Yaniv Almog

Prior Statin Therapy Is Associated With a Decreased Rate of Severe Sepsis

Background—Statins have anti-inflammatory properties that are independent of their lipid-lowering abilities. We hypothesized that statin therapy before the onset of an acute bacterial infection may have a protective effect against severe sepsis. The aim of this study was to determine whether patients treated with statins develop severe sepsis less frequently. Methods and Results—In this prospective observational cohort study, consecutive patients admitted with presumed or documented acute bacterial infection were enrolled. The primary outcomes were the rate of severe sepsis and intensive care unit (ICU) admission. Of the 361 patients enrolled, 82 (22.7%) were treated with statins before their admission. Both groups had a similar severity of illness on admission. Severe sepsis developed in 19% of patients in the no-statin group and in only 2.4% of the statin group (P<0.001). Statin treatment was associated with a relative risk of developing severe sepsis of 0.13 (95% CI, 0.03 to 0.52) and an absolute risk reduction of 16.6%. The overall ICU admission rate was 10.2% (37/361): 12.2% of the no-statin group required ICU admission, whereas in the statin group only 3.7% were admitted to the ICU (P=0.025), reflecting a relative risk of ICU admission of 0.30 (95% CI, 0.1 to 0.95). Conclusions—Prior therapy with statins may be associated with a reduced rate of severe sepsis and ICU admission. If supported by prospective controlled trials, statins may have a role in the primary prevention of sepsis.

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.

Pharmacokinetic dosing of aminoglycosides: a controlled trial

PURPOSE To evaluate whether individualized pharmacokinetic dosing of aminoglycosides can reduce nephrotoxicity and improve the outcome of patients with gram-negative sepsis. METHODS We conducted a prospective controlled trial at a tertiary care university hospital. Eighty-one patients with suspected or documented gram-negative infections were enrolled. All were treated with either gentamicin or amikacin, according to clinical judgement. Patients were allocated to one of two groups based on the last digit (odd/even) of their identification number. In the study group (pharmacokinetic dosing) of 43 patients, plasma aminoglycoside levels were determined 1 hour after initiation of drug infusion and 8 to 16 hours later to estimate the elimination half-life and volume of distribution, from which the subsequent dosage schedule was calculated. Target peak plasma levels were 20 microg/mL for gentamicin and 60 microg/mL for amikacin. Target trough levels were <1 microg/mL for both drugs. The control group (fixed once-daily dosing) consisted of 38 patients who were prescribed single daily doses of gentamicin or amikacin. The primary endpoints were renal toxicity (> or = 25% increase in serum creatinine level or a serum creatinine level > or = 1.4 mg/dL) and 28-day mortality. RESULTS The two study groups were similar in age, sex, indications for therapy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and clinical assessment at baseline. Although the pharmacokinetic group received significantly greater doses of aminoglycosides than did the once-daily group, the incidence of nephrotoxicity was significantly lower in the pharmacokinetic group (5% [2/43] vs. 21% [8/38], P = 0.03). There was no statistically significant difference in 28-day mortality (27% [12/43] vs. 22% [8/38], P = 0.3). CONCLUSION These results suggest that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.

Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patients

OBJECTIVES Radial artery pressure is known to differ from central arterial pressure in normal patients (distal pulse amplification) and in the early postcardiopulmonary bypass period. The adequacy of the radial artery as a site for blood pressure monitoring in critically ill patients receiving high-dose vasopressors has not been carefully examined. DESIGN Prospective observational study comparing simultaneous intra-arterial measurements of radial (peripheral) and femoral artery (central) pressures. SETTING Clinical investigation in a university-based surgical intensive care unit. PATIENTS Fourteen critically ill patients with presumed sepsis who received norepinephrine infusions at a rate of > or =5 microg/min. INTERVENTIONS All patients were managed in accordance with our standard practice for presumed sepsis, which consisted of intravascular volume repletion followed by vasopressor administration titrated to a mean arterial pressure of > or =60 mm Hg. MEASUREMENTS AND MAIN RESULTS Systolic and mean arterial pressures were significantly higher when measured from the femoral vs. radial site (p < .005). The higher mean arterial pressures enabled an immediate reduction in norepinephrine infusions in 11 of the 14 patients. No change in cardiac output or pulmonary artery occlusion pressure was noted after dose reduction. In the two patients in whom simultaneous recordings were made after discontinuation of norepinephrine infusions, equalization of mean arterial pressures was observed. CONCLUSIONS Radial artery pressure underestimates central pressure in hypotensive septic patients receiving high-dose vasopressor therapy. Clinical management, based on radial pressures, may lead to excessive vasopressor administration. Awareness of this phenomena may help minimize adverse effects of these potent agents by enabling dosage reduction.

The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases*

Objective:Statins have pleiotropic effects that are independent of their lipid-lowering ability. We have previously shown that prior statin therapy is associated with a decreased risk of severe sepsis in patients admitted with acute bacterial infection. The aim of this study was to determine whether statin therapy is associated with a decreased risk of infection-related mortality. Design:A prospective, observational, population-based study. Setting:Tertiary university medical center. Patients:Using a computerized database, 11,490 patients with atherosclerotic diseases were identified and followed for up to 3 yrs. Two groups of patients were compared: those receiving statins in the final month before follow-up termination and those who were not. Interventions:None. Measurements and Main Results:The primary outcome was infection-related mortality. Of the 11,362 patients included in the final analysis, 5,698 (50.1%) belonged to the statin group. Median follow-up was 19.8 months (interquartile range, 14.3–33.3). The risk of infection-related mortality was significantly lower in the statin compared with the no-statin group (0.9% vs. 4.1%), reflecting a relative risk of 0.22 (95% confidence interval, 0.17–0.28). Stepwise Cox proportional hazard survival analysis including a propensity score for receiving statins revealed that the protective effect of statins adjusted for all known potential confounders remained highly significant (hazard ratio, 0.37; 95% confidence interval, 0.27–0.52). Conclusions:Therapy with statins may be associated with a reduced risk of infection-related mortality. This protective effect is independent of all known comorbidities and dissipates when the medication is discontinued. If this finding is supported by prospective controlled trials, statins may play an important role in the primary prevention of infection-related mortality.

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 role of cardiac troponin I as a prognosticator in critically ill medical patients: a prospective observational cohort study

IntroductionMyocardial injury is frequently unrecognized in intensive care unit (ICU) patients. Cardiac troponin I (cTnI), a surrogate of myocardial injury, has been shown to correlate with outcome in selected groups of patients. We wanted to determine if cTnI level measured upon admission is an independent predictor of mortality in a heterogeneous group of critically ill medical patients.MethodsWe conducted a prospective observational cohort study; 128 consecutive patients admitted to a medical ICU at a tertiary university hospital were enrolled. cTnI levels were measured within 6 h of admission and were considered positive (>0.7 ng/ml) or negative. A variety of clinical and laboratory variables were recorded.ResultsBoth cTnI positive and negative groups were similar in terms of age, sex and pre-admission co-morbidity. In a univariate analysis, positive cTnI was associated with increased mortality (OR 7.0, 95% CI 2.44–20.5, p < 0.001), higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores and a higher rate of multi-organ failure and sepsis. This association between cTnI and mortality was more pronounced among elderly patients (>65 years of age). Multivariate analysis controlling for APACHE II score revealed that elevated cTnI levels are not independently associated with 28-day mortality.ConclusionIn critically ill medical patients, elevated cTnI level measured upon admission is associated with increased mortality rate. cTnI does not independently contribute to the prediction of 28-day mortality beyond that provided by APACHE II.

The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial

Background: Evidence from observational studies have raised the possibility that statin treatment reduces the incidence of certain bacterial infections, particularly pneumonia. We analyzed data from a randomized controlled trial of rosuvastatin to examine this hypothesis. Methods: We analyzed data from the randomized, double-blind, placebo-controlled JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). In this trial, 17 802 healthy participants (men 50 years and older and women 60 and older) with a low-density lipoprotein (LDL) cholesterol level below 130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level of 2.0 mg/L or greater were randomly assigned to receive either rosuvastatin or placebo. We evaluated the incidence of pneumonia on an intention-to-treat basis by reviewing reports of adverse events from the study investigators, who were unaware of the treatment assignments. Results: Among 17 802 trial participants followed for a median of 1.9 years, incident pneumonia was reported as an adverse event in 214 participants in the rosuvastatin group and 257 in the placebo group (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.69–1.00). In analyses restricted to events occurring before a cardiovascular event, pneumonia occurred in 203 participants given rosuvastatin and 250 given placebo (HR 0.81, 95% CI 0.67–0.97). Inclusion of recurrent pneumonia events did not modify this effect (HR 0.81, 95% CI 0.67–0.98), nor did adjustment for age, sex, smoking, metabolic syndrome, lipid levels and C-reactive protein level. Interpretation: Data from this randomized controlled trial support the hypothesis that statin treatment may modestly reduce the incidence of pneumonia. (ClinicalTrials.gov trial register no. NCT0023968.)

Gram-Negative Cellulitis Complicating Cirrhosis

Gram-negative infections are common in patients with cirrhosis, but skin infections are usually caused by gram-positive cocci. Gram-negative bacteria should be considered as a potential etiologic agent in patients with cirrhosis and severe bullous cellulitis. Culture of the bullous fluid may facilitate diagnosis and management. Early recognition is important because the course of the disease is usually rapid and fatal. We report 4 cases of fulminant gram-negative bullous cellulitis and septic shock in patients with cirrhosis.

Plasma Level of N Terminal Pro-Brain Natriuretic Peptide as a Prognostic Marker in Critically Ill Patients

We studied whether N-terminal pro brain natriuretic peptide (NT-pro BNP) measured at intensive care unit admission is an independent predictor of mortality in critically ill patients. We conducted a prospective observational cohort study enrolling 78 patients with APACHE II scores more than 12. Serum NT-pro BNP and cardiac troponin T were measured at admission, and echocardiography was performed within 24 h. The primary end-point was 30-day mortality. The median NT-pro BNP levels of the 22 (28.2%) patients who died were significantly more frequent than that of those who survived (8328 versus 1016 pg/mL; P = 0.001). Patients with NT-pro BNP levels more than 1900 pg/mL had significantly more frequent mortality (47.2% versus 11.9%; P = 0.03). This group also had more frequent moderate to severe left ventricular dysfunction (30.6% versus 9.5%; P = 0.02) and abnormal cardiac troponin T levels (33.3% versus 14.3%; P = 0.05). Multivariate analyses adjusted for APACHE-II revealed that a NT-pro BNP level more than 1900 pg/mL is an independent predictor of mortality.