Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties

Analyses of cerebral microdialysis in patients with traumatic brain injury: relations to intracranial pressure, cerebral perfusion pressure and catheter placement

<p>Abstract</p> <p>Background</p> <p>Cerebral microdialysis (MD) is used to monitor local brain chemistry of patients with traumatic brain injury (TBI). Despite an extensive literature on cerebral MD in the clinical setting, it remains unclear how individual levels of real-time MD data are to be interpreted. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are important continuous brain monitors in neurointensive care. They are used as surrogate monitors of cerebral blood flow and have an established relation to outcome. The purpose of this study was to investigate the relations between MD parameters and ICP and/or CPP in patients with TBI.</p> <p>Methods</p> <p>Cerebral MD, ICP and CPP were monitored in 90 patients with TBI. Data were extensively analyzed, using over 7,350 samples of complete (hourly) MD data sets (glucose, lactate, pyruvate and glycerol) to seek representations of ICP, CPP and MD that were best correlated. MD catheter positions were located on computed tomography scans as pericontusional or nonpericontusional. MD markers were analyzed for correlations to ICP and CPP using time series regression analysis, mixed effects models and nonlinear (artificial neural networks) computer-based pattern recognition methods.</p> <p>Results</p> <p>Despite much data indicating highly perturbed metabolism, MD shows weak correlations to ICP and CPP. In contrast, the autocorrelation of MD is high for all markers, even at up to 30 future hours. Consequently, subject identity alone explains 52% to 75% of MD marker variance. This indicates that the dominant metabolic processes monitored with MD are long-term, spanning days or longer. In comparison, short-term (differenced or Δ) changes of MD vs. CPP are significantly correlated in pericontusional locations, but with less than 1% explained variance. Moreover, CPP and ICP were significantly related to outcome based on Glasgow Outcome Scale scores, while no significant relations were found between outcome and MD.</p> <p>Conclusions</p> <p>The multitude of highly perturbed local chemistry seen with MD in patients with TBI predominately represents long-term metabolic patterns and is weakly correlated to ICP and CPP. This suggests that disturbances other than pressure and/or flow have a dominant influence on MD levels in patients with TBI.</p

The endothelin system and cardiopulmonary dysfunction in porcine endotoxin shock

The endothelium-derived peptide endothelin-1, acting via the endothelinA and endothelinB receptors, possesses strong vasoconstrictive properties shown to affect pulmonary and systemic circulation as well as cardiac function. During septic and endotoxin shock a marked increase in circulating plasma endothelin-1 levels is observed which is associated with morbidity, cardiac dysfunction and lung injury. Also metabolites of the cyclooxygenase pathway are increased in these conditions. The aims of the present thesis were to study the involvement of the endothelin system in endotoxin shock with special reference to pulmonary and cardiovascular dysfunction by the use of nonselective and selective endothelin receptor antagonists. Further, to elucidate the contribution to pulmonary hypertension by cyclooxygenase products. The studies were conducted in a porcine endotoxin shock model. Pulmonary and systemic haemodynamics, cardiac function, splenic, intestinal and renal blood flows together with lung compliance, gas exchange, acid-base balance and tissue prepro endothelin-1 mRNA, plasma big endothelin-1and endothelin-1-like immunoreactivity levels were measured. Endotoxin induced a hypodynamic shock with a biphasic pulmonary hypertension, a decrease in cardiac output, stroke volume, mean arterial blood pressure, an impaired pulmonary gas exchange and a systemic metabolic acidosis. This was associated with an increase in prepro endothelin-1mRNA, plasma big endothelin-1and endothelin-1-like immunoreactivity levels. Pretreatment with a nonselective endothelin receptor antagonist reduced basal vascular tone in the pulmonary, systemic and splenic circulation. The late phase of endotoxin-induced pulmonary hypertension was counteracted and cardiac output, stroke volume, splenic and intestinal blood flow were increased. A further elevation of plasma endothelin-1-like immunoreactivity but not in tissue prepro endothelin-1 mRNA or plasma big endothelin-1-like immunoreactivity levels was seen. By combining the pretreatment with cyclooxygenase inhibition also the early phase of pulmonary hypertension was counteracted. During established shock, administration of nonselective endothelin receptor antagonists abolished the pulmonary hypertension, reversed the decrease in cardiac index, counteracted a diminished stroke volume index and resulted in higher coronary blood flow compared to control animals. No negative effect on cardiac contractility was seen. Further, alveolar content of protein and leukocytes were decreased and the metabolic acidosis was counteracted. Selective endothelinA receptor antagonism during established shock was also effective in counteracting endotoxin-induced pulmonary hypertension but was essentially without effects on cardiac function, metabolic acidosis and plasma endothelin-1-like immunoreactivity levels. Selective endothelinB receptor antagonism resulted in cardiovascular collapse and death. Combining the two selective antagonists resulted in similar enhancements in pulmonary and cardiovascular function as nonselective endothelin receptor antagonism. In conclusion: In the present hypodynamic endotoxin shock model, profound effects on pulmonary and cardiovascular functions are seen. The cyclooxygenase pathway participates in the early phase of pulmonary hypertension whereas in the late phase the endothelin system is involved, largely via the endothelinA receptor. Both endothelin receptor types are involved in the disturbances in systemic circulation and cardiac function. Endothelin receptor antagonism does not affect endothelin-1synthesis but increases plasma endothelin- I-like immunoreactivity levels further, most probably due to antagonism of the endothelinB receptor. In porcine endotoxin shock, pulmonary and cardiovascular dysfunction occurs simultaneously with an increased production of endothelin-1, reflected in an increase in plasma endothelin-1 like immunoreactivity levels. Thus, the endothelin system is deeply involved in the cardiopulmonary dysfunction in the current model, and a simultaneous blockade of both the endothelinA and endothelinB receptor counteracts these disturbances, even when administered during established shock

Hand- och benstyrka vid intensivvårdsavdelning (IVA)-mottagning, -en retrospektiiv studie

Strength in hand and legs at intensive care unit (ICU) follow up-reception: a retrospective studyEarly mobilization is well established in intensive care and includes sitting, standing and walking and thereby lower extremity activation. Equivalent strategy for upper extremity activation is lacking, therefore, there might be a higher degree of remaining disability in the hand/arm. This retrospective study aimed to describe the strength in hand and legs, and the relationship therebetween, at an intensive care unit (ICU) follow up-reception. Hand dynamometer and Timed-Stands Test (TST) were measured and correlated to illness severity by Simplified Acute Physiology Score III (SAPS3). Data from 47 participants was compared to matched control values. The hand strength was lower (p=0,028) with low effect (r=-0,2), of clinical relevance as it may affect the ability in activities of daily living (ADL). There were no significant differences for strength in the legs, correlation between strength and illness severity and for comparison of strength divided by illness severity. Larger studies are recommended

Cardiac effects of endothelin receptor antagonism in endotoxemic pigs.

Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock, and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. Sixteen domestic pigs were anesthetized and subjected to endotoxin for 5 h. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after 3 h. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function [end-systolic elastance (Ees), preload recruitable stroke work (PRSW), power(max)/end-diastolic volume (PWR(max)/EDV) and dP/dt(max)/end-diastolic volume (dP/dt(max)/EDV)] but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PWR(max)/EDV, and dP/dt(max)/EDV, while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function