Vasopressin in septic shock: effects on pancreatic,renal, and hepatic blood flow

Introduction  

Vasopressin has been shown to increase blood pressure in catecholamine-resistant septic shock. The aim of this study was to measure the effects of low-dose vasopressin on regional (hepato-splanchnic and renal) and microcirculatory (liver, pancreas, and kidney) blood flow in septic shock.     

N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report

Background  

N-acetylcysteine (NAC) has been shown to improve splanchnic blood flow in experimental studies. This report evaluates the effects of NAC on liver perfusion and lactate signal intensities in the liver tissue of septic shock patients using proton magnetic resonance imaging and spectroscopy. Furthermore, the monoethylglycinexylidide (MEGX) test was used to investigate hepatic function.     

Short-term effects of terlipressin bolus infusion on sublingual microcirculatory blood flow during septic shock

Purpose  

Terlipressin bolus infusion may contribute to overshooting increases in systemic vascular resistance with concomitant reductions in systemic blood flow and oxygen delivery. Whether these effects negatively impact on microcirculatory perfusion is still not known. The objective of the present study was, therefore, to elucidate the effects of a single terlipressin bolus dose of 0.5 mg on microcirculatory perfusion in patients with catecholamine-dependent septic shock.     

Sublingual microcirculatory changes during high-volume hemofiltration in hyperdynamic septic shock patients

Introduction  

Previous studies have suggested that high volume hemofiltration (HVHF) may contribute to revert hypotension in severe hyperdynamic septic shock patients. However, arterial pressure stabilization occurs due to an increase in systemic vascular resistance, which could eventually compromise microcirculatory blood flow and perfusion. The goal of this study was to determine if HVHF deteriorates sublingual microcirculation in severe hyperdynamic septic shock patients.     

Rescue treatment with terlipressin in children with refractory septic shock: a clinical study

Introduction  

Refractory septic shock has dismal prognosis despite aggressive therapy. The purpose of the present study is to report the effects of terlipressin (TP) as a rescue treatment in children with catecholamine refractory hypotensive septic shock.     

Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial

Introduction  

It is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock.     

Classification of sepsis,severe sepsis and septic shock: the impact of minor variations in data capture and definition of SIRS criteria

Purpose  

To quantify the effects of minor variations in the definition and measurement of systemic inflammatory response syndrome (SIRS) criteria and organ failure on the observed incidences of sepsis, severe sepsis and septic shock.     

Effects of changes in arterial pressure on organ perfusion during septic shock

Introduction  

Septic shock is characterized by altered tissue perfusion associated with persistent arterial hypotension. Vasopressor therapy is generally required to restore organ perfusion but the optimal mean arterial pressure (MAP) that should be targeted is uncertain. The aim of this study was to assess the effects of increasing MAP using norepinephrine (NE) on hemodynamic and metabolic variables and on microvascular reactivity in patients with septic shock.     

Increased MerTK expression in circulating innate immune cells of patients with septic shock

Purpose

A new pathway of three protein tyrosine kinase receptors, namely, the TAM receptor family [Tyro-3, Axl and Mer tyrosine kinase (MerTK)], has recently been described to negatively control immune responses. The objective of this prospective, observational, clinical study was to investigate the expression patterns of TAM receptors in circulating white blood cells collected from patients with septic shock.

Methods

The expression of TAM receptors was measured by flow cytometry in circulating leukocytes from patients with septic shock sampled on days (D) 1–2 (n = 47) and D3–4 (n = 37) after the onset of shock, severe trauma patients at D1–2 after trauma (n = 51) and healthy individuals (n = 23).

Results

On D1–2 after injury, MerTK was overexpressed in monocytes and neutrophils collected from patients with septic shock in comparison with those collected from healthy volunteers and trauma patients. This phenomenon was also observed for mRNA. Conversely, the expression of Tyro-3 and Axl was higher in monocytes from trauma patients versus healthy volunteers or those in septic shock. MerTK expression between D1–2 and D3–4 remained elevated in patients suffering from septic shock who died or developed an intensive care unit-acquired infection, whereas it decreased in patients who recovered uneventfully. This in vivo observed expression pattern was reproduced ex vivo after the incubation of healthy volunteer cells with plasma from septic shock or trauma patients.

Conclusions

MerTK expression in circulating innate immune cells is increased in patients with septic shock in comparison with healthy volunteers and trauma patients. Persistent MerTK overexpression after septic shock is associated with adverse outcome. The role of this family of receptors in the pathophysiology of injury-induced immune dysfunctions deserves to be specifically investigated.     

Effects of norepinephrine on renal perfusion,filtration and oxygenation in vasodilatory shock and acute kidney injury

Purpose  

The use of norepinephrine (NE) in patients with volume-resuscitated vasodilatory shock and acute kidney injury (AKI) remains the subject of much debate and controversy. The effects of NE-induced variations in mean arterial blood pressure (MAP) on renal blood flow (RBF), oxygen delivery (RDO₂), glomerular filtration rate (GFR) and the renal oxygen supply/demand relationship (renal oxygenation) in vasodilatory shock with AKI have not been previously studied.     

Impairment of renal function using hyperoncotic colloids in a two hit model of shock: a prospective randomized study

Introduction  

One of the therapeutic essentials in severe sepsis and septic shock is an adequate fluid replacement to restore and maintain circulating plasma volume, improve organ perfusion and nutritive microcirculatory flow. The type of solution to be used as a fluid replacement remains under discussion. The aim of the study was to evaluate the effects of clinically used fluid replacement solutions on renal function and inflammatory response.     

Recombinant human activated protein C attenuates cardiovascular and microcirculatory dysfunction in acute lung injury and septic shock

Introduction

This prospective, randomized, controlled, experimental animal study looks at the effects of recombinant human activated protein C (rhAPC) on global hemodynamics and microcirculation in ovine acute lung injury (ALI) and septic shock, resulting from smoke inhalation injury.

Methods

Twenty-one sheep (37 ± 2 kg) were operatively prepared for chronic study and randomly allocated to either the sham, control, or rhAPC group (n = 7 each). The control and rhAPC groups were subjected to insufflation of four sets of 12 breaths of cotton smoke followed by instillation of live Pseudomonas aeruginosa into both lung lobes, according to an established protocol. Healthy sham animals were not subjected to the injury and received only four sets of 12 breaths of room air and instillation of the vehicle (normal saline). rhAPC (24 μg/kg/hour) was intravenously administered from 1 hour post injury until the end of the 24-hour experiment. Regional microvascular blood flow was analyzed using colored microspheres. All sheep were mechanically ventilated with 100% oxygen, and fluid resuscitated with lactated Ringer's solution to maintain hematocrit at baseline levels.

Results

The rhAPC-associated reduction in heart malondialdehyde (MDA) and heart 3-nitrotyrosine (a reliable indicator of tissue injury) levels occurred parallel to a significant increase in mean arterial pressure and to a significant reduction in heart rate and cardiac output compared with untreated controls that showed a typical hypotensive, hyperdynamic response to the injury (P < 0.05). In addition, rhAPC significantly attenuated the changes in microvascular blood flow to the trachea, kidney, and spleen compared with untreated controls (P < 0.05 each). Blood flow to the ileum and pancreas, however, remained similar between groups. The cerebral blood flow as measured in cerebral cortex, cerebellum, thalamus, pons, and hypothalamus, was significantly increased in untreated controls, due to a loss of cerebral autoregulation in septic shock. rhAPC stabilized cerebral blood flow at baseline levels, as in the sham group.

Conclusions

We conclude that rhAPC stabilized cardiovascular functions and attenuated the changes in visceral and cerebral microcirculation in sheep suffering from ALI and septic shock by reduction of cardiac MDA and 3-nitrotyrosine.     

Comparative effects of recombinant human activated protein C and dexamethasone in experimental septic shock

Purpose  

To compare the effects of recombinant human activated protein C (APC) and glucocorticoids alone and in combination in non-anesthetized resuscitated septic shock induced by cecal ligation and puncture (CLP) on (a) survival, (b) hemodynamics, and (c) vascular reactivity. The effects of treatments on major cellular pathways likely implicated were also studied.     

Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock

Introduction  

Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo.     

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

Introduction  

Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.     

Influence of Red Blood Cell Storage Time on Clinical Course and Cytokine Profile in Septic Shock Patients

Background

Previous investigations have suggested beneficial effects of fresh versus stored red blood cell transfusion in critically ill patients. The present study investigates the effects of red blood cell storage time on the clinical course and hemodynamic and laboratory parameters in patients with septic shock.

Patients and Methods

18 patients with septic shock received 2 erythrocyte units stored for ? 7 days (n = 8) or > 7 days (n = 10). The sequential organ failure assessment (SOFA) score was calculated for 7 days. Hemodynamic parameters (cardiac index, extravascular lung water) were determined using transpulmonary thermodilution. Laboratory parameters (lactate, base excess, C-reactive protein, procalcitonin, IL-1Β, IL-6, TNF-α, sVCAM-1, sICAM-1) were monitored before and 1, 3, 6, 12, 24, and 48 h after transfusion. The Mann-Whitney-U test and Neumann test were used for group comparison and trend assessment, respectively.

Results

We failed to observe significant differences with respect to SOFA scores between patients receiving fresh or stored erythrocytes. However, a significant trend towards an improvement in the SOFA score was found in the group receiving fresh erythrocytes (p < 0.01). No significant differences in hemodynamic or laboratory parameters were found between both groups. Conclusion: While the present findings do not provide clear-cut evidence supporting beneficial effects of fresh red blood cells in septic shock, they warrant larger randomized studies to confirm or refute such effects.     

Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients

Purpose  

Improvements in survival after septic shock will most likely rely on our capacity to manage individualized therapies based on the measurement of rapidly accessible biomarkers. As the early phase of septic shock is dominated by severe alterations of the cardiovascular system, the predictive value for mortality of pro-vasopressin (pro-AVP) and pro-adrenomedullin (pro-ADM), two vasoactive pro-hormones, was assessed.     

N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report

Background

N-acetylcysteine (NAC) has been shown to improve splanchnic blood flow in experimental studies. This report evaluates the effects of NAC on liver perfusion and lactate signal intensities in the liver tissue of septic shock patients using proton magnetic resonance imaging and spectroscopy. Furthermore, the monoethylglycinexylidide (MEGX) test was used to investigate hepatic function.

Methods

Five septic shock patients received 150 mg/kg body weight NAC as an intravenous bolus injection over 15 min. Lidocaine was injected both prior to and following NAC administration in order to determine MEGX formation. Measurements (hemodynamics, oxygen transport-related variables, blood samples for lactate, liver-related markers) were performed 1 hour before and 1 hour after NAC injection. In addition to the proton magnetic resonance imaging patients received two proton magnetic resonance spectra, one prior to and one 30 min subsequent to the onset of the NAC infusion at a 1.5 Tesla clinical scanner, for measurement of liver perfusion and liver lactate signal intensity.

Main findings

Following NAC infusion, the lactate signal intensity in the liver tissue showed a median decrease of 89% (11–99%), there was a median increase in liver perfusion of 41% (-14 to 559%), and the MEGX serum concentration increased three times (1.52–5.91).

Conclusions

A decrease in the lactate signal intensity in the liver tissue and an increase in the MEGX serum concentration and in liver perfusion might indicate improved liver function as a result of NAC administration. Patients with compromised hepatosplanchnic function, such as patients with septic shock due to peritonitis, may therefore benefit from NAC therapy.     

Clinical relevance of the severe abnormalities of the T cell compartment in septic shock patients

Introduction  

Given the pivotal role of T lymphocytes in the immune system, patients with septic shock may show T cell abnormalities. We have characterised the T cell compartment in septic shock and assess its clinical implications.     

Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock

Introduction

Stimulation of beta₂-adrenergic receptors (β₂-ARs) inhibits tumor necrosis factor-alpha (TNF-α) release in monocytes. In septic shock, endogenous catecholamines induce β₂-AR downregulation, leading to an increased TNF-α release. The aims of this study were to analyze the molecular mechanisms of β-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4).

Methods

We conducted in vitro stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin B (SEB) without or with isoprenaline, forskolin (an activator of adenylate cyclase), or ropipram (an inhibitor of PDE4). We also conducted flow cytometric analysis of Toll-like receptor (TLR) 4 and TLR2 surface expression and intracellular TNF-α production of untreated and stimulated CD14⁺ monocytes. Protein expression of β-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting.

Results

Investigations were done by LPS (100 ng/mL) or SEB (10 ng/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14⁺ monocytes of healthy volunteers were able to produce TNF-α. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14⁺ monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14⁺ monocytes of healthy volunteers were compared with patients with septic shock: protein expression of β₂-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found.

Conclusions

In septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of β₂-ARs and upregulation of the inhibitory G protein in CD14⁺ monocytes. Beta-adrenergic downregulation is overcome by inhibitors of PDE4. These results provide a mechanistic rationale for the therapeutic use of selective PDE4 inhibitors in the treatment of septic shock.