Patrik Rossi

Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock.

Objective Levosimendan is a novel inodilator that improves cardiac contractility by sensitizing troponin C to calcium. This drug has proved to be effective in treating advanced congestive heart failure but has not been evaluated in septic settings. The purpose of the present study was to study the effects of this drug in a porcine model of endotoxemia. Design Prospective experimental study. Subjects Fourteen landrace pigs. Interventions All animals were anesthetized and catheterized for measurement of central and pulmonary hemodynamics. Ultrasonic flow probes were placed around the renal artery and portal vein to measure blood flow. A tonometer was placed in the ileum to measure mucosal pH. Levosimendan was given to six animals as a bolus (200 &mgr;g·kg−1) followed by a continuous infusion (200 &mgr;g·kg−1· hr−1). Thirty minutes after onset of levosimendan treatment, all animals received endotoxin (20 &mgr;g·kg−1·hr−1 for 3 hrs). Measurements and Main Results At baseline, levosimendan induced a systemic vasodilation with a reduction in blood pressure and an increase in heart rate. A tendency to an increase in cardiac index did not reach statistical significance (p = .055).Cardiac index and systemic oxygen delivery were markedly improved in the levosimendan group during endotoxemia. Systemic vascular resistance and blood pressure were reduced in the levosimendan group. The latter parameter, however, was only different from the control group during the initial phase of endotoxin shock but not at the late, most pronounced phase of shock. Levosimendan also efficiently attenuated endotoxin-induced pulmonary hypertension. Portal venous blood flow and gut oxygen delivery were improved, but no concomitant reduction in endotoxin-induced intestinal mucosal acidosis was observed. Renal blood flow was unaffected, as was the endotoxin-induced increase in plasma endothelin-1-like immunoreactivity.These findings support previous reports of calcium desensitization as a potential component in septic myocardial depression. Furthermore, the vasodilatory properties of this drug were well tolerated in the current model of hypodynamic endotoxin shock, and they may have contributed to improved regional blood flow as seen in the gut as well as improved systemic perfusion by means of reduced biventricular afterload. Conclusion Pretreatment with levosimendan in pigs subjected to endotoxin shock improved cardiac output and systemic and gut oxygen delivery. In addition, pulmonary hypertension largely was attenuated without any adverse effects on gas exchange. These results are promising in several aspects, but the role of levosimendan in the treating circulatory failure in sepsis remains to be established.

Comparison of a single indicator and gravimetric technique for estimation of extravascular lung water in endotoxemic pigs

Objectives:To compare the single thermal indicator dilution (STID) technique for measurement of extravascular lung water (EVLWSTID) with gravimetrically determined EVLW (EVLWGRAV) in anesthetized pigs under sham and endotoxemic conditions. Design:Open experimental comparative animal study. Setting:University animal research laboratory. Subjects:Fifteen anesthetized landrace pigs. Interventions:Endotoxin infusion during 5 hrs in five pigs. Six animals were only anesthetized and rested for 5 hrs. In four additional animals, the impact on EVLWSTID measurements by changes in pulmonary perfusion, ventilation, and the combination of the two was studied. The alterations in ventilation and perfusion were induced by caval balloon inflation, inflation of the pulmonary artery catheter balloon, and bronchial plugging respectively. Measurements and Main Results:The STID technique, with default settings of the intrathoracic blood volume (ITBV) to global end-diastolic volume (GEDV) (i.e., the extrapulmonary intravascular volume between the point of injection of the indicator, and the point of detection) relationship (ITBV = 1.25GEDV), systematically overestimated the EVLW index compared with the gravimetrical method (mean bias of 5.4 mL/kg). By adapting the ITBV to GEDV relationship to the current model (ITBV = 1.52GEDV + 49.7), the accuracy of the STID technique improved. Moreover, the measurement of EVLWSTID proved to be reduced by manipulation of pulmonary perfusion and ventilation. However, the STID technique could detect an increase in EVLW during endotoxemia independent of the ITBV/GEDV relationship used. Conclusion:Despite technological improvement, the dilution techniques for the measurement of EVLW might still be influenced by changes in perfusion and ventilation. The STID technique, in addition, might demand adjustment of the ITBV/GEDV relationship to the particular condition and species subjected to measurement. The STID technique may, however, be a useful tool for monitoring changes of EVLW over time, but further studies are warranted to confirm this.

Early predictors of morbidity and mortality in trauma patients treated in the intensive care unit

Background: We investigated the incidence and severity of post‐injury morbidity and mortality in intensive care unit (ICU)‐treated trauma patients. We also identified risk factors in the early phase after injury that predicted the later development of complications.

Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock.

Objective:To evaluate the effects of endothelin receptor antagonism on cardiac performance in endotoxin shock. Design:Prospective, experimental study. Setting:A university-affiliated research institution. Subjects:Domestic anesthetized landrace pigs. Interventions:Thirty-seven pigs were anesthetized and subjected to echocardiography, coronary sinus catheterization, and monitoring of central and regional hemodynamics in order to assess cardiac performance. All animals received endotoxin for 5 hrs. Twenty pigs served as endotoxin controls. Tezosentan, a dual endothelin-A and -B receptor antagonist, was administered during established endotoxemic shock. Seven pigs received an infusion of tezosentan of 1·mg·kg−1·hr−1 (tezo1), and an additional ten pigs received a higher dose of 10 mg·kg−1·hr−1 (tezo10). Measurements and Main Results:Endotoxemia evoked a state of shock with pulmonary hypertension and metabolic acidosis. A decrease in stroke volume and coronary perfusion pressure as well as an increase in troponin I was also noted. Tezosentan administration resulted in a significant increase in cardiac index, stroke volume index, left ventricular stroke work index, and left ventricular end-diastolic area index. Decreases in systemic and pulmonary vascular resistance indexes were also evident after intervention. This was achieved without changes in heart rate or systemic arterial or pulmonary artery occlusion pressures in tezo1 animals compared with controls. In addition, metabolic variables were improved by tezosentan. These effects were sustained only in the tezo1 group. In the higher dosage, tezosentan resulted in a deterioration of cardiac performance and 50% mortality rate. The endotoxin-induced increase in troponin I was attenuated in the tezo1 group compared with controls. Conclusions:In this porcine model of volume-resuscitated, endotoxemic shock, endothelin-receptor blockade with tezosentan improved cardiac performance. However, the effect was not sustained with higher doses of tezosentan, possibly due to reduced coronary perfusion pressure. These findings show differentiated, dose-dependent effects by dual endothelin receptor blockade on endotoxin-induced cardiovascular dysfunction.

Tezosentan counteracts endotoxin-induced pulmonary edema and improves gas exchange

Sepsis-induced acute lung injury is still associated with high morbidity and mortality. The pathophysiology is complex, and markers of injury include increased extravascular lung water. To evaluate the effects of the novel dual endothelin receptor antagonist tezosentan on endotoxin-induced changes in extravascular lung water and gas exchange, 16 pigs were anaesthetized and catheterized. Twelve animals were subjected to 5 h of endotoxemia. After 2 h, six of these animals received a bolus of tezosentan 1 mg kg−1 followed by a continuous infusion of 1 mg kg−1 h−1 to the end of the experiment at 5 h. Conventional pulmonary and hemodynamic parameters were measured. Extravascular lung water was determined in these pigs after 5 h of endotoxemia, as well as in the four additional nonendotoxemic sham animals. Tezosentan in the current dosage counteracted the deterioration of lung function caused by endotoxin, as measured by dead space, venous admixture, and compliance. In addition, pulmonary hypertension was attenuated. Tezosentan had a marked effect on the endotoxin-induced increase in extravascular lung water that was reduced to levels observed in nonendotoxemic sham animals. These results suggest that endothelin is involved in endotoxin-induced lung injury and the development of pulmonary edema. Dual endothelin receptor antagonism may be of value in the treatment of sepsis-related acute lung injury.

Comparison of gravimetric and a double-indicator dilution technique for assessment of extra-vascular lung water in endotoxaemia

Objective. To compare a molecular double-indicator dilution technique with the gravimetrical reference method for measurement of extra-vascular lung water in porcine endotoxin shock.Design. Open comparative experimental study.Setting. Animal research laboratory.Measurements and results. In fourteen anaesthetised, mechanically ventilated landrace pigs, central and pulmonary haemodynamics as well as pulmonary gas exchange were measured. Extra-vascular lung water was quantitated gravimetrically as well as with a molecular double indicator dilution technique. Eight of these animals were subjected to endotoxaemia, the rest serving as sham controls. No difference in extra-vascular lung water was observed between the two methods in sham animals. Furthermore, extra-vascular lung water assessed with the molecular double-indicator dilution technique at the initiation of endotoxin infusion did not differ significantly from the corresponding values for sham animals. Endotoxaemia induced a hypodynamic shock with concurrent pulmonary hypertension and a pronounced deterioration in gas exchange. No increase in extra-vascular lung water was detected with the molecular double-indicator dilution technique in response to endotoxin, whereas this parameter was significantly higher when assessed with the gravimetric method.Conclusion. The molecular double-indicator dilution technique showed similar results as the gravimetrical method for assessment of extra-vascular lung water in non-endotoxaemic conditions. However, during endotoxin-induced lung injury the molecular double indicator dilution technique failed to detect the significant increase in extra-vascular lung water as measured by the gravimetric method. These data suggest that the molecular double indicator dilution technique may be of limited value during sepsis-induced lung injury.

Palmar skin conductance variability and the relation to stimulation, pain and the motor activity assessment scale in intensive care unit patients

IntroductionMany intensive care unit (ICU) patients describe pain and other adverse feelings that may impact long-term psychological morbidity. Sympathetically mediated palmar skin conductance variability is related to emotionally induced perspiration and correlates with pain levels in the perioperative setting but has not been studied in ICU patients.MethodsTwenty non-intubated and 20 intubated general ICU patients were included in this observational study. Patients were monitored with the MED-STORM Pain Monitoring System®. The number of skin conductance fluctuations per second (NSCF) was measured in parallel with bedside observation during one hour of intensive care, including rest, procedures and patient-staff interactions. Arousal-agitation level was monitored with the motor activity assessment scale (MAAS). Pain was monitored with the numeric rating scale (0 to 10) in patients able to communicate or by observation in patients unable to communicate.ResultsIn non-intubated patients, NSCF increased with increasing stimulation/pain but also with higher MAAS (P = 0.002). An interaction effect was found, with increased NSCF response to stimulation/pain with increasing MAAS (P < 0.001).In intubated patients, NSCF increased significantly with increasing stimulation/pain (P < 0.001). In contrast to non-intubated patients, no difference in NSCF between MAAS levels was found for any given degree of stimulation in intubated patients.ConclusionsIn critically ill patients, NSCF may be more useful evaluating emotional distress rather than pain alone. It needs to be assessed whether NSCF monitoring is clinically useful and whether controlling emotional distress with the aid of such monitoring may impact on patient care and outcomes.

Inhaled tezosentan reduces pulmonary hypertension in endotoxin-induced lung injury.

ABSTRACT The vasoconstrictive and proinflammatory peptide endothelin 1 (ET-1) is highly involved in the pathogenesis of sepsis and associated lung injury. Systemic administration of ET-receptor antagonists has been beneficial in experimental pulmonary hypertension. We wanted to study the effects of inhaled tezosentan, a dual endothelin-receptor antagonist on endotoxin-induced pulmonary hypertension, deterioration of gas exchange, and edema formation. After 2 h of endotoxemia, 28 anesthetized, mechanically ventilated pigs were randomized to either inhaled tezosentan 0.5 mg · kg−1 (TEZO0.5, n = 7), 0.05 mg · kg−1 (TEZO0.05, n = 7), intravenous 0.5 mg · kg−1 (TEZOiv, n = 7), or control (n = 7). Cardiopulmonary hemodynamics and gas-exchange parameters were recorded as well as extravascular lung water and pulmonary capillary pressure. In addition, plasma levels of tezosentan and ET-1 were analyzed. The protocol lasted for 5 h. Endotoxin-induced pulmonary hypertension (mean pulmonary artery pressure) was efficiently reduced by all treatments (TEZO0.5 24 ± 2, TEZO0.05 27 ± 2, TEZOiv 26 ± 1, and control 37 ± 2 mmHg at 4 h). TEZO0.5 and TEZOiv also reduced pulmonary capillary pressure. All treatments led to a modest reduction in extravascular lung water, whereas no effects were noted on oxygenation or systemic circulation. Despite similar effects on pulmonary hypertension systemic treatment resulted in significantly higher plasma levels of ET-1 (twofold) and tezosentan (10- to 100-fold). Inhalation of the dual ET-receptor antagonist tezosentan was feasible and efficiently counteracted endotoxin-induced pulmonary hypertension. These effects were obtained with only minor systemic uptake of tezosentan and without affecting circulating levels of plasma ET-1 as compared with intravenous administration.

Endotoxin Induces Differentiated Contractile Responses in Porcine Pulmonary Arteries and Veins

Background/Aims: Sepsis-induced lung injury is characterized by pulmonary hypertension, edema and deteriorated gas exchange. As in vivo studies have indicated that bacterial endotoxin predominantly induces a pulmonary venous constriction, we aimed to investigate effects of endotoxin on isolated porcine pulmonary vessels. Methods: Pulmonary arteries and veins were examined using in vitro isometric force recordings. Endothelin-receptor protein expression and distribution were analyzed by Western blot and immunohistochemistry. Freshly isolated preparations and vessels incubated (24 h) with/without endotoxin (10 µg·ml–1) were compared. The contractile responses to phenylephrine, UK14.304, U46619, PGF2α, endothelin-1 (ET-1) and sarafotoxin were recorded, as well as the relaxation in response to acetylcholine, isoproterenol and nitroprusside. Results: In freshly isolated vessels, phenylephrine-induced contractions had a 5-times larger amplitude in arteries than in veins. The amplitude of the contractions in response to sarafotoxin was nearly 2 times larger in veins than in arteries, but there was no difference in responses to ET-1. Endotoxin markedly reduced phenylephrine-induced contractions in both arteries and veins, whereas the responses to ET-1 and sarafotoxin were augmented in veins only. No apparent changes in ET receptor expression or distribution were detected with Western blot or immunohistochemistry. Conclusion: Endotoxin differentially and selectively alters the contractile responses of porcine pulmonary vessels in vitro, towards a situation where the α-1 adrenergic responses of arteries are attenuated and the ET responses of veins are augmented. In situations with high adrenergic activity and high circulating ET levels, such as sepsis, these results may provide a mechanism contributing to pulmonary hypertension and edema formation.

Heparin-binding protein (HBP/CAP37) – a link to endothelin-1 in endotoxemia-induced pulmonary oedema?

Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro‐inflammatory peptide endothelin‐1 (ET‐1) correlate with mortality. During sepsis, neutrophils release heparin‐binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET‐signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET‐receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET‐receptor agonist infusions.