Marius Terblanche

Statins and sepsis: multiple modifications at multiple levels

Sepsis, an infection-induced inflammatory syndrome, is a leading and increasing cause of mortality worldwide. Animal and human observational studies suggest statins may prevent the morbidity and mortality associated with the sepsis syndrome. In this Review, we describe the demonstrated mechanisms through which statins modulate the inflammatory response associated with sepsis. These mechanisms include effects on cell signalling with consequent changes at the transcriptional level, the induction of haem oxygenase, the direct alteration of leucocyte-endothelial cell interaction, and the reduced expression of MHC II. Since statins do not target individual inflammatory mediators, but possibly reduce the overall magnitude of the systemic response, this effect could prove an important distinguishing feature modulating the host response to septic insults. This work establishes the biological plausibility needed for future trials of statins in critical illness.

Statins: panacea for sepsis?

Sepsis occurs when the immune system responds to a localised infection at a systemic level, thereby causing tissue damage and organ dysfunction. Statins have proven health benefits in many diseases involving vascular inflammation and injury. Recent animal data suggest that the administration of a statin before a sepsis-inducing insult reduces morbidity and improves survival. The immunomodulatory and anti-inflammatory effects of statins, collectively referred to as pleiotropic effects, lend biological plausibility to such findings. Limited human data hint at reduced mortality rates in bacteraemic patients, and a reduced risk of sepsis in patients with bacterial infections concurrently taking statins. These lines of evidence point to a potential new treatment and prevention modality for sepsis. The stage is set for randomised controlled clinical trials that will determine whether statins represent a safe and beneficial treatment in critically ill, septic patients and whether statins are effective at preventing sepsis in high-risk clinical settings.

The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial.

Objectives:Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. Design:Prospective open-label randomized controlled pilot trial. Setting:Four adult ICUs in London teaching hospitals. Patients:Sixty-one adult patients who had septic shock. Interventions:Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6–12 and 24–36 hours after hydrocortisone/placebo administration. Measurements and Main Results:Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1–5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32–0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, –32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. Conclusions:Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.

Do statins have a role in preventing or treating sepsis

Statins have a variety of properties that are independent of their lipid lowering ability. These anti-inflammatory, antioxidant, immunomodulatory, and antiapoptotic features have been collectively referred to as pleiotropic effects. Severe sepsis is an intense infection-induced inflammatory syndrome that ultimately results in organ dysfunction. Because so many cascades are triggered during sepsis, merely blocking a single component may be insufficient to arrest the inflammatory process. A growing body of evidence suggests that statins may indeed have a protective effect against severe sepsis and reduce the rate of infection-related mortality. This novel primary prevention concept may have far-reaching implications for the future management of serious infections. Moreover, it was recently shown that statins potentially improve outcome after the onset of sepsis. The stage is now set for randomized clinical trials that will determine the precise role, if any, that statins may have in preventing and treating sepsis.

Potential metabolic consequences of statins in sepsis

Objective: Statins may be important for the prevention and management of sepsis; however, through their impact on ubiquinone synthesis, they may impair mitochondrial and organ function in the septic patient. Here we provide a narrative review of the function and roles of ubiquinone in cellular metabolism, the interactions with statins, and the potential consequences in the critically ill. Data Source: Literature search using the PubMed database. Search terms included statins, mitochondria, ubiquinone, and sepsis. Conclusion: Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and act by decreasing mevalonate levels, a precursor for cholesterol synthesis. However, mevalonate is also a precursor for ubiquinone, an integral component of the mitochondrial respiratory chain and an important antioxidant. Plasma ubiquinone is inversely related to statin levels, and impaired statin metabolism or excretion can decrease ubiquinone levels markedly. This is potentially important as critical illness markedly impairs statin metabolism. As mitochondrial dysfunction may be a major contributor to sepsis-induced organ failure, it is plausible that low ubiquinone levels may exacerbate mitochondrial and organ dysfunction. Furthermore, although the clinical relevance of low ubiquinone levels is currently unknown in the critically ill, this is often cited as a possible cause of the myopathy and rhabdomyolysis associated with statin use.

Statins, bugs and prophylaxis: intriguing possibilities

Statin therapy may represent a potential prophylactic intervention in certain high-risk scenarios, for example in pandemic influenza and in those undergoing aggressive medical treatments. Emerging data indicate a potential prophylactic role in these high-risk groups.

Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study

IntroductionObservational studies suggest statin therapy reduces incident sepsis, but few studies have examined the impact on new organ failure. We tested the hypothesis that statin therapy, administered for standard clinical indications to ventilated intensive care unit patients, prevents acute organ failure without harming the liver.MethodsWe performed a retrospective, single-centre cohort study in a tertiary mixed medical/surgical intensive care unit. Mechanically ventilated patients without nonrespiratory organ failure within 24 hours after admission were assessed (during the first 15 days) for new acute organ failure (defined as Sequential Organ Failure Assessment (SOFA) score 3 or 4), liver failure (defined as new hepatic SOFA ≥3, or a 1.5 times increase of bilirubin from baseline to a value ≥20 mmol/l), and alanine transferase (ALT) > 165 IU/l. The effect of statin administration was explored in generalised linear mixed models.ResultsA total of 1,397 patients were included. Two hundred and nineteen patients received a median (interquartile range) of three (two, eight) statin doses. Patients receiving statins were older (67.4 vs. 55.5 years, P < 0.0001), less likely female (25.1% vs. 37.9%, P = 0.0003) and sicker (Acute Physiology and Chronic Health Evaluation (APACHE) II score 20.3 vs. 17.8, P < 0.0001). Considering outcome events at least 1 day after statin administration, statin patients were equally likely to develop acute organ failure (28.4% vs. 22.3%, P = 0.29) and hepatic failure (9.5% vs. 7.6%, P = 0.34), but were more likely to experience an ALT increase to > 165 IU/l ((11.2% vs. 4.8%, P = 0.0005). Multivariable analysis showed that APACHE II score (odds ratio (OR) = 1.05 per point; 95% confidence interval (CI) = 1.03 to 1.07) and APACHE II admission category (P < 0.0001), but not statin administration (OR = 1.21; 95% CI = 0.92 to 1.62), were significantly associated with acute organ failure occurring on or after the day of first statin administration. Statin administration was not associated with liver impairment (OR = 1.08; 95% CI = 0.66 to 1.77) but was associated with a rise in ALT > 165 IU/l (OR = 2.25; 95% CI = 1.32 to 3.84), along with APACHE II score (P = 0.016) and admission ALT (P = 0.0001).ConclusionsConcurrent statin therapy does not appear to protect against the development of new acute organ failure in critically ill, ventilated patients. The lack of effect may be due to residual confounding, a relatively low number of doses received, or an absence of true effect. Randomised controlled trials are needed to confirm a protective effect.

A web-based survey of United Kingdom sedation practice in the intensive care unit☆☆☆

PURPOSE The purpose of this work was to obtain a detailed perspective of sedation practice. Sedation included sedative and opioid choice, presence of local guidelines, and use of scoring systems. METHODS A Web-based survey was designed. The aim was to gain sufficient detail of UK sedation while also being succinct enough to complete in 15 minutes. It was composed of relevant demographics, policy, sedative choice, and analgesia. The survey was piloted before launch. The investigators selected the intensive care unit (ICU) pharmacist as the respondent. RESULTS One hundred fifty-seven ICUs responded. Eighty-nine (59%) reported use of sedation guidelines, 78% undertook sedation holds, and 87% use sedation scores. Only 42% used a daily sedation target. Seventy (43%) assess for delirium; 27 of those use a validated tool. Propofol (89%) use was common, followed by midazolam (49%). Morphine (49%), fentanyl (34%), and alfentanil (34%) were the most frequently used opioids. CONCLUSION This survey confirmed expected variation in UK sedation practice. Recognized strategies such as target sedation score and sedation policy are underused. A 43% uptake in delirium screening suggests that larger engagement is required to meet national standards.

Tissue saturation measurement--exciting prospects, but standardisation and reference data still needed.

Sepsis and shock result in disturbances in microcirculatory perfusion and tissue oxygen utilisation that may not be reflected in global measures of haemodynamics. Near-infrared spectroscopy enables measurement of tissue oxygen saturation (StO2) and provides information on local microvascular and mitochondrial function. This measure could be incorporated with existing targets of goal-directed therapy to provide an integrated approach to haemodynamic resuscitation of both the macro- and microcirculation in various shock states. However, key methodological factors must be addressed before widespread clinical application.

Beyond the randomized clinical trial: citrate for continuous renal replacement therapy in clinical practice.

Background: Premature circuit clotting is a major problem during continuous renal replacement therapy (CRRT). Six randomized controlled trials confirmed that regional anticoagulation with citrate is superior to heparin. Our objective was to compare circuit patency with citrate, heparin and epoprostenol in routine clinical practice. Methods: We retrospectively analysed data on circuit patency of all circuits used in a single centre between September 2008 and August 2009. We differentiated between premature filter clotting, elective discontinuation and waste. Results: 309 patients were treated with CRRT (n = 2,059 circuits). The mean age was 65.7; 63.8% were male. The methods to maintain circuit patency were unfractionated heparin (42.3%), epoprostenol (23.0%), citrate (14.7%), combinations of different anticoagulants (14.6%) and no anticoagulation (4.7%). Premature clotting was the most common reason for circuit discontinuation among circuits anticoagulated with heparin, epoprostenol or combinations of different anticoagulants (59-62%). Among circuits anticoagulated with citrate the main reason for discontinuation was elective (61%). Hazard regression analysis confirmed significantly better circuit survival with citrate. Changing from heparin to citrate decreased the risk of premature circuit clotting by 75.8%. Conclusion: In routine clinical practice, regional anticoagulation with citrate is associated with significantly better circuit patency than heparin or epoprostenol.