situation was desperate. High-dose corticosteroids were instituted, and during a five days' treatment his condition improved dramatically. After discontinuation of glucocorticoids he made further progress and was discharged from the ICU after another eleven days. INTERPRETATION: In this particular patient, administration of glucocorticoids had a striking effect. The influence of glucocorticoids on the activation of the transcription factor NF-kappa B and a resulting reduced synthesis of a number of key inflammatory molecules may be one explanation for the positive course.

Acute Disease↗
PubMed2001

Moderate hypothermia blunts the inflammatory response and reduces organ injury after acute haemorrhage.

BACKGROUND: Reduced body temperature is a common companion to trauma/haemorrhage. Several clinical studies have identified hypothermia as an independent risk variable predisposing to increased morbidity and mortality. At the same time it is known that most enzymatic reactions are downregulated at temperatures below 37 degrees C. Theoretically this should restrain the inflammatory response and protect the host from remote organ injury. The study was performed to test this hypothesis. METHODS: Twenty-six male Sprague Dawley rats were used for the experiments. Volume controlled haemorrhagic shock was induced by withdrawal of 2.5 ml blood/100 g body weight over 10 min. Half of the animals (n=13) were then cooled to 32.5-33 degrees C, the other half (n=13) were kept normothermic (37.5+/-0.5 degrees C). Seventy-five minutes after initiation of bleeding, two-thirds of the blood was retransfused. Thereafter the rats were observed for 2 h. Key substances of systemic inflammation were determined (plasma values of TNF-alpha, IL-6, IL-10, and corticosterone; reactive oxygen species in peritoneal phagocytes), plasma markers of organ function and integrity (AST, ALT, alphaGST, creatinine, urea), and survival. RESULTS: Hypothermia reduced the release of IL-6 (P<0.01). The reductions of plasma levels of TNFalpha (P=0.07) and IL-10 (P=0.09) were less clear-cut. The release of reactive oxygen species diminished (P<0.01). Organ injury was ameliorated, as reflected by decreased levels of AST (P<0.01), alphaGST (P<0.01), and creatinine (P<0.01). Both groups experienced an almost identical increase of plasma corticosterone. None of the hypothermic rats died, compared to two normothermic. CONCLUSION: Moderate hypothermia had an organ protective effect in this model of controlled haemorrhagic shock. This coincided with a significant reduction of the proximal cytokine IL-6 and reactive oxygen species, which conceivably influenced the outcome.

Animals↗
PubMed2001

Hepatocellular damage in porcine endotoxemia: beneficial effects of selective versus non-selective nitric oxide synthase inhibition?

UNLABELLED: While nitric oxide (NO) is implicated as an important mediator of hypotension in sepsis and endotoxemia, its role as a mediator of tissue injury in shock is controversial. During porcine endotoxemia (lipopolysaccharide (LPS) 1.7 microg kg(-1) x h(-1) i.v. for 6 h), we compared circulatory and morphological changes in the liver induced by two different NO synthase inhibitors (N(G)-nitro-L-arginine methyl ester, L-NAME, 25 mg x kg(-1) i.v. and aminoethyl-isothiourea, AE-ITU, 10 mg x kg(-1) i.v.), both given after 3 h. LPS induced time-dependent tissue reactions with edema, sinusoidal dilation, packing of red cells and leukocyte infiltration, progressing to endothelial cell and hepatocyte damage, formation of thrombi, and at 6 h widespread necrosis. These changes were similar in all pigs receiving LPS, regardless of treatment with NOS inhibitors. LPS caused significant increases in aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alpha glutathione S-transferase (alpha-GST), L-NAME caused further increases in AST, ALP and alpha-GST, while AE-ITU prevented the late increase in ALP and alpha-GST observed in the other LPS groups. LPS reduced liver blood flow by approximately 40%. L-NAME further reduced flow by approximately 50%, while AE-ITU restored liver blood flow to baseline values. CONCLUSION: L-NAME in endotoxemia had detrimental effects on liver circulation, while AE-ITU improved liver blood flow and attenuated the late increase in liver enzymes. Liver morphology was unaffected within the 3-h observation time after NOS inhibition.

Animals↗
PubMed2001

The role of Kupffer cell inhibition in porcine endotoxemia.

The selective Kupffer cell inhibitor gadolinium chloride (GdCl3) has been demonstrated to protect animals from lethality in experimental endotoxemia and sepsis in rodent models. This study was designed to investigate the effect of Kupffer cell blockade on the early response to endotoxin in a large animal model. Using a porcine endotoxemia model, animals were randomized to receive either GdCl3 (10 mg/kg or 30 mg/kg; n = 8 in each group) or vehicle saline (n = 8) 24 h before exposure to endotoxin. Pretreatment with GdCl3 resulted in a dose dependent reduction in early hepatic oxygen consumption as well as oxygen extraction ratio in response to continuous infusion of endotoxin. At 5 h there was significant lower serum AST level in animals given 30 mg/kg of GdCl3 as compared to the two other groups. Pretreatment with GdCl3 induced a dose dependent reduction of Kupffer cells in the liver sinusoids. Despite this, all animals deteriorated with continuous infusion of endotoxin as evidenced by the progressive reduction in cardiac output, mean arterial pressure and total liver blood flow. Also, increases in pulmonary arterial pressure, portal venous pressure and systemic, pulmonary and hepatic vascular resistance were seen. This is consistent with activation of other cell populations and defense mechanisms by endotoxin, perpetuating the septic response. However, modulation of reticuloendothelial cell function seems feasible also in larger animals, and our results stimulate to further research on potential immunomodulatory tools in early sepsis.

Animals↗
PubMed1999

Selective inhibition of inducible nitric oxide synthase maintains haemodynamic stability without untoward consequences for hepatic function or morphology.

OBJECTIVE: To examine the effects of the inducible nitric oxide synthase inhibitor aminoethyl-isothiourea (AE-ITU) on haemodynamic measurements, and correlate these with hepatic morphology and function in a porcine model of endotoxaemia. DESIGN: Experimental study. ANIMALS: 15 juvenile pigs. INTERVENTIONS: Flow probes were placed around the hepatic artery and portal vein. Catheters were introduced into the portal and hepatic veins, pulmonary artery, and aorta. Infusion of AE-ITU was started one hour before that of endotoxin (study group n = 6); thereafter both substances were infused simultaneously until the end of the study (6 hours). The controls (n = 9) had endotoxin alone. MAIN OUTCOME MEASURES: Hepatic morphology assessed by light and electron microscopy; and hepatic integrity and function by transaminase activities and oxygen consumption. Systemic, pulmonary, and hepatic blood flow and pressure. RESULTS: AE-ITU maintained systemic blood pressure (p < 0.05 compared with controls) without causing pulmonary hypertension. Neither hepatic morphology nor function were adversely influenced. CONCLUSION: In endotoxaemia AE-ITU has a favourable haemodynamic profile which is achieved without impairment of hepatic function or morphology.

Animals↗
PubMed1998

The nitric oxide donor sodium nitroprusside protects against hepatic microcirculatory dysfunction in early endotoxaemia.

OBJECTIVE: Endotoxin rapidly inhibits the activity of the constitutive endothelial nitric oxide synthase (ecNOS); this precedes the production of NO from inducible NOS (iNOS). This leaves a period in early endotoxaemia with a supposed scarcity of NO. The present study was conducted to examine the effects of external supplementation of NO on liver microcirculation and function. MATERIAL: 13 male Sprague Dawley rats. INTERVENTIONS: The rats underwent laparotomy, and the left liver lobe was exteriorised. All animals were given a bolus dose of endotoxin (LPS) 5 mg/kg intraportally. One group (n = 6) had a continuous infusion of sodium nitroprusside (SNP) 1.4 microg/kg per min started concurrently, the other group (n = 7) was treated with normal saline. The study was terminated after 3 h LPS. MEASUREMENTS AND RESULTS: Intravital microscopy was performed at baseline, at 2 h and 3 h LPS. Hepatic function was assessed by arterial ketone body ratio, acid base values, and bile flow. At baseline 1% of the sinusoids were without perfusion. After 2 h LPS this figure had risen to 9.8+/-1.5% in the SNP group versus 16.9+/-1.4% in the controls (p < 0.05 vs controls). The corresponding values after 3 h LPS were 13.5+/-1.5 versus 19.3+/-1.5% (p < 0.05 vs controls). The leukocyte count in sinusoids and venules had a similar development. Functional parameters were all slightly better preserved in the SNP group, but with no individual significance versus controls. CONCLUSIONS: Infusion of the NO donor SNP in early endotoxaemia attenuates the detrimental effects of LPS on liver microcirculation, most probably by alleviating a relative deficit of NO at the microcirculatory level.

Animals↗
PubMed1998

Effects of the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methyl ester and aminoethyl-isothiourea on the liver microcirculation in rat endotoxemia.

BACKGROUND/METHODS: The question whether nitric oxide protects or impairs organ perfusion during early endotoxemia has not been completely answered. To evaluate the regulative function of nitric oxide on organ microvascular perfusion and leukocyte accumulation during endotoxemia, we studied the influence of a non-selective nitric oxide inhibitor and a preferential inducible nitric oxide synthase inhibitor (respectively, N(G)-nitro-L-arginine methyl ester and aminoethyl-isothiourea) on liver microcirculation (intravital fluorescence microscopy) in a rat model. RESULTS: Two hours after intraportal injection of lipopolysaccharide (5 mg/kg in 10 min) the rats were randomly treated and received a bolus dose of N(G)-nitro-L-arginine methyl ester (10 mg/kg, n = 7), aminoethyl-isothiourea (10 mg/kg, n = 6) or normal saline, (n = 7). After 1 h, N(G)-nitro-L-arginine methyl ester blockade yielded a higher rate of non-perfused sinusoids than normal saline (27 +/- 2% vs 19 +/- 5%, p < 0.05). LPS-induced leukocyte stagnation in sinusoids was further increased (p < 0.05) in all groups after 1 h treatment, but N(G)-nitro-L-arginine methyl ester clearly accentuated leukocyte accumulation in sinusoids as compared to normal saline (69 +/- 19% vs 16 +/- 4%, p < 0.05). Both modalities of nitric oxide blockade elicited a significant enhancement in the number of leukocytes adherent to the postsinusoidal venules in contrast to normal saline (N(G)-nitro-L-arginine methyl ester 48 +/- 17%, aminoethyl-isothiourea 33 +/- 9% vs normal saline 1 +/- 5%, p < 0.05). CONCLUSIONS: We conclude that complete nitric oxide blockade aggravates lipopolysaccharide-induced hepatic microvascular perfusion failure and enhances leukocyte accumulation, in both sinusoids and post-sinusoidal venules. The preferential inducible nitric oxide synthase inhibitor aminoethyl-isothiourea has a moderate negative effect, favoring leukocyte adhesion in postsinusoidal venules, and its usefulness demands further research, especially concerning its late effects.

Animals↗
PubMed1998

Aminoethyl-isothiourea, a selective inhibitor of inducible nitric oxide synthase activity, improves liver circulation and oxygen metabolism in a porcine model of endotoxemia.

The role of nitric oxide (NO) in hepatic oxygen transport is unclear. We investigated the effects of aminoethyl-isothiourea (AE-ITU), a selective inhibitor of iNOS activity, on liver blood flow and oxygen consumption (VO2H) in the pig. Endotoxin (lipopolysaccharide, LPS) was given intraportally (1.7 microg/kg/h), followed by AE-ITU (10 mg/kg) after 3 h (n = 7), LPS controls (n = 8) received LPS for 6 h. AE-ITU controls (n = 6) received saline/AE-ITU. LPS (treatment group) caused significant reductions at 3 h in cardiac output (CO) from 4.4 +/- .4 to 2.7 +/- .3 L/min, in hepatic artery flow (Q(HA)) from 266 +/- 53 to 127 +/- 19 mL/min, and in portal venous flow (Q(PV)) from 630 +/- 50 to 323 +/- 33 mL/min. Hepatic oxygen delivery (DO2H) was reduced from 93 +/- 11 to 38 +/- 5 mL/min (p < .05), while hepatic oxygen extraction ratio (ERO2H) increased, and VO2H was maintained. Similar changes were observed in LPS controls. AE-ITU caused no changes in saline controls. After injection of AE-ITU during LPS infusion, CO was unchanged, while Q(HA) increased gradually from 127 +/- 20 to 268 +/- 40 mL/min over 3 h (p < .05) and DO2H from 38 +/- 5 to 60 +/- 5 mL/in (p < .05). ERO2H increased from .54 +/- .04 to .69 +/- .03 in 30 min, while VO2H increased from 23 +/- 4 to 35 +/- 3 mL/in in 3 h (p < .05). Thus, AE-ITU restored hepatic arterial blood flow and increased hepatic oxygen consumption in pigs with endotoxemia.

Animals↗
PubMed1998

Hepatic oxygen metabolism in porcine endotoxemia: the effect of nitric oxide synthase inhibition.

The role of endotoxin (lipopolysaccharide, LPS) and nitric oxide in hepatic oxygen metabolism was investigated in 36 pigs receiving 1) LPS (1.7 microgram. kg-1. h-1) for 7 h and NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) after 3 h, 2) LPS, 3) NaCl and L-NAME, and 4) NaCl. Infusion of LPS reduced hepatic oxygen delivery (DO2H) from 60 +/- 4 to 30 +/- 5 ml/min (P < 0.05) and increased the oxygen extraction ratio from 0.29 +/- 0.07 to 0.68 +/- 0.04 after 3 h (P < 0.05). Hepatic oxygen consumption (VO2H) was maintained (18 +/- 4 and 21 +/- 4 ml/min, change not significant), but acidosis developed. Administration of L-NAME during endotoxemia caused further reduction of DO2H from 30 +/- 3 to 13 +/- 2 ml/min (P < 0.05) and increased hepatic oxygen extraction ratio from 0.46 +/- 0.04 to 0.80 +/- 0.03 (P < 0.05). There was a decrease in VO2H from 13 +/- 2 to 9 +/- 2 ml/min that did not reach statistical significance, probably representing a type II error. Acidosis was aggravated. Administration of L-NAME in the absence of endotoxin also increased the hepatic oxygen extraction ratio, but no acidosis developed. In a different experiment, liver blood flow was mechanically reduced in the presence and absence of endotoxin, comparable to the flow reductions caused by L-NAME. The increase in hepatic oxygen extraction ratio (0.34) and maximum hepatic oxygen extraction ratio (approximately 0.90) was similar whether DO2H was reduced by occlusion or by L-NAME. We concluded that L-NAME has detrimental circulatory effects in this model. However, neither endotoxin nor L-NAME seemed to prevent the ability of the still circulated parts of the liver to increase hepatic oxygen extraction ratio to almost maximum when oxygen delivery was reduced. The effect of L-NAME on oxygen transport thus seems to be caused by a reduction in DO2H rather than by alterations in oxygen extraction capabilities.

Animals↗
PubMed1997

Use of selective and nonselective nitric oxide synthase inhibitors in rat endotoxemia: effects on hepatic morphology and function.

Endotoxin has profound effects on nitric oxide (NO) production, and considerable controversies exist as to whether these alterations are beneficial or deleterious. Increased mortality has been reported from nonselective inhibition of NO synthase. Results from selective inhibition of the inducible isoform (iNOS) appear largely positive. In a model of rat endotoxemia we have compared the early effects on hepatic morphology and function of selective and nonselective NO inhibition. Two hours after endotoxin injection (5 mg/kg intraportally) the rats were treated with either the selective iNOS inhibitor aminoethyl isothiourea (AE-ITU, 10 mg/kg), the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or normal saline. The animals were observed for another hour. Using an immunohistochemical method, induction of iNOS was demonstrated in various tissues in all slices examined. No unequivocal benefit from NO inhibition was noted. Electron microscopic examination revealed widespread alterations of liver morphology, without obvious differences between the groups. Liver function, as assessed by ketone body ratio, hepatic venous acid base values, and bile production, was generally more adversely affected after NO inhibition. Even with the iNOS selective inhibitor AE-ITU no benefit was noted. We conclude that during the early phases of endotoxemia therapeutic reduction of NO production has no positive effects on liver function or morphology.

Acid-Base Equilibrium↗
PubMed1997

Modulators of nitric oxide in porcine endotoxemia: effects on hepatic oxygen delivery and consumption.

In a porcine model of endotoxemia we have studied the effects of nitric oxide (NO) on hepatic oxygen delivery and consumption. After 3 h of endotoxemia, NO biosynthesis was modulated by a bolus dose of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Fifteen minutes thereafter a continuous infusion of the NO donor sodium nitroprusside (SNP) was started. Endotoxin significantly reduced hepatic oxygen delivery from 3.4 +/- 0.6 to 2.2 +/- 0.3 ml/kg/min at 3 h. Due to an increased extraction ratio (ER), oxygen consumption was nearly unaffected. L-NAME further diminished oxygen delivery to 1.0 +/- 0.2 ml/kg/min within 15 min (p < 0.05), but despite an increase in ER from 47 to 68% (p < 0.05), oxygen consumption tended to decrease (from 1.0 to 0.7 ml/ kg/min, nonsignificant). A similar tendency was observed in a control group of 9 pigs which was treated in the same way as the study group, except for the SNP infusion. SNP induced an almost selective increase in hepatic arterial flow, with a corresponding increase in oxygen delivery to 1.8 +/- 0.3 ml/kg/min (p < 0.05). At the same time ER was reduced from 68 to 42% (p < 0.05). Oxygen consumption remained unaltered. The control group exhibited no change in either oxygen delivery or consumption. The study shows that nonselective inhibition of NO synthesis is detrimental to hepatic perfusion and oxygen transport. The NO donor SNP increased oxygen delivery via a selective increase in hepatic arterial flow, but failed to influence oxygen consumption. This was probably mainly due to a massive shutdown of sinusoids, which did not reopen when flow was increased. A functioning microcirculation thus seems to be a prerequisite for the stimulation of organ blood flow to be effective.

Animals↗
PubMed1996

The NO donor sodium nitroprusside reverses the negative effects on hepatic arterial flow induced by endotoxin and the NO synthase inhibitor L-NAME.

In previous studies we have observed that the nitric oxide synthase inhibitor L-NAME induces a profound deterioration of liver circulation in experimental endotoxemia. Using the same porcine model we now have evaluated the possibility of modulating these effects with the nitric oxide donor sodium nitroprusside. Infusion of endotoxin led to a gradual deterioration of hemodynamic parameters, including liver blood flow. The decreases in portal blood flow paralleled and matched the decreases in cardiac output, and no compensatory increase in hepatic arterial flow occurred. L-NAME had detrimental effects on hemodynamics, including the liver circulation. The latter effects could, however, partially be reversed by sodium nitroprusside. Hepatic arterial flow increased from 1.9 to 7.2 ml/kg/min, with a concomitant decrease in hepatic arterial resistance from 5,364 to 1,746 dyn s/cm5 kg. A control group exhibited no significant change in either flow or resistance. The response to sodium nitroprusside was rapid and vigorous, and probably largely due to relaxation of the hepatic arterioles, and not to abatement of intrahepatic edema or plugging of the sinusoids. Furthermore, we conclude that the endotoxin-induced dysfunction of the hepatic arterial buffer response may be due to a selective inhibition of vascular endothelial function.

Animals↗
PubMed1984

Peroperative hypothermia.

Heat loss during anesthesia and operation and subsequent hypothermia will increase the postoperative oxygen demand and may endanger patients with restricted cardiopulmonary reserves. Forty patients scheduled for intra-abdominal aortic surgery and 40 patients scheduled for peripheral vascular surgery on the lower limbs were investigated using a warming blanket, humidified heated inspired anesthetic gases at 37-40 degrees C, or both these methods together. A fourth group of patients received no active warming. A warming blanket used alone gave no protection against hypothermia when compared with no active warming. In the abdominal surgical group, there was a steady fall in temperature throughout the operation if no warming method was employed. In this group the use of humidified, heated inspired gases was significantly better than no treatment after 2 h of anesthesia (P less than 0.05). The combination of humidified and heated inspired gases and a warming blanket gave significantly better heat preservation after 40 min (P less than 0.05). Patients undergoing peripheral vascular surgery had similar but smaller drops in temperature with the different types of warming procedures employed. The differences in temperature between the intra-abdominal and extra-abdominal operations were statistically significant after 3 h (P less than 0.05).

Aged↗