Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized,double-blind,placebo-controlled,pilot trial

IntroductionWe previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function.MethodsWe performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ≥18 years) with severe sepsis or septic shock between November 2012 and January 2014 were included. Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between groups using repeated measures models.ResultsWe enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was 62 ± 16 years and 47 % were female. Baseline characteristics and CoQ10 levels were similar for both groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We found no difference between the two groups in any of the secondary outcomes.ConclusionsIn this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis or septic shock, with the administration of oral ubiquinol. Further research is needed to address whether ubiquinol administration can result in improved clinical outcomes in this patient population.

Trial registration

Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01948063","term_id":"NCT01948063"}}NCT01948063. Registered on 18 February 2013.     

Critical illness is associated with decreased plasma levels of coenzyme Q10: A cross-sectional study

Purpose

Plasma coenzyme Q10 (CoQ10) levels are lower in patients with septic shock (SS) than in healthy controls (HCs). However, CoQ10 status in critically ill patients without SS is unknown. Here, we investigated CoQ10 concentrations in patients with SS and without SS as compared with HCs.

Materials and Methods

We enrolled 36 critically ill patients and 18 HCs. Plasma CoQ10 concentrations were measured, and patients' clinical and demographical data were collected.

Results

Plasma CoQ10 concentrations were lower in critically ill patients (0.50 ± 0.36 μg/mL, P < .001), both in patients with SS (0.37 ± 0.25 μg/mL, P = .002) and patients without SS (0.56 ± 0.39, P = .04), as compared with HCs (0.79 ± 0.19). Coenzyme Q10 levels did not differ between patients with SS and patients without SS (P = .13). In critically ill patients, CoQ10 levels inversely correlated with age (r = − 0.40, P = .015) and did not correlate with partial pressure of oxygen in the arterial blood/fraction of inspired oxygen, Simplified Acute Physiology Score II, Systemic Organ Failure Assessment score, or mortality. Lower CoQ10 levels were associated with lower activities of daily living score after discharge (P = .005), independent of age.

Conclusions

Decreased plasma CoQ10 levels are not specific to patients with SS, but rather observed in a broad range of critically ill patients. In critically ill patients, CoQ10 insufficiency may be associated with various conditions; age may be a risk factor.     

Cerebral microcirculation is impaired during sepsis: an experimental study

Introduction  

Pathophysiology of brain dysfunction due to sepsis remains poorly understood. Cerebral microcirculatory alterations may play a role; however, experimental data are scarce. This study sought to investigate whether the cerebral microcirculation is altered in a clinically relevant animal model of septic shock.     

Increased muscle-to-serum lactate gradient predicts progression towards septic shock in septic patients

Purpose  

During septic shock, muscle produces lactate and pyruvate by way of an exaggerated Na⁺, K⁺-ATPase-stimulated aerobic glycolysis associated with epinephrine stimulation. We hypothesized that patients with sepsis without shock and increased epinephrine levels or an increased muscle-to-serum lactate gradient are likely to evolve towards septic shock. Thus, in sepsis patients, we investigated (1) whether muscle produces lactate and pyruvate, and (2) whether muscle lactate production is linked to epinephrine levels and the severity of the patient's condition.     

Activated protein C in septic shock: a propensity-matched analysis

Introduction  

The use of human recombinant activated protein C (rhAPC) for the treatment of severe sepsis remains controversial despite multiple reported trials. The efficacy of rhAPC remains a matter of dispute. We hypothesized that patients with septic shock who were treated with rhAPC had an improved in-hospital mortality compared to patients with septic shock with similar acuity who did not receive rhAPC.     

Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy

Introduction  

Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.     

Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study

Introduction  

The use of low-dose steroid therapy in the management of septic shock has been extensively studied. However, the association between the timing of low-dose steroid therapy and the outcome has not been evaluated. Therefore, we evaluated whether early initiation of low-dose steroid therapy is associated with mortality in patients with septic shock.     

Plasma from septic shock patients induces loss of muscle protein

Introduction  

ICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.     

Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock?

Purpose  

Response to fluid challenge is often defined as an increase in cardiac index (CI) of more than 10–15%. However, in clinical practice CI values are often not available. We evaluated whether changes in mean arterial pressure (MAP) correlate with changes in CI after fluid challenge in patients with septic shock.     

Critical illness-related corticosteroid insufficiency in cancer patients

Purpose  

Critically ill cancer patients with sepsis represent a high-risk sub-group for the development of critical illness-related corticosteroid insufficiency (CIRCI); however, the incidence of CIRCI in this population is unknown. The purpose of this study was to determine the incidence of CIRCI in cancer patients with severe sepsis or septic shock.     

Prognostic values of serum cytokines in septic shock

Objective

To prospectively evaluate the prognostic values of two serum cytokine levels, TNFα and IL 6 serially measured at predetermined intervals in septic shock patients unresponsive to correction of hypoxaemia and plasma volume expansion and treated according to a strict protocol designed to meet specific therapeutic goals (goal-directed therapy). The evolution of serum lactate levels and oxygen-derived parameters was also investigated.

Design

A prospective case series study. Patients were followed-up until they were discharged from the hospital, or died.

Setting

ICU of a university hospital.

Patients

30 consecutive patients with septic shock of various origins.

Interventions

The therapy was aimed at achieving and maintaining for at least 24 h supranormal values CI (≥4.01·min^?1·m^?2), oxygen delivery (DO₂≥550ml· min^?1·m^?2) and oxygen uptake (VO₂≥150ml·min^?1· m^?2) using a combination of fluid loading, norepinephrine, dobutamine and dopamine. A significant decrease in TNFα levels was associated with a favourable outcome while TNFα levels remained elevated in the patients who died in shock or of multiple organ failure. No prognostic value was associated with changes in IL 6 concentrations. In a stepwise logistic regression analysis, only TNFα levels contributed significantly to prediction of patients' outcome. A significant decrease in serum lactate concentrations was observed both in survivors and in patients who survived the episode of septic shock, but subsequently died of multiple organ failure. A positive DO₂/VO₂ relationship was observed only in survivors but did not contribute significantly to prediction of patient outcome.

Conclusions

TNFα is a major mediator involved in the pathogenesis of septic shock and its decrease was significantly associated with a favourable outcome. IL 6 is certainly involved in the pathophysiology of septic shock but further studies are required to determine whether or not it is directly involved in the mediation of late and lethal complications of septic shock. Serum lactate levels and oxygen-derived variables were of less interest as prognostic factors.     

Interleukin-10 gene down-expression in circulating mononuclear cells during infusion of drotrecogin-α activated: a pilot study

Introduction  

The purpose of this study was to investigate the gene expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in circulating mononuclear cells harvested from septic shock patients on drotrecogin-α activated (DAA) in order to determine whether this treatment has any effect on the inflammation phase.     

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.     

Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury

Purpose

To study the impact of inflammation/sepsis on the concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in plasma and urine in adult intensive care unit (ICU) patients and to estimate the predictive properties of NGAL in plasma and urine for early detection of acute kidney injury (AKI) in patients with septic shock.

Methods

Sixty-five patients admitted to the general ICU at the Karolinska University Hospital Solna, Sweden, with normal plasma creatinine were assessed for eligibility. Twenty-seven patients with systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock without AKI and 18 patients with septic shock and concomitant AKI were included in the final analysis. Plasma and urine were analyzed twice daily for plasma NGAL (pNGAL), C-reactive protein (CRP), procalcitonin, myeloperoxidase, plasma cystatin C, plasma creatinine, urine NGAL (uNGAL), urine cystatin C, and urine α1-microglobulin.

Results

Of the 45 patients, 40 had elevated peak levels of pNGAL. Peak levels of pNGAL were not significantly different between septic shock patients with and without AKI. Peak levels of uNGAL were below the upper reference limit in all but four patients without AKI. uNGAL was a good predictor (area under ROC 0.86) whereas pNGAL was a poor predictor (area under ROC 0.67) for AKI within the next 12 h in patients with septic shock.

Conclusions

pNGAL is raised in patients with SIRS, severe sepsis, and septic shock and should be used with caution as a marker of AKI in ICU patients with septic shock. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI.     

Vasopressin and copeptin levels in children with sepsis and septic shock

Purpose

Levels of vasopressin and its precursor copeptin in pediatric sepsis and septic shock are not well defined. The main aim of this study is to compare the serum levels of vasopressin and copeptin in children with septic shock or sepsis and in healthy children. We hypothesized that vasopressin and copeptin levels are elevated in early and late stages of pediatric septic shock.

Methods

Three groups were included: healthy children, children with clinical diagnosis of sepsis, and children admitted to the pediatric intensive care unit (PICU) with diagnosis of sepsis shock. Blood samples were drawn from children in all groups within 24 h of admission. For the septic shock group, additional samples at 24-h intervals were drawn up to 120 h after PICU admission. We used competitive immunoassays to determine vasopressin and copeptin levels.

Results

There were 70 children in the control group, 53 children in the sepsis group, and 13 in the septic shock group. At baseline, there was a difference in median vasopressin levels [60.9 (Interquartile range: 32.3, 138.0) vs. 141.1 (45.2, 542) vs. 326 (55.6, 399) pg/mL, p < 0.05], but there was no difference in copeptin levels [1.2 (0.8, 1.8) vs. 1.5 (1.0, 2.2) vs. 0.9 (0.8, 1.2) ng/mL, p = 0.14] between the three groups. There was no difference in vasopressin and copeptin levels in early and late stages of pediatric septic shock.

Conclusions

Baseline vasopressin levels were different between the three groups. In pediatric septic shock, vasopressin and copeptin levels are not robust markers for severity and clinical outcomes.     

Effect of mode of hydrocortisone administration on glycemic control in patients with septic shock: a prospective randomized trial

Introduction  

Low-dose hydrocortisone treatment is widely accepted therapy for the treatment of vasopressor-dependent septic shock. The question of whether corticosteroids should be given to septic shock patients by continuous or by bolus infusion is still unanswered. Hydrocortisone induces hyperglycemia and it is possible that continuous hydrocortisone infusion would reduce the fluctuations in blood glucose levels and that tight blood glucose control could be better achieved with this approach.     

High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality

Introduction  

Current guidelines recommend maintaining central venous oxygen saturation (ScvO₂) higher than 70% in patients with severe sepsis and septic shock. As high levels of ScvO₂ may reflect an inadequate use of oxygen, our aim was to evaluate the relation between maximal ScvO₂ levels (ScvO_2max ) and survival among intensive care unit (ICU) patients with septic shock.     

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.     

Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock

Purpose  

Sepsis-induced immunosuppression is postulated to contribute to a heightened risk of nosocomial infection (NI). This prospective, single-center, observational study was conducted to assess whether low monocyte human leukocyte antigen-DR expression (mHLA-DR), proposed as a global biomarker of sepsis immunosuppression, was associated with an increased incidence of NI after septic shock.     

Effects of coenzyme Q10 in hemorrhagic shock

We studied the effects of coenzyme Q10 (CoQ10) on pulmonary function and chemical mediators in a canine model of hemorrhagic shock. One group received 10 mg/kg of CoQ10 before hemorrhage. During the study, percent change from baseline of peak airway pressure, total lung compliance of the lung and chest wall, and blood lactate levels appeared to be significantly smaller in dogs pretreated with CoQ10 than in controls. Furthermore, CoQ10 was found to maintain blood histamine levels and to attenuate the increase in leukotriene C4. The mechanism of the beneficial effects of CoQ10 in hemorrhagic shock is presently unknown, but our data suggest that it may be useful in the treatment of hemorrhagic shock.