Thomas Rimmelé

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

Clinical review: Blood purification for sepsis

Sepsis is the primary cause of death in the intensive care unit. Extracorporeal blood purification therapies have been proposed for patients with sepsis in order to improve outcomes since these therapies can alter the host inflammatory response by non-selective removal of inflammatory mediators or bacterial products or both. Recent technological progress has increased the number of techniques available for blood purification and their performance. In this overview, we report on the latest advances in blood purification for sepsis and how they relate to current concepts of disease, and we review the current evidence for high-volume hemofiltration, cascade hemofiltration, hemoadsorption, coupled plasma filtration adsorption, high-adsorption hemofiltration, and high-cutoff hemofiltration/hemodialysis. Promising results have been reported with all of these blood purification therapies, showing that they are well tolerated, effective in clearing inflammatory mediators or bacterial toxins (or both) from the plasma, and efficacious for improvement of various physiologic outcomes (for example, hemodynamics and oxygenation). However, numerous questions, including the timing, duration, and frequency of these therapies in the clinical setting, remain unanswered. Large multicenter trials evaluating the ability of these therapies to improve clinical outcomes (that is, mortality or organ failure), rather than surrogate markers such as plasma mediator clearance or transient improvement in physiologic variables, are required to define the precise role of blood purification in the management of sepsis.

Patient Mortality Is Associated With Staff Resources and Workload in the ICU: A Multicenter Observational Study.

Objective:Matching healthcare staff resources to patient needs in the ICU is a key factor for quality of care. We aimed to assess the impact of the staffing-to-patient ratio and workload on ICU mortality. Design:We performed a multicenter longitudinal study using routinely collected hospital data. Setting:Information pertaining to every patient in eight ICUs from four university hospitals from January to December 2013 was analyzed. Patients:A total of 5,718 inpatient stays were included. Interventions:None. Measurements and Main Results:We used a shift-by-shift varying measure of the patient-to-caregiver ratio in combination with workload to establish their relationships with ICU mortality over time, excluding patients with decision to forego life-sustaining therapy. Using a multilevel Poisson regression, we quantified ICU mortality-relative risk, adjusted for patient turnover, severity, and staffing levels. The risk of death was increased by 3.5 (95% CI, 1.3–9.1) when the patient-to-nurse ratio was greater than 2.5, and it was increased by 2.0 (95% CI, 1.3–3.2) when the patient-to-physician ratio exceeded 14. The highest ratios occurred more frequently during the weekend for nurse staffing and during the night for physicians (p < 0.001). High patient turnover (adjusted relative risk, 5.6 [2.0–15.0]) and the volume of life-sustaining procedures performed by staff (adjusted relative risk, 5.9 [4.3–7.9]) were also associated with increased mortality. Conclusions:This study proposes evidence-based thresholds for patient-to-caregiver ratios, above which patient safety may be endangered in the ICU. Real-time monitoring of staffing levels and workload is feasible for adjusting caregivers’ resources to patients’ needs.

Alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to patients with ventilator-associated pneumonia.

Objectives:To determine the steady-state serum and alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to critically ill patients with ventilator-associated pneumonia and various degrees of renal failure. Design:Prospective comparative study. Setting:An intensive care unit and research ward in a university hospital. Patients:Forty patients with microbiologically documented ventilator-associated pneumonia. Interventions:Patients were randomized to receive piperacillin/tazobactam daily continuous infusions of 12/1.5 g or 16/2 g after a loading dose of 4/0.5 g. The serum and alveolar piperacillin/tazobactam concentrations were determined at steady-state with high performance liquid chromatography. Measurements and Main Results:The median (interquartile) serum and alveolar piperacillin concentrations were respectively 25.3 mg/L (23.1–32.6) and 12.7 mg/L (6.7–18.0) for 12/1.5 g/day, and 38.9 mg/L (32.9–59.6) and 19.1 mg/L (14.0–21.5), respectively, for 16/2 g/day in patients with no/mild renal failure. In patients with moderate/advance renal failure, the median (interquartile) serum and alveolar piperacillin concentrations were 102.4 mg/L (97.4–112.6) and 44.1 mg/L (33.4–48.3), respectively, for 12/1.5 g/day, and 135.3 mg/L (119.5–146.2) and 54.9 mg/L (45.2–110.3), respectively, for 16/2 g/day. Our results show great variability in piperacillin/tazobactam concentrations, with an alveolar percentage penetration of 40–50% for piperacillin and 65–85% for tazobactam and a negative association between serum or alveolar concentrations and creatinine clearance. Conclusions:A target piperacillin serum concentration of at least 35–40 mg/L is probably required to provide alveolar concentrations exceeding the susceptibility breakpoint for Gram-negative bacteria (16 mg/L) during ventilator-associated pneumonia. In patients with no/mild renal failure, a continuous daily dose of piperacillin/tazobactam 16/2 g allows reaching this target concentration, which might be not observed with 12/1.5 g/day. In patients with moderate/advanced renal failure, both dosages achieve serum concentrations far above the 35–40 mg/L threshold, suggesting that in that case, therapeutic drug monitoring should be performed in order to adjust the daily dose.

Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis

The effect of extracorporeal blood purification on clinical outcomes in sepsis is assumed to be related to modulation of plasma cytokine concentrations. To test this hypothesis directly, we treated rats that had a cecal ligation followed by puncture (a standard model of sepsis) with a modest dose of extracorporeal blood purification that did not result in acute changes in a panel of common cytokines associated with inflammation (TNF-α, IL-1β, IL-6, and IL-10). Pre- and immediate post-treatment levels of these cytokines were unchanged compared to the sham therapy of extracorporeal circulation without blood purifying sorbent. The overall survival to 7 days, however, was significantly better in animals that received extracorporeal blood purification compared to those with a sham procedure. This panel of common plasma cytokines along with alanine aminotransferase and creatinine was significantly lower 72 h following extracorporeal blood purification compared to sham-treated rats. Thus, the effects of this procedure on organ function and survival do not appear to be due solely to immediate changes in the usual measured circulating cytokines. These results may have important implications for the design and conduct of future trials in sepsis including defining alternative targets for extracorporeal blood purification and other therapies.

Pharmacokinetics and intrapulmonary diffusion of levofloxacin in critically ill patients with severe community-acquired pneumonia.

Objective:To determine the steady-state plasma and epithelial lining fluid concentrations of intravenous levofloxacin, 500 mg, administered once or twice daily in critically ill patients with severe community-acquired pneumonia. Design:Prospective, open-label study. Setting:An intensive care unit and a clinical pharmacokinetic laboratory in two university hospitals. Patients:Twenty-four adult patients with severe community-acquired pneumonia and receiving mechanical ventilation were enrolled. Interventions:All subjects received 1-hr intravenous infusions of 500 mg levofloxacin once or twice daily. The plasma and epithelial lining fluid levofloxacin concentrations were determined at steady-state after 2 days of therapy with high-performance liquid chromatography. Measurements and main results:The median (interquartile range [IQR]) plasma and epithelial lining fluid peak levofloxacin concentrations were 12.6 (IQR, 12.0–14.1) and 11.9 (IQR, 8.7–13.7) mg/L, respectively, in the once-daily group and 19.7 (IQR, 19.0–22.0) and 17.8 (IQR, 16.2–23.5) mg/L in the twice-daily group, showing a pulmonary percentage penetration of >100% in both groups. The median (IQR) total body exposures were 151 (IQR, 137–174) and 416 (IQR, 406–472) mg·hr/L, respectively, in the once-daily and twice-daily groups. Conclusions:Our results suggest that in critically ill patients who are receiving mechanical ventilation and have severe community-acquired pneumonia and creatinine clearance of >40 mL/min, the administration of 500 mg of intravenous levofloxacin once and twice daily allows for the exceeding of pharmacodynamic thresholds predictive of outcome (i.e., peak concentration to minimum inhibitory concentration ratio of >10 or area under concentration-time curve to minimal inhibitory concentration ratio of >125 hrs) both in serum and epithelial lining fluid for pathogens with minimum inhibitory concentration values of ≤1 mg/L and >1 mg/L, respectively.

Background infusion is not beneficial during labor patient-controlled analgesia with 0.1% ropivacaine plus 0.5 μg/ml sufentanil

BackgroundAlthough patient-controlled epidural analgesia (PCEA) during labor has been extensively studied in recent clinical trials, the role of a background infusion associated with self-administered boluses is still debated. The authors designed a study to assess whether the use of PCEA with or without background infusion could improve the comfort of parturients and their satisfaction during labor and delivery without affecting the total consumption of local anesthetics. MethodsOne hundred thirty-three laboring parturients requesting epidural analgesia administered via PCEA with a solution of 0.1% ropivacaine plus 0.5 &mgr;g/ml sufentanil were randomly assigned to four groups, according to the rate of background infusion used (0, 3, 6, and 9 ml/h). Local anesthetic requirements, maternal satisfaction, verbal pain scores, incidence of side effects, and outcome of labor were compared among groups. ResultsPatient demographics, labor characteristics, side effects, and Apgar scores were similar in each group. No significant differences were observed between groups in verbal pain scores during labor, number of supplemental boluses, or maternal satisfaction. A significantly greater overall total drug consumption with a 6-ml/h or a 9-ml/h background infusion (74 and 78 ml, respectively) was observed in comparison with PCEA without a background infusion (55 ml). A similar relation was observed for hourly use during both the first and the second stage of labor. ConclusionThe results of this study suggest that the use of a background infusion with PCEA during labor leads to a greater consumption of anesthetic solution without improving comfort and satisfaction of parturients. Moreover, not using a background infusion does not provide an increased incidence of supplemental boluses (which might cause problems in a busy unit) and allows for a substantial reduction in the cost of analgesia.

High-volume hemofiltration in the intensive care unit: a blood purification therapy.

High-volume hemofiltration is an extracorporeal therapy that has been available in the intensive care unit for more than 10 yr. Recent improvements in technology have made its clinical application easier and safer. However, the definition, indications, and management of this technique are still unclear, and considerable controversy and confusion remain. The aim of this review is to analyze the available data while taking into account the distinction between two very different clinical situations: acute kidney injury requiring renal support, and severe inflammatory states where blood purification has been suggested as an adjuvant therapy. For patients with acute kidney injury requiring renal replacement therapy, the two largest multicenter studies performed to date established that high ultrafiltration flow rates are not necessary. Conversely, much experimental and some clinical evidence suggest that high-volume hemofiltration can be beneficial for the subset of critically ill patients with severe inflammatory states such as septic shock.

Blood Purification in Sepsis: A New Paradigm

Sepsis is one of the main causes of death in critically ill patients. The pathophysiology of sepsis is complex and not completely understood. The proinflammatory and anti-inflammatory response leads to cell and organ dysfunction and, in many cases, death. Thus, the goal of the intervention is to restore the homeostasis of circulating mediators rather than to inhibit selectively the proinflammatory or anti-inflammatory mediators. Blood purification has been reported to remove a wide array of inflammatory mediators. The effects are broad-spectrum and auto-regulating. Blood purification has also been demonstrated to restore immune function through improving antigen-presenting capability, adjusting leukocyte recruitment, oxidative burst and phagocytosis, and improving leukocyte responsiveness. A great deal of work has to be done in order to find and optimize the best extracorporeal blood purification therapy for sepsis. New devices specifically target the pathophysiological mechanisms involved in these conditions. High-volume hemofiltration, hemoadsorption, coupled plasma filtration adsorption, and high cutoff membrane are now being tested in septic patients. Preliminary data indicate the feasibility of these modified techniques in sepsis. Their impact on patient prognosis, however, still needs proof by large randomized clinical trials. Finally, the emerging paradigm of sepsis-induced immune suppression provides additional rationale for the development of extracorporeal blood purification therapy for sepsis.

Severe metabolic or mixed acidemia on intensive care unit admission: incidence, prognosis and administration of buffer therapy. A prospective, multiple-center study.

IntroductionIn this study, we sought describe the incidence and outcomes of severe metabolic or mixed acidemia in critically ill patients as well as the use of sodium bicarbonate therapy to treat these illnesses.MethodsWe conducted a prospective, observational, multiple-center study. Consecutive patients who presented with severe acidemia, defined herein as plasma pH below 7.20, were screened. The incidence, sodium bicarbonate prescription and outcomes of either metabolic or mixed severe acidemia were analyzed.ResultsAmong 2, 550 critically ill patients, 200 (8%) presented with severe acidemia, and 155 (6% of the total admissions) met the inclusion criteria. Almost all patients needed mechanical ventilation and vasopressors during their ICU stay, and 20% of them required renal replacement therapy within the first 24 hours of their ICU stay. Severe metabolic or mixed acidemia was associated with a mortality rate of 57% in the ICU. Delay of acidemia recovery as opposed to initial pH value was associated with increased mortality in the ICU. The type of acidemia did not influence the decision to administer sodium bicarbonate.ConclusionsThe incidence of severe metabolic or mixed acidemia in critically ill patients was 6% in the present study, and it was associated with a 57% mortality rate in the ICU. In contradistinction with the initial acid-base parameters, the rapidity of acidemia recovery was an independent risk factor for mortality. Sodium bicarbonate prescription was very heterogeneous between ICUs. Further studies assessing specific treatments may be of interest in this population.