Bala Venkatesh

A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis

RATIONALE Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. METHODS Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87-191] vs. 244 [187-317] pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). CONCLUSIONS Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).

Clinical review: adiponectin biology and its role in inflammation and critical illness.

Adiponectin is an adipokine first described just over a decade ago. Produced almost exclusively by adipocytes, adiponectin circulates in high concentrations in human plasma. Research into this hormone has revealed it to have insulin-sensitizing, anti-inflammatory and cardioprotective roles. This review discusses the history, biology and physiological role of adiponectin and explores its role in disease, with specific focus on adiponectin in inflammation and sepsis. It appears that an inverse relationship exists between adiponectin and inflammatory cytokines. Low levels of adiponectin have been found in critically ill patients, although data are limited in human subjects at this stage. The role of adiponectin in systemic inflammation and critical illness is not well defined. Early data suggest that plasma levels of adiponectin are decreased in critical illness. Whether this is a result of the disease process itself or whether patients with lower levels of this hormone are more susceptible to developing a critical illness is not known. This observation of lower adiponectin levels then raises the possibility of therapeutic options to increase circulating adiponectin levels. The various options for modulation of serum adiponectin (recombinant adiponectin, thiazolidinediones) are discussed.

Continuation of statin therapy in patients with presumed infection: A randomized controlled trial

RATIONALE In patients on prior statin therapy who are hospitalized for acute infections, current literature is unclear on whether statins should be continued during their hospitalization. OBJECTIVES To test the hypothesis that continuation of therapy with statins influences the inflammatory response to infection and that cessation may cause an inflammatory rebound. METHODS Prospective randomized double-blind placebo-controlled trial of atorvastatin (20 mg) or matched placebo in 150 patients on preexisting statin therapy requiring hospitalization for infection. MEASUREMENTS AND MAIN RESULTS The primary end point was progression of sepsis during hospitalization. At baseline, the rate of severe sepsis was 32% in both groups. Compared with baseline, the odds ratio for severe sepsis declined in both groups: 0.43 placebo and 0.5 statins (Day 3) versus 0.14 placebo and 0.12 statins (Day 14). The rate of decline of severe sepsis was similar between the groups (odds ratio 1.17 [0.56-2.47], P = 0.7 Day 3; 0.85 [0.21-3.34], P = 0.8 Day 14). IL-6 and C-reactive protein declined in both groups with no statistically significant difference (P = 0.7 and P = 0.2, respectively). An increase in cholesterol occurred in the placebo group (P < 0.0001). Most patients were not critically ill. Hospital mortality was 6.6%, with no difference between the groups (6 [8%] of 75 statin group; 4 [5.3%] of 75 placebo group; P = 0.75). CONCLUSIONS This study does not support a beneficial role of continuing preexisting statin therapy on sepsis and inflammatory parameters. Cessation of established statin therapy was not associated with an inflammatory rebound. Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN 12605000756628).

Changes in serum adiponectin concentrations in critical illness: a preliminary investigation

IntroductionAdiponectin plays an important role in the regulation of tissue inflammation and insulin sensitivity. Perturbations in adiponectin concentration have been associated with obesity and the metabolic syndrome. Data on adiponectin pathophysiology in critical illness are limited.MethodsTwenty three critically ill patients (9 severe sepsis, 7 burns, 7 trauma). Adiponectin assays on Days 3 (D3) and 7 (D7). Simultaneous, cortisol, cortisone and CRP measurements. Data from 16 historical controls were used for comparison.ResultsThe mean plasma adiponectin concentration for the ICU cohort on D3 and D7 were not significantly different (4.1 ± 1.8 and 5.0 ± 3.3 mcg/ml respectively, P = 0.38). However, these were significantly lower than the mean plasma adiponectin in the control population (8.78 ± 3.81 mcg/ml) at D3 (P < 0.0001) and D7 (P = 0.002). Plasma adiponectin showed a strong correlation with plasma cortisol in the ICU group on both D3 (R2 = 0.32, P < 0.01) and D7 (R2 = 0.64, 0.001). There was an inverse correlation between plasma adiponectin and CRP on D7, R = -0.35.ConclusionsIn this preliminary study, critical illness was associated with lower adiponectin concentrations as compared with controls. A significant relationship between plasma cortisol and adiponectin in critically ill patients was evident, both during the early and late phases. These data raise the possibility that adiponectin may play a part in the inflammatory response in patients with severe illness.

Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease

BACKGROUND & AIMS Adrenal insufficiency (AI) has been reported in patients with advanced liver disease. Diagnosing AI is problematic owing to controversies in using total serum cortisol as a measure of adrenal function. No published data exist on directly measured plasma free cortisol (PFC) in patients with liver disease. METHODS This prospective study compared serum total and measured plasma free cortisol to evaluate adrenal function in clinically stable cirrhotic patients and healthy controls. Cortisol levels were measured at baseline and following 250 μg corticotrophin. AI was defined by total cortisol increments (delta cortisol) of less than 250 nmol/L, or a peak total cortisol under 500 nmol/L after cosyntropin. We used a peak plasma free cortisol concentration of 33 nmol/L as the threshold for AI. RESULTS Forty-three consecutive patients and 10 healthy controls were studied. Cirrhotic patients had significantly lower peak (526 vs. 649 nmol/L, p=0.004) and delta total cortisol (264 vs. 397 nmol/L, p = 0.002) responses compared to healthy controls. However, basal plasma free cortisol was higher in patients (10.9 vs. 6.4 nmol/L, p = 0.03), and there were no differences in peak plasma free cortisol (p = 0.69) between the two groups. The prevalence of AI using total cortisol criteria was 58% compared to 12% using free cortisol (p<0.001). CONCLUSION In patients with stable severe liver disease, a significant discrepancy exists between the rates of diagnosis of AI using the total and free cortisol criteria. We would advise caution in the interpretation of adrenal function testing using total cortisol measurements in this group.

Cerebral Perfusion Pressure in Neurotrauma : A Review

It is now well recognized that low cerebral blood flow (and cerebral perfusion pressure (CPP)) is associated with poor outcome after traumatic brain injury. What is less clear is whether altering cerebral blood flow or CPP will lead to clinical improvement. Initial studies indicated that increasing CPP may be beneficial and the Brain Trauma Foundation acknowledged this by incorporating a target of 70 mm Hg in the 1996 guidelines. However, the lack of a demonstrable benefit and the increased complication rate associated with this approach led to a reduction in the CPP goal to 60 mm Hg. More recently, evidence that autoregulation may be disrupted after traumatic brain injury has led some authors to propose an individualized approach to CPP management. Furthermore, with the advent of advanced neuromonitoring techniques, clinicians are able to more closely monitor the effects of hemodynamic manipulations on cerebral metabolism. As yet, there is no strong outcome evidence to support this approach. Until then, the current debate over the optimal approach to CPP management is likely to continue.

Uni- and Interdisciplinary Effects on Round and Handover Content in Intensive Care Units

Objective: The aim of this study was to explore differences in the verbal content of handovers and rounds conducted in uni- and interdisciplinary social contexts. We expected higher proportions of goals to be articulated during interdisciplinary rounds. Background: Lack of explanatory connections between round improvement initiatives and outcomes suggest insufficient understanding about health care communications, especially the role of social interaction. Methods: The recognition-primed abstract decomposition space (RP-ADS) was used to analyze the information content of nurse handovers and morning rounds in a unidisciplinary- (physicians only) and an interdisciplinary-round intensive care unit (ICU). Data were collected using audio recordings of rounds and handovers for five patients for 5 days each in both ICUs. Results: Hierarchical log-linear analyses show strong associations between events (medical rounds vs. nurses’ shift handovers), type (uni- vs. interdisciplinary), and focus (levels of the RP-ADS) with highly significant combined two-way and higher-order interactions, LRχ2(df = 4) = 30.91, p < .0001. All tests of partial association were also highly significant. Differences among levels of the variables were evaluated using standardized residuals. Conclusion: Nurses focused on RP-ADS data and intervention levels, whereas physicians focused on diagnoses and expectations. Clinical goals that integrate these orientations emerged to a greater extent in interdisciplinary rounds. In addition, social context of rounds appears to influence nurse handovers. Unidisciplinary ICU nurse handovers consisted of a series of data-and intervention-related observations, whereas ICU nurse handovers in interdisciplinary ICUs tended to integrate data, interventions and clinical goals. Application: These results are relevant to the design and implementation of clinical communication improvement initiatives and support tools.

Vitamin D and the critically ill patient.

Purpose of reviewTo summarize the current knowledge on vitamin D with a special focus on critically ill patients. Recent findingsVitamin D deficiency is associated with adverse health outcomes including increased risk of cardiovascular disease, morbidity and mortality in the general population. In critically ill patients, the pleiotropic effects of vitamin D including its role in immune function are of great interest. SummaryTo date, it is not clear whether vitamin D deficiency is a surrogate marker for increased morbidity or whether treatment with sufficiently large doses of vitamin D may improve patient outcome in an intensive care setting.

Serial changes in plasma total cortisol, plasma free cortisol and tissue cortisol activity in patients with septic shock: An observational study

ABSTRACT Published data on adrenocortical function in septic shock have enrolled patients at various stages of critical illness and predominantly used plasma total cortisol, with minimal information on serial changes. Moreover, plasma free cortisol and tissue corticosteroid activity may not be strongly associated; however, few published data exist. The aim of this prospective observational study was to investigate serial changes in plasma total and free cortisol and tissue cortisol activity in septic shock. Twenty-nine adult patients admitted with septic shock to a tertiary-level intensive care unit were enrolled. A low-dose corticotropin test was performed on day 1. Plasma total and free cortisol, cortisone, transcortin, and urinary free cortisol and cortisone were analyzed on days 1 to 5, 7, and 10. Urinary and plasma cortisol-cortisone ratios (F:E ratio) were calculated as indices of 11-&bgr; hydroxysteroid dehydrogenase 2 and global 11-&bgr; hydroxysteroid dehydrogenase activity, respectively. Baseline total and free plasma cortisol values from 10 healthy control subjects were obtained for comparative analysis. Baseline plasma total and free cortisol levels were significantly higher than controls (457.8 ± 193 vs. 252 ± 66 nmol/L, P = 0.0002; and 50.83 ± 43.19 vs. 6.4 ± 3.2, P < 0.0001, respectively). Plasma free cortisol rose proportionately higher than total cortisol (124% ± 217.3% vs. 40% ± 33.2%, P = 0.007) following corticotropin. Baseline plasma and urinary F:E ratios were elevated over the reference ranges (13.13 ± 1.5, 1.69 ± 2.8) and were not correlated with plasma free cortisol values (r = 0.2, 0.3 respectively). Over the study period, total cortisol levels and plasma F:E ratios remained elevated, whereas plasma free cortisol levels and urinary F:E ratio declined. At baseline, plasma free cortisol levels were higher in patients who subsequently survived (23.7 ± 10.5 vs. 57.9 ± 45.8 nmol/L, P = 0.04). In septic shock, there is a differential response of plasma total and free cortisol over time and in response to corticotropin. Changes in plasma and urinary F:E ratios suggest tissue modulation of 11-&bgr; hydroxysteroid dehydrogenase activity. Total plasma cortisol measurements may not reflect the global adrenal response in septic shock. ABBREVIATIONS 11&bgr;-HSD—11&bgr;-hydroxysteroid dehydrogenase APACHE—Acute Physiology and Chronic Health Evaluation CBG—corticosteroid-binding globulin FC—free plasma cortisol F:E ratio—cortisol-cortisone ratio SOFA—Sequential Organ Failure Assessment

Continuous measurement of cerebral blood flow velocity using transcranial Doppler reveals significant moment-to-moment variability of data in healthy volunteers and in patients with subarachnoid hemorrhage.

OBJECTIVE The reliability of intermittent transcranial Doppler has not been accepted widely because of problems with interobserver variability and lack of accuracy. The limitations of intermittent transcranial Doppler are thought to be overcome by continuous measurement systems. However, little published data exist on their accuracy, feasibility, and moment-to-moment variability. In this study we aimed to determine the time-related variability of continuous transcranial Doppler signal from volunteers and patients with subarachnoid hemorrhage and to examine the feasibility, ease of use, and quality of data generated from continuous transcranial Doppler for the detection of vasospasm. DESIGN Prospective observational study. SETTING Intensive care unit in a tertiary referral center. SUBJECTS Ten volunteers and eight patients with aneurysmal subarachnoid hemorrhage. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The middle cerebral artery blood flow velocities were recorded continuously from both patients and volunteers. The moment-to-moment variability of continuously recorded data was calculated. There was a wide range of velocity measurements in both volunteers and patients. There was a significant moment-to-moment variability in both volunteers (-31% to 58%) and in patients (-38% to 78%). There was a greater number of observations exceeding 10% moment-to-moment variability in the patient group with regard to systolic and diastolic velocities compared with volunteers (8% vs. 2%, p < .001). There was a trend toward a longer duration of good quality data in volunteers compared with patients (98 +/- 0.5% vs. 96 +/- 9%). CONCLUSIONS Continuous measurement of cerebral blood flow velocities revealed a significant moment-to-moment variability in both patients and in volunteers, the magnitude of which was greater in the patients. The clinical implications of these findings are discussed.