Epidemiology and Predictors of Long-Stays in Medical ICU: A Retrospective Cohort Study.

INTRODUCTION: Prolonged stays in ICU have been associated with overconsumption of resources but little is known about their epidemiology. We aimed to identify predictors and prognostic factors of extended stays, studying a long-stay population. METHODS: We present a retrospective cohort study between July 2000 and December 2013 comparing patients hospitalized in a medical ICU for ≥30 days (long-stay patients-LSP) with patients hospitalized for <30 days (short-stay patients-SSP). Admission characteristics were collected from the local database for every patient and evolution during the ICU stay was retrieved from LSP files. RESULTS: Among 8906 patients hospitalized in the ICU, 417 (4.7%) were LSP. At admission, male sex (adjusted odds-ratio (aOR) 1.4 [1.1; 1.7]), inpatient (aOR 2.0 [1.6; 2.4]) and in-ICU hospitalizations for respiratory (aOR 2.9 [1.6; 3.5]) or infectious diseases (aOR 1.6 [1.1; 2.5]) were all independently associated with a long stay in the ICU, while hospitalizations for metabolic (aOR 0.2 [0.1; 0.5]) or cardiovascular diseases (aOR 0.3 [0.2; 0.5]) were in favor of a short stay. In-ICU and in-hospital LSP mortality were 38.8% and 48.2%. Age (aOR 1.02 [1.00-1.04]), catecholamines (aOR 3.9 [1.9; 8.5]), renal replacement therapy (aOR 2.4 [1.3; 4.3]), primary disease-related complications (aOR 2.5 [1.4; 4.6]) and nosocomial infections (aOR 4.1 [1.8; 10.1]) were independently associated with mortality in LSP. CONCLUSION: LSP were highly comorbid patients mainly hospitalized for respiratory diseases. Their mortality was mostly related to nosocomial infections but the majority were discharged alive from the hospital.

How to strengthen the presence of patients in health technology assessments conducted by the health authorities.

The constant development of health technologies, combined with the increase in the cost of treatment, means that States must continually make choices about the introduction of new technologies into their healthcare system and how they are to be funded. In France, the systematic participation of patients in these processes is one of the targets to be met in terms of healthcare democracy. Although, on an international level, patient involvement in these assessments is constantly growing, it is difficult to define due to the presence of unstabilised elements in terms of both terminology and assessment methods. As a result, patient and public involvement in health technology assessments varies considerably from one country to the next, from one field to the next and even from one type of technology to the next. Several types of involvement exist, ranging from studies conducted to collect patient "insight" (experience, perception, needs, preferences, attitudes to treatment and health, etc.) to processes aimed at including patients in assessments (as individuals, as representatives of associations, etc.). Given the scope and complexity of the subject, and the difficulty involved in understanding all the different aspects of health technologies and innovations, the members of the Round Table chose to concentrate on health technology assessments (medicinal products and medical devices) to develop national recommendations on all possible types of patient involvement in the health technology assessment processes conducted by the health authorities in France.

Biosimilars: from Technical to Pharmacoeconomic Considerations.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Biosimilars: from technical to pharmacoeconomic considerations. 30th Rencontres Nationales de Pharmacologie et Recherche clinique pour l'Innovation et l'Evaluation des Technologies de Santé. Tables rondes.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Impact of inodilator drugs on echocardiographic assessments of left ventricular filling pressure in patients with decompensated end-stage heart failure*.

OBJECTIVES: We investigated the impact of inodilators on the accuracy of E/e' ratio as a surrogate for pulmonary artery occlusion pressure in patients with decompensated end-stage systolic heart failure. SETTING: The ratio of early diastolic transmitral flow velocity to tissue Doppler mitral annular early diastolic velocity, E/e', and pulmonary artery occlusion pressure have been shown to be correlated. The validity of E/e' for predicting pulmonary artery occlusion pressure in patients with decompensated end-stage systolic heart failure was recently challenged, but the influence of inodilators was not taken into account, despite the reported influence of these drugs on left ventricular relaxation properties. PATIENTS AND INTERVENTION: Invasive hemodynamic monitoring and echocardiographic data were collected prospectively from 39 patients with decompensated end-stage systolic heart failure (92% male), aged 56 ± 13 years. These patients had dilated ventricles with a low cardiac index (1.9 ± 0.6 L/min/m) and high pulmonary artery occlusion pressure (22 ± 8 mm Hg), and 90% required inodilator support during hospitalization. MEASUREMENTS AND MAIN RESULTS: The correlation between septal E/e' and pulmonary artery occlusion pressure was good for examinations in the absence of inodilators (n = 21) (r = 0.7; p < 0.001), but no correlation was found when inodilators were used (n = 31). Lateral and mean E/e' were poorly correlated with pulmonary artery occlusion pressure, if at all, in both cases. CONCLUSIONS: By modifying ventricular relaxation properties and the influence of filling pressure on e', inodilator agents severely impair the correlation between E/e' and pulmonary artery occlusion pressure in patients with decompensated end-stage systolic heart failure.

Global prospective epidemiologic and surveillance study of ventilator-associated pneumonia due to Pseudomonas aeruginosa.

OBJECTIVE: To estimate the prevalence of ventilator-associated pneumonia caused by Pseudomonas aeruginosa in patients at risk for ventilator-associated pneumonia and to describe risk factors for P. aeruginosa ventilator-associated pneumonia. DESIGN: Prospective, observational study. SETTING: ICUs at 56 sites in 11 countries across four regions: the United States (n = 502 patients), Europe (n = 495), Latin America (n = 500), and Asia Pacific (n = 376). PATIENTS: Adults intubated and mechanically ventilated for 48 hours to 7 days, inclusive. INTERVENTIONS: None (local standard of care). MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia prevalence as defined by local investigators were 15.6% (293/1,873) globally, 13.5% in the United States, 19.4% in Europe, 13.8% in Latin America, and 16.0% in Asia Pacific (p = 0.04). Corresponding P. aeruginosa ventilator-associated pneumonia prevalences were 4.1%, 3.4%, 4.8%, 4.6%, and 3.2% (p = 0.49). Of 50 patients with P. aeruginosa ventilator-associated pneumonia who underwent surveillance testing, 19 (38%) had prior P. aeruginosa colonization and 31 (62%) did not (odds ratio, 7.99; 95% CI, 4.31-14.71). Of predefined risk factors for multidrug resistance (hereafter, risk factors), the most frequent in all patients were antimicrobial therapy within 90 days (51.9% of enrolled patients) and current hospitalization of more than or equal to 5 days (45.3%). None of these risk factors were significantly associated with P. aeruginosa ventilator-associated pneumonia by multivariate logistic regression. Risk factors associated with prior P. aeruginosa colonization were antimicrobial therapy within 90 days (odds ratio, 0.46; 95% CI, 0.29-0.73) and high proportion of antibiotic resistance in the community or hospital unit (odds ratio, 1.79; 95% CI, 1.14-2.82). CONCLUSIONS: Our findings suggest that ventilator-associated pneumonia remains a common ICU infection and that P. aeruginosa is one of the most common causative pathogens. The odds of developing P. aeruginosa ventilator-associated pneumonia were eight times higher in patients with prior P. aeruginosa colonization than in uncolonized patients, which in turn was associated with local resistance.

Medico-economic evaluation of healthcare products. Methodology for defining a significant impact on French health insurance costs and selection of benchmarks for interpreting results.

Decree No. 2012-1116 of 2 October 2012 on medico-economic assignments of the French National Authority for Health (Haute autorité de santé, HAS) significantly alters the conditions for accessing the health products market in France. This paper presents a theoretical framework for interpreting the results of the economic evaluation of health technologies and summarises the facts available in France for developing benchmarks that will be used to interpret incremental cost-effectiveness ratios. This literature review shows that it is difficult to determine a threshold value but it is also difficult to interpret then incremental cost effectiveness ratio (ICER) results without a threshold value. In this context, round table participants favour a pragmatic approach based on "benchmarks" as opposed to a threshold value, based on an interpretative and normative perspective, i.e. benchmarks that can change over time based on feedback.

Medico-economic evaluation of health products in the context of the Social Security Financing Act for 2012.

The participants in round table 6 of the Giens Workshops 2012 drafted recommendations based on the collective interpretation of important elements of the decree concerning the medico-economic evaluation of health products published a few days earlier (02 October 2012). The medico-economic evaluation (MEE), becomes an additional determinant for fixing the prices of health products by the Health products economic committee (Comité économique des produits de santé, CEPS) via the hierarchisation of treatment strategies, and thus modifies the market access conditions. Limiting the analysis to medicinal products and medical devices for which a major, important or moderate improvement in the medical service rendered (ASMR) or of the expected service (ASA) has been requested and presenting a significant budget impact on the Social Security expenses, excludes health products with ASMR or ASA with a lower level requested which often create complex price fixing problems and often have a major budget impact. This latter concept remains to be defined in detail. The MEE envisaged for the first registration must include the need to confirm or refute the initial hypotheses especially concerning the actual position in the therapeutic strategy at the time of renewal of the registration. For the first registration, the conventional reference to European prices guaranteeing a minimum price to innovative medicinal products, the medico-economic models submitted by the industry to the French Drug Authority (Haute autorité de santé, HAS) must be used to guide the compilation of new data to be requested at the time of the registration renewal and to negotiate the level of the discounts in the framework of a price-volume agreement, if applicable. The MEE will allow comparing the result of the analysis to the model hypothesis at the time of the renewal of the registration, which may contribute to the renegotiation (either up or down) of the price of health goods. The costs related to obtaining new data must be controlled. In order for the MEE to allow confirming the relationship between the price requested and the benefit expected, the group privileges the definition of reference values with an indicative and non-normative value, likely to evolve with time rather than a threshold. Concerning the evaluation procedure: the time to market access must not be lengthened; while the possibility of regular meetings between the industry and the HAS is recommended to avoid methodological divergences. A transitory period should allow the implementation of the entire evaluation procedure which must also take into account the specificities of health products registered before the 3 October 2013.

Assessment of body cell mass at bedside in critically ill patients.

Critical illness affects body composition profoundly, especially body cell mass (BCM). BCM loss reflects lean tissue wasting and could be a nutritional marker in critically ill patients. However, BCM assessment with usual isotopic or tracer methods is impractical in intensive care units (ICUs). We aimed to modelize the BCM of critically ill patients using variables available at bedside. Fat-free mass (FFM), bone mineral (Mo), and extracellular water (ECW) of 49 critically ill patients were measured prospectively by dual-energy X-ray absorptiometry and multifrequency bioimpedance. BCM was estimated according to the four-compartment cellular level: BCM = FFM - (ECW/0.98) - (0.73 × Mo). Variables that might influence the BCM were assessed, and multivariable analysis using fractional polynomials was conducted to determine the relations between BCM and these data. Bootstrap resampling was then used to estimate the most stable model predicting BCM. BCM was 22.7 ± 5.4 kg. The most frequent model included height (cm), leg circumference (cm), weight shift (Δ) between ICU admission and body composition assessment (kg), and trunk length (cm) as a linear function: BCM (kg) = 0.266 × height + 0.287 × leg circumference + 0.305 × Δweight - 0.406 × trunk length - 13.52. The fraction of variance explained by this model (adjusted r(2)) was 46%. Including bioelectrical impedance analysis variables in the model did not improve BCM prediction. In summary, our results suggest that BCM can be estimated at bedside, with an error lower than ±20% in 90% subjects, on the basis of static (height, trunk length), less stable (leg circumference), and dynamic biometric variables (Δweight) for critically ill patients.

Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized,double-blind, placebo-controlled trial.

OBJECTIVE: The type III secretion system is an important Pseudomonas aeruginosa-virulence determinant in animal models of infection and in humans. Antibody-mediated inhibition of the PcrV protein, an essential component of this system, might abrogate the Pseudomonas aeruginosa ability to damage epithelial cells, neutrophils, and macrophages, thereby limiting its pathogenicity. The objective of the trial was to determine the safety, pharmacokinetics, and ability to prevent Pseudomonas aeruginosa ventilator-associated pneumonia of KB001, a recombinant, PEGylated, engineered, human Fab' fragment that specifically binds to a Pseudomonas aeruginosa PcrV epitope and blocks its function. DESIGN: Multicenter, randomized, placebo-controlled, double-blind, phase-2a trial. SETTING: Ten intensive care units across France. PATIENTS: Thirty-nine Pseudomonas aeruginosa-colonized, but not infected, mechanically ventilated patients. INTERVENTIONS: Patients were randomized 1:1:1 to receive a single intravenous infusion of KB001, 3 mg/kg (n=13) or 10 mg/kg (n=14), or placebo (n=12). MEASUREMENTS AND MAIN RESULTS: The primary end points were KB001 safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Secondary end points included serum and lung KB001 pharmacokinetics, and Pseudomonas aeruginosa pneumonia rate within 28 days of its infusion. KB001 was well tolerated and not immunogenic. The 3- and 10-mg/kg groups had respective maximum serum concentrations of 52,811-88,660 and 121,857-285,454 ng/mL, with mean elimination half-lives of 8.1 and 9.3 days. KB001 was detected in endotracheal aspirates from all patients receiving it, as early as day 1 and up to 28 days. Respective mean endotracheal aspirate/serum concentration ratios were 0.092 and 0.085 for the 3- and 10-mg/kg groups, who developed Pseudomonas aeruginosa pneumonia less frequently (33% and 31%, respectively) than placebo recipients (60%). CONCLUSIONS: KB001 was safe and well tolerated in this study, with a favorable pharmacokinetic profile and promising potential for reducing Pseudomonas aeruginosa pneumonia incidence in intensive care unit mechanically ventilated patients colonized with this bacterium.

Drowning after falling from a medium-height bridge: multiple trauma victims.

INTRODUCTION: Drowning following a fall from a bridge can lead to cardiac arrest caused by hypoxia, hypothermia, or severe traumatic injury. Every year patients are brought to our hospital who have nearly drowned in the local river after a jump from a bridge (approximate height 16-22 meters). We report traumatic injuries in patients admitted to our hospital for out-of-hospital cardiac arrest due to drowning. METHODS: We retrospectively reviewed the charts of all patients admitted to the intensive care units of our hospital for out-of-hospital cardiac arrest due to drowning after a jump from a bridge in the Seine River between 2002 and 2010. All clinical or radiologic evidence of trauma was recorded. RESULTS: A total of 37 patients where admitted to our hospital for out-of-hospital cardiac arrest due to drowning. Fourteen patients had radiologic examinations. Five of these examinations showed evidence of severe trauma. In one case, clinical examination showed evidence of severe peripheral neurologic trauma. Seven of these patients (19%) were discharged from the hospital alive. CONCLUSIONS: Patients found nearly drowned in a river spanned by a medium-height bridge should undergo spinal immobilization and complete radiologic examination as soon as possible.

In-hospital cardiac arrests admitted alive in intensive care units: Insights from the CubRéa database.

BACKGROUND: In-hospital cardiac arrest(IHCA) has received little attention compared with out-of-hospital cardiac arrest. AIM: To address the paucity of data on IHCA patients, we examined key features, variations in mortality and predictors of death among patients admitted in French intensive care units(ICUs) from 1997 to 2015. METHODS: Using the database of the Collège des Utilisateurs de Bases de données en Réanimation(CUB-Réa) that prospectively collects data from ICUs in the greater Paris area, we determined temporal trends in the incidence of IHCA, patients' outcomes, crude and Simplified Acute Physiology Score(SAPS)-II Standardized mortality and predictors of in-ICU mortality. RESULTS: Of the 376,325 ICU admissions, 15,324(4.08%) had IHCA, with incidence increasing from 2.78% to 3.83%(p < 0.001). Over time, the patient age increased by 0.7 years(p = 0.04) and SAPS-II increased by 2.3%(p < 0.001). Crude in-ICU mortality decreased from 78% to 62.5% over the past 18 years(p < 0.001). The SAPS-II-standardized mortality also decreased over time from 78.4% to 68.3%(p < 0.001) representing a 10.1% relative decrease from 1997 to 2015. In multivariate analysis, admission in a more recent time-period was an independent correlate of decreased mortality(OR 0.40, 95%CI 0.35-0.46). CONCLUSION: Occurrence of IHCA increased over time but remains an uncommon reason for being admitted to ICU. From 1997 to 2015, we observed a change in patient profile, with older and more critically ill patients, despite which in-ICU mortality has substantially decreased in IHCA patients, likely resulting from a global improvement in the process of care and more widespread implementation of rapid response teams.

Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens.

BACKGROUND: Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. METHODS: Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit. RESULTS: A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%). CONCLUSIONS: The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.

Biological markers and diagnosis of ventilator-associated pneumonia.

Evaluation of a new biomarker from bronchoalveolar fluid, the Clara cell protein 10, adds data to the search for a diagnostic marker for ventilator-associated pneumonia (VAP). For more than 15 years, investigators tried to identify such a marker for predicting or diagnosing VAP. Unfortunately, the results of a number of these studies are disappointing. For optimal management of critically ill, ventilated patients with clinical suspicion of VAP, clinicians need accurate microbiological information to decide to treat in case of confirmed infection and to guide the initial choice of antibiotic therapy with identification of the responsible pathogen(s). Thus, today, the potential advantages of biomarkers are to improve the rapidity and performance of current diagnostic procedures and to reduce antibiotic exposure and selective pressure.

Analysis of the medication-use process in North American hospital systems: underlining key points for adoption to improve patient safety in French hospitals.

This project was designed to underline any actions relative to medication error prevention and patient safety improvement setting up in North American hospitals which could be implemented in French Parisian hospitals. A literature research and analysis of medication-use process in the North American hospitals and a validation survey of hospital pharmacist managers in the San Diego area was performed to assess main points of hospital medication-use process. Literature analysis, survey analysis of respondents highlighted main differences between the two countries at three levels: nationwide, hospital level and pharmaceutical service level. According to this, proposal development to optimize medication-use process in the French system includes the following topics: implementation of an expanded use of information technology and robotics; increase pharmaceutical human resources allowing expansion of clinical pharmacy activities; focus on high-risk medications and high-risk patient populations; develop a collective sense of responsibility for medication error prevention in hospital settings, involving medical, pharmaceutical and administrative teams. Along with a strong emphasis that should be put on the identified topics to improve the quality and safety of hospital care in France, consideration of patient safety as a priority at a nationwide level needs to be reinforced.

Increased intensity of treatment and decreased mortality in elderly patients in an intensive care unit over a decade.

OBJECTIVES: Data collected from two cohorts of patients aged > or =80 yrs and admitted to an intensive care unit in France were compared to determine whether intensive care unit care and survival had evolved from the 1990s to the 2000s. DESIGN: Retrospective cohort study on patient data attained during intensive care unit stays. SETTING: 18-bed intensive care unit in an academic medical center. PATIENTS: Two cohorts of patients aged > or =80 yrs, admitted to an intensive care unit at a 10-yr interval. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The first cohort comprised 348 patients admitted between January 1992 and December 1995, and the second cohort, 373 patients admitted between January 2001 and December 2004. There was no difference in age between the two cohorts, but patients in the second had significantly less history of functional limitation and significantly more acute illness (Simplified Acute Physiology Score II 43 +/- 18 vs. 57 +/- 25, respectively, p < .0001). Patients in the second cohort had a significantly higher Omega Score, had a higher occurrence of renal replacement therapy, and received vasopressors more frequently than the patients in the first cohort, even when adjusted for age, sex, Knaus classification, Simplified Acute Physiology Score II, and intensive care unit admission cause. Intensive care unit mortality was 65% and 64% for the first and second cohorts, respectively. In multivariate analysis (including age, Knaus classification, Simplified Acute Physiology Score II and first vs. second period) for association with intensive care unit survival, the 2001-2004 period was associated with a near tripling of chances of survival (odds ratio 2.9; 95% confidence interval, 1.92-4.47, p < .0001). CONCLUSIONS: The characteristics and intensity of treatment for elderly people admitted to the intensive care unit changed significantly over a decade. The intensity of treatments has increased over time and survival has improved over time as well. A potential link between increased treatment and improved survival in the elderly may be evoked.

Impact of energy deficit calculated by a predictive method on outcome in medical patients requiring prolonged acute mechanical ventilation.

To assess energy balance in very sick medical patients requiring prolonged acute mechanical ventilation and its possible impact on outcome, we conducted an observational study of the first 14 d of intensive care unit (ICU) stay in thirty-eight consecutive adult patients intubated at least 7 d. Exclusive enteral nutrition (EN) was started within 24 h of ICU admission and progressively increased, in absence of gastrointestinal intolerance, to the recommended energy of 125.5 kJ/kg per d. Calculated energy balance was defined as energy delivered - resting energy expenditure estimated by a predictive method based on static and dynamic biometric parameters. Mean energy balance was - 5439 (sem 222) kJ per d. EN was interrupted 23 % of the time and situations limiting feeding administration reached 64 % of survey time. ICU mortality was 72 %. Non-survivors had higher mean energy deficit than ICU survivors (P = 0.004). Multivariate analysis identified mean energy deficit as independently associated with ICU death (P = 0.02). Higher ICU mortality was observed with higher energy deficit (P = 0.003 comparing quartiles). Using receiver operating characteristic curve analysis, the best deficit threshold for predicting ICU mortality was 5021 kJ per d. Kaplan-Meier analysis showed that patients with mean energy deficit > or =5021 kJ per d had a higher ICU mortality rate than patients with lower mean energy deficit after the 14th ICU day (P = 0.01). The study suggests that large negative energy balance seems to be an independent determinant of ICU mortality in a very sick medical population requiring prolonged acute mechanical ventilation, especially when energy deficit exceeds 5021 kJ per d.

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status.

INTRODUCTION: In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock. METHODS: Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM. RESULTS: Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 microg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 x (BW/70)0.60 x (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 - 56.7) at C0 vs. 4.5 (0.3 - 38.9) nmol/L at C1, P < 0.001). CONCLUSIONS: Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients.