Pierre Damas

Cytokine serum level during severe sepsis in human IL-6 as a marker of severity

Forty critically ill surgical patients with documented infections were studied during their stay in an intensive care unit. Among these patients, 19 developed septic shock and 16 died, 9 of them from septic shock. Interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF alpha), and interleukin 6 (IL-6) were measured each day and every 1 or 2 hours when septic shock occurred. Although IL-1 beta was never found, TNF alpha was most often observed in the serum at a level under 100 pg/mL except during septic shock. During these acute episodes TNF alpha level reached several hundred pg/mL, but only for a few hours. In contrast, IL-6 was always increased in the serum of acutely ill patients (peak to 500,000 pg/mL). There was a direct correlation between IL-6 peak serum level and TNF alpha peak serum level during septic shock and between IL-6 serum level and temperature or C-reactive protein serum level. Moreover, IL-6 correlated well with APACHE II score, and the mortality rate increased significantly in the group of patients who presented with IL-6 serum level above 1000 pg/mL. Thus, IL-6 appears to be a good marker of severity during bacterial infection.

Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans.

In a study of serum levels of tumor necrosis factor (TNF alpha) and interleukin-1 beta (IL-1 beta) in patients developing sepsis in the ICU, high TNF alpha levels were found in patients with septic shock. Normal values are 75 +/- 15 pg/ml; in these patients, TNF alpha serum level ranged from 100 to 5000 pg/ml with a mean of 701 +/- 339 pg/ml and a median of 250 pg/ml. There was a correlation between TNF alpha level and sepsis severity score as well as with mortality. In contrast, IL-1 beta serum levels were only slightly increased and were not correlated with severity or mortality.

Sepsis and serum cytokine concentrations.

OBJECTIVE To look for relationships between the classification of sepsis and plasma cytokine concentrations. DESIGN Prospective, consecutive entry study of patients meeting severe sepsis criteria and having bacteriologically documented infections. SETTING University hospital, surgical intensive care unit. PATIENTS Fifty consecutive patients developing severe sepsis or septic shock between December 1991 and December 1993. MEASUREMENTS AND MAIN RESULTS Concentrations of tumor necrosis factor, interleukin (IL)-6, IL-8, and leukemia inhibitory factor were measured by immunoradiometric assay in the plasma of patients as soon as they developed severe sepsis or septic shock. Septic shock patients were divided into three groups in a blinded fashion (i.e., without knowing the results of the concentrations of cytokines), according to the presence of sustained hyperlactacidemia and to the rapidity of the onset of sepsis. Peak concentrations of all cytokines were statistically different between severe sepsis and septic shock patients. This finding was almost exclusively due to the data from patients with rapid onset of septic shock, who demonstrated very high but transient cytokine concentrations. Septic shock patients may thus have different profiles in the time course of their cytokine concentrations. The transient, high peak concentrations of cytokines were also related to transient leukopenia. Among the cytokines measured, IL-8 appeared to be the one that correlated best with lactacidemia, the presence of disseminated intravascular coagulation, severe hypoxemia, the Acute Physiology and Chronic Health Evaluation II score, and mortality rate. CONCLUSIONS According to the profiles of the cytokines, septic shock patients do not represent a homogeneous population. These profiles should be described in order to distinguish between patients, and the profiles may be useful to identify those patients susceptible to new therapies.

VOLUNTARY BRAIN PROCESSING IN DISORDERS OF CONSCIOUSNESS

Background: Disentangling the vegetative state from the minimally conscious state is often difficult when relying only on behavioral observation. In this study, we explored a new active evoked-related potentials paradigm as an alternative method for the detection of voluntary brain activity. Methods: The participants were 22 right-handed patients (10 traumatic) diagnosed as being in a vegetative state (VS) (n = 8) or in a minimally conscious state (MCS) (n = 14). They were presented sequences of names containing the patient’s own name or other names, in both passive and active conditions. In the active condition, the patients were instructed to count her or his own name or to count another target name. Results: Like controls, MCS patients presented a larger P3 to the patient’s own name, in the passive and in the active conditions. Moreover, the P3 to target stimuli was higher in the active than in the passive condition, suggesting voluntary compliance to task instructions like controls. These responses were even observed in patients with low behavioral responses (e.g., visual fixation and pursuit). In contrast, no P3 differences between passive and active conditions were observed for VS patients. Conclusions: The present results suggest that active evoked-related potentials paradigms may permit detection of voluntary brain function in patients with severe brain damage who present with a disorder of consciousness, even when the patient may present with very limited to questionably any signs of awareness.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES study

ObjectiveThis study investigated whether treatment with the anti-tumor necrosis factor-&agr; monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DesignMulticenter, double-blind, randomized, placebo-controlled study. SettingEighty-four intensive care units in academic medical centers in Europe and Israel. PatientsA total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. InterventionsTreatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. Measurements and Main Results The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p < .001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. ConclusionsThe IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: relationship with synovitis and steroid treatment

Objective: To determine matrix metalloproteinase-3 (MMP-3) serum levels in patients with rheumatic diseases and to study the relation between MMP-3 and C reactive protein (CRP) levels. Methods: MMP-3 serum levels were determined by enzyme linked immunosorbent assay (ELISA) in (a) patients with active inflammatory rheumatic diseases: rheumatoid arthritis (RA), psoriatic arthritis, polymyalgia rheumatica, acute crystal arthritis, and ankylosing spondylitis; (b) patients with active inflammatory systemic diseases: cutaneo-articular or renal systemic lupus erythematosus (SLE), systemic sclerosis, and vasculitides; (c) patients with non-inflammatory rheumatic diseases: osteoarthritis and fibromyalgia; (d) critically ill patients without rheumatic diseases, representing an acute inflammatory control group; (e) healthy controls. Results: MMP-3 serum levels were significantly increased in patients with active RA, psoriatic arthritis, and polymyalgia rheumatica, whether treated or not by corticosteroids, and in female patients with acute crystal arthritis. MMP-3 serum levels were normal in steroid-free patients with active cutaneo-articular or renal SLE, systemic sclerosis, and vasculitides but were significantly increased in steroid treated patients. MMP-3 levels were normal in fibromyalgia, osteoarthritis, ankylosing spondylitis, and acute inflammatory controls. MMP-3 was significantly correlated with CRP in RA (r=0.5, p=0.0004) but not in any of the other disease groups. Conclusions: MMP-3 serum levels are increased in inflammatory rheumatic diseases characterised by joint synovitis, such as RA, polymyalgia rheumatica, psoriatic arthritis, and acute crystal arthritis—that is, whether the diseases are acute or chronic, erosive or not. They are normal in SLE, systemic sclerosis, and vasculitides as well as in non-rheumatic inflammatory controls, but are significantly increased by steroids. These data strongly suggest that serum MMP-3 reflects synovial inflammation.

Are blood transfusions associated with greater mortality rates? Results of the Sepsis Occurrence in Acutely Ill Patients study.

Background:Studies have suggested worse outcomes in transfused patients and improved outcomes in patients managed with restricted blood transfusion strategies. The authors investigated the relation of blood transfusion to mortality in European intensive care units (ICUs). Methods:The Sepsis Occurrence in Acutely Ill Patients study was a multicenter, observational study that included all adult patients admitted to 198 European ICUs between May 1 and May 15, 2002 and followed them until death, until hospital discharge, or for 60 days. Patients were classified depending on whether they had received a blood transfusion at any time during their ICU stay. Results:Of 3,147 patients, 1,040 (33.0%) received a blood transfusion. These patients were older (mean age, 62 vs. 60 yr; P = 0.035) and were more likely to have liver cirrhosis or hematologic cancer, to be a surgical admission, and to have sepsis. They had a longer duration of ICU stay (5.9 vs. 2.5 days; P < 0.001) and a higher ICU mortality rate (23.0 vs. 16.3%; P < 0.001) but were also more severely ill on admission (Simplified Acute Physiology Score II, 40.2 vs. 34.7; P < 0.001; Sequential Organ Failure Assessment score, 6.5 vs. 4.5; P < 0.001). There was a direct relation between the number of blood transfusions and the mortality rate, but in multivariate analysis, blood transfusion was not significantly associated with a worse mortality rate. Moreover, in 821 pairs matched according to a propensity score, there was a higher 30-day survival rate in the transfusion group than in the other patients (P = 0.004). Conclusion:This observational study does not support the view that blood transfusions are associated with increased mortality rates in acutely ill patients.

Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial

OBJECTIVE To determine the efficacy and safety of using natural platelet-activating factor receptor antagonist (PAFra), BN 52021, to treat patients with severe Gram-negative bacterial sepsis. DESIGN A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. SETTING Fifty-nine academic medical center intensive care units in Europe. PATIENTS Six hundred nine patients with severe sepsis, suspected to be related to Gram-negative bacterial infection, who received PAFra or placebo. INTERVENTIONS Patients were randomized to receive either a dose of PAFra (120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. MEASUREMENTS AND MAIN RESULTS The patients were well matched at study entry for severity of illness and for risk factors known to influence the outcome of sepsis. Among all randomized patients, the 28-day, all-cause mortality rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAFra group (p=.50). When analyzed on the basis of the previously defined target population, the 28-day, all-cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduction in mortality rate (p=.29). In patients with documented infection involving other organisms, there was no difference between treated and placebo groups. When the outcomes of organ dysfunctions were examined in the overall population and in the documented Gram-negative bacterial infection population, the number of patients who resolved hepatic dysfunction tended to be higher in the treated group than in the placebo group (p=.06). The number of adverse events reported were not different between the two groups. CONCLUSIONS A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bacterial infection. If PAFra treatment has any therapeutic activity in severe Gram-negative bacterial sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

A French validation study of the Coma Recovery Scale-Revised (CRS-R)

Primary objective: The aim of the present study was to explore the concurrent validity, inter-rater agreement and diagnostic sensitivity of a French adaptation of the Coma Recovery Scale–Revised (CRS-R) as compared to other coma scales such as the Glasgow Coma Scale (GCS), the Full Outline of UnResponsiveness scale (FOUR) and the Wessex Head Injury Matrix (WHIM). Research design: Multi-centric prospective study. Method and procedures: To test concurrent validity and diagnostic sensitivity, the four behavioural scales were administered in a randomized order in 77 vegetative and minimally conscious patients. Twenty-four clinicians with different professional backgrounds, levels of expertise and CRS-R experience were recruited to assess inter-rater agreement. Main outcomes and results: Good concurrent validity was obtained between the CRS-R and the three other standardized behavioural scales. Inter-rater reliability for the CRS-R total score and sub-scores was good, indicating that the scale yields reproducible findings across examiners and does not appear to be systematically biased by profession, level of expertise or CRS-R experience. Finally, the CRS-R demonstrated a significantly higher sensitivity to detect MCS patients, as compared to the GCS, the FOUR and the WHIM. Conclusion: The results show that the French version of the CRS-R is a valid and sensitive scale which can be used in severely brain damaged patients by all members of the medical staff.

Renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury

IntroductionOutcome studies in patients with acute kidney injury (AKI) have focused on differences between modalities of renal replacement therapy (RRT). The outcome of conservative treatment, however, has never been compared with RRT.MethodsNine Belgian intensive care units (ICUs) included all adult patients consecutively admitted with serum creatinine >2 mg/dl. Included treatment options were conservative treatment and intermittent or continuous RRT. Disease severity was determined using the Stuivenberg Hospital Acute Renal Failure (SHARF) score. Outcome parameters studied were mortality, hospital length of stay and renal recovery at hospital discharge.ResultsOut of 1,303 included patients, 650 required RRT (58% intermittent, 42% continuous RRT). Overall results showed a higher mortality (43% versus 58%) as well as a longer ICU and hospital stay in RRT patients compared to conservative treatment. Using the SHARF score for adjustment of disease severity, an increased risk of death for RRT compared to conservative treatment of RR = 1.75 (95% CI: 1.4 to 2.3) was found. Additional correction for other severity parameters (Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA)), age, type of AKI and clinical conditions confirmed the higher mortality in the RRT group.ConclusionsThe SHARF study showed that the higher mortality expected in AKI patients receiving RRT versus conservative treatment can not only be explained by a higher disease severity in the RRT group, even after multiple corrections. A more critical approach to the need for RRT in AKI patients seems to be warranted.