Predicting the microbial cause of community-acquired pneumonia: can physicians or a data-driven method differentiate viral from bacterial pneumonia at patient presentation?

BACKGROUND: Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia? METHODS: We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values < 0.1 were considered clinically relevant. RESULTS: We included 153 patients with CAP (70.6% men; 62 [51-73] years old; mean SAPSII, 37 [27-47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia). CONCLUSION: Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy.

Comparison of the in vitro pharmacological profiles of long-acting muscarinic antagonists in human bronchus.

BACKGROUND AND PURPOSE: Long-acting muscarinic antagonists (LAMAs) have been recommended for the treatment of chronic obstructive pulmonary disease and (more recently) asthma. However, the in vitro pharmacological profiles of the four LAMAs currently marketed (tiotropium, umeclidinium, aclidinium and glycopyrronium) have not yet been compared (relative to ipratropium) by using the same experimental approach. EXPERIMENTAL APPROACH: With a total of 560 human bronchial rings, we investigated the antagonists' potency, onset and duration of action for inhibition of the contractile response evoked by electrical field stimulation. We also evaluated the antagonists' potency for inhibiting cumulative concentration-contraction curves for acetylcholine and carbachol. KEY RESULTS: The onset and duration of action were concentration-dependent. At submaximal, equipotent concentrations, the antagonists' onsets of action were within the same order of magnitude. However, the durations of action differed markedly. After washout, ipratropium's inhibitory activity decreased rapidly (within 30-90 min) but those of tiotropium and umeclidinium remained stable (at above 70%) for at least 9 h. Aclidinium and glycopyrronium displayed less stable inhibitory effects, with a progressive loss of inhibition at submaximal concentrations. In contrast to ipratropium, all the LAMAs behaved as insurmountable antagonists by decreasing the maximum responses to both acetylcholine and carbachol. CONCLUSIONS AND IMPLICATIONS: The observed differences in the LAMAs' in vitro pharmacological profiles in the human bronchus provide a compelling pharmacological rationale for the differences in the drugs' respective recommended daily doses and frequencies of administration.

Epinephrine Dose Has a Preventive Effect on the Occurrence of Stress Ulcer-Induced Gastrointestinal Bleeding in Critically Ill Patients.

BACKGROUND: Epinephrine may impair splanchnic blood flow, but the impact of epinephrine dose on the occurrence of clinically significant gastrointestinal bleeding (CSGB) caused by stress ulcer remains unclear. We investigated the effect of epinephrine dose on the occurrence of stress ulcer-related CSGB in intensive care unit (ICU) patients. METHODS: In this prospective, observational, cohort study conducted in a French teaching hospital, 40 consecutive ICU patients receiving epinephrine infusion in whom a stress ulcer was diagnosed by an upper gastrointestinal endoscopy were included, from February 2010 to July 2015. The effects of epinephrine dose, and other covariates, on the occurrence of stress ulcer-related CSGB were analyzed using a multiple logistic regression model for repeated measures: At each observation, each patient serves as his own control. RESULTS: A total of 1484 time-dependent epinephrine dose modifications were available for analysis. The median epinephrine dose rate was 0.8 (0-9.5) mg/h, and the median epinephrine cumulative dose was 44.8 (2.6-2343) mg. Epinephrine, expressed as the average dose per day at time t, had a significant protective effect on the occurrence of stress ulcer (odds ratio 0.22; 95% confidence interval (CI), 0.12-0.38; p < 0.0001, for a log10 increase of epinephrine dose). Enteral feeding had also a protective effect (odds ratio 0.55; 95% CI 0.41-0.72; p < 0.0001, for a log10 increase of kcal/day). Only renal replacement therapy increased the occurrence of stress ulcer in the model. CONCLUSIONS: An increase in the average dose of epinephrine per day increased the time to occurrence of stress ulcer in critically ill patients.

Effectiveness of heart rate control on hemodynamics in critically ill patients with atrial tachyarrhythmias managed by amiodarone.

Atrial tachyarrhythmias (AT) are common in intensive care unit (ICU) patients and might contribute to hemodynamic instability if heart rate (HR) is persistently too rapid. We aimed to assess if HR control below 115 or 130bpm with amiodarone improves hemodynamics in ICU patients with AT. This observational study included 73 ICU patients with disabling AT receiving amiodarone for HR control. A total of 525 changes (mainly within 4-8h) in mean arterial pressure (MAP) and 167 changes in plasma lactate in response to HR variations above 115 or 130bpm were analyzed. Epinephrine, sedative drugs, fluid loading, use of diuretics, continuous renal replacement therapy and amiodarone dosing were among covariables assessed. Univariable analysis showed that HR variations above 115bpm were poorly correlated to change in MAP (r=0.11, p<0.01). Multivariable analysis showed that changes in MAP were still positively associated to HR variation (p<0.05) and to initiation or termination of epinephrine (p<0.05) or sedatives infusions (p<0.05). Changes in plasma lactate did not correlate to HR variations above 115bpm. When considering 130 bpm as a threshold, HR variations were not associated to changes in MAP or to changes in plasma lactate. Amiodarone dose was associated to HR decrease but not to MAP or plasma lactate increase. In ICU patients with AT, strict HR control below 115bpm or 130bpm with amiodarone does not improve hemodynamics. A prospective randomized trial assessing strict versus lenient HR control in this setting is needed.

The impact of low-frequency, low-force cyclic stretching of human bronchi on airway responsiveness.

BACKGROUND: In vivo, the airways are constantly subjected to oscillatory strain (due to tidal breathing during spontaneous respiration) and (in the event of mechanical ventilation) positive pressure. This exposure is especially problematic for the cartilage-free bronchial tree. The effects of cyclic stretching (other than high-force stretching) have not been extensively characterized. Hence, the objective of the present study was to investigate the functional and transcriptional response of human bronchi to repetitive mechanical stress caused by low-frequency, low-force cyclic stretching. METHODS: After preparation and equilibration in an organ bath, human bronchial rings from 66 thoracic surgery patients were stretched in 1-min cycles of elongation and relaxation over a 60-min period. For each segment, the maximal tension corresponded to 80% of the reference contraction (the response to 3 mM acetylcholine). The impact of cyclic stretching (relative to non-stretched controls) was examined by performing functional assessments (epithelium removal and incubation with sodium channel agonists/antagonists or inhibitors of intracellular pathways), biochemical assays of the organ bath fluid (for detecting the release of pro-inflammatory cytokines), and RT-PCR assays of RNA isolated from tissue samples. RESULTS: The application of low-force cyclic stretching to human bronchial rings for 60 min resulted in an immediate, significant increase in bronchial basal tone, relative to non-cyclic stretching (4.24 ± 0.16 g vs. 3.28 ± 0.12 g, respectively; p < 0.001). This cyclic stimulus also increased the affinity for acetylcholine (-log EC50: 5.67 ± 0.07 vs. 5.32 ± 0.07, respectively; p p < 0.001). Removal of airway epithelium and pretreatment with the Rho-kinase inhibitor Y27632 and inward-rectifier K+ or L-type Ca2+ channel inhibitors significantly modified the basal tone response. Exposure to L-NAME had opposing effects in all cases. Pro-inflammatory pathways were not involved in the response; cyclic stretching up-regulated the early mRNA expression of MMP9 only, and was not associated with changes in organ bath levels of pro-inflammatory mediators. CONCLUSION: Low-frequency, low-force cyclic stretching of whole human bronchi induced a myogenic response rather than activation of the pro-inflammatory signaling pathways mediated by mechanotransduction.

Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

IMPORTANCE: Acetazolamide has been used for decades as a respiratory stimulant for patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, but no large randomized placebo-controlled trial is available to confirm this approach. OBJECTIVE: To determine whether acetazolamide reduces mechanical ventilation duration in critically ill patients with COPD and metabolic alkalosis. DESIGN, SETTING, AND PARTICIPANTS: The DIABOLO study, a randomized, double-blind, multicenter trial, was conducted from October 2011 through July 2014 in 15 intensive care units (ICUs) in France. A total of 382 patients with COPD who were expected to receive mechanical ventilation for more 24 hours were randomized to the acetazolamide or placebo group and 380 were included in an intention-to treat analysis. INTERVENTIONS: Acetazolamide (500-1000 mg, twice daily) vs placebo administered intravenously in cases of pure or mixed metabolic alkalosis, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES: The primary outcome was the duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy. Secondary outcomes included changes in arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality. RESULTS: Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379 [99.7%] with endotracheal intubation) completed the study. For the acetazolamide group (n = 187), compared with the placebo group (n = 193), no significant between-group differences were found for median duration of mechanical ventilation (-16.0 hours; 95% CI, -36.5 to 4.0 hours; P = .17), duration of weaning off mechanical ventilation (-0.9 hours; 95% CI, -4.3 to 1.3 hours; P = .36), daily changes of minute-ventilation (-0.0 L/min; 95% CI, -0.2 to 0.2 L/min; P = .72), or partial carbon-dioxide pressure in arterial blood (-0.3 mm Hg; 95% CI, -0.8 to 0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference, -0.8 mEq/L; 95% CI, -1.2 to -0.5 mEq/L; P < .001) and number of days with metabolic alkalosis (between-group difference, -1; 95% CI, -2 to -1 days; P < .001) decreased significantly more in the acetazolamide group. Other secondary outcomes also did not differ significantly between groups. CONCLUSIONS AND RELEVANCE: Among patients with COPD receiving invasive mechanical ventilation, the use of acetazolamide, compared with placebo, did not result in a statistically significant reduction in the duration of invasive mechanical ventilation. However, the magnitude of the difference was clinically important, and it is possible that the study was underpowered to establish statistical significance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01627639.

The consequences of sudden fluid shifts on body composition in critically ill patients.

INTRODUCTION: Estimation of body composition as fat-free mass (FFM) is subjected to many variations caused by injury and stress conditions in the intensive care unit (ICU). Body cell mass (BCM), the metabolically active part of FFM, is reported to be more specifically correlated to changes in nutritional status. Bedside estimation of BCM could help to provide more valuable markers of nutritional status and may promote understanding of metabolic consequences of energy deficit in the ICU patients. We aimed to quantify BCM, water compartments and FFM by methods usable at the bedside for evaluating the impact of sudden and massive fluid shifts on body composition in ICU patients. METHODS: We conducted a prospective experimental study over an 6 month-period in a 18-bed ICU. Body composition of 31 consecutive hemodynamically stable patients requiring acute renal replacement therapy for fluid overload (ultrafiltration ≥5% body weight) was investigated before and after the hemodialysis session. Intra-(ICW) and extracellular (ECW) water volumes were calculated from the raw values of the low- and high-frequency resistances measured by multi-frequency bioelectrical impedance. BCM was assessed by a calculated method recently developed for ICU patients. FFM was derived from BCM and ECW. RESULTS: Intradialytic weight loss was 3.8 ± 0.8 kg. Percentage changes of ECW (-7.99 ± 4.60%) and of ICW (-7.63 ± 5.11%) were similar, resulting ECW/ICW ratio constant (1.26 ± 0.20). The fall of FFM (-2.24 ± 1.56 kg, -4.43 ± 2.65%) was less pronounced than the decrease of ECW (P < 0.001) or ICW (P < 0.001). Intradialytic variation of BCM was clinically negligible (-0.38 ± 0.93 kg, -1.56 ± 3.94%) and was significantly less than FFM (P < 0.001). CONCLUSIONS: BCM estimation is less driven by sudden massive fluid shifts than FMM. Assessment of BCM should be preferred to FFM when severe hydration disturbances are present in ICU patients.

Acute right-sided heart failure caused by Neisseria meningitidis.

Meningococcal myocarditis is a rarely diagnosed infection and could be the consequence of primary invasive infection or late immunologic complications. An unusual presentation of meningococcemia in an immunocompetent adult is described, with Neisseria meningitidis identified as the cause of selective right-sided heart failure in a case of acute myocarditis.

The expression and relaxant effect of bitter taste receptors in human bronchi.

BACKGROUND: Bitter-taste receptors (TAS2Rs) have recently been involved in the relaxation of mouse and guinea pig airways, and increased expression of TAS2Rs was shown in blood leucocytes from asthmatic children. We sought to identify and characterize the TAS2Rs expressed in isolated human bronchi and the subtypes involved in relaxation. METHODS: Human bronchi were isolated from resected lungs and TAS2R transcripts were assessed with RT-qPCR. Relaxation to TAS2R agonists was tested in organ bath in the presence or absence of pharmacological modulators of the signalling pathways involved in bronchial relaxation. RESULTS: We detected the expression of TAS2R transcripts in human bronchi. The non-selective agonists chloroquine, quinine, caffeine, strychnine and diphenidol produced a bronchial relaxation as effective and potent as theophylline but much less potent than formoterol and isoproterenol. Denatonium, saccharin and colchicine did not produce relaxation. Receptor expression analysis together with the use of selective agonists suggest a predominant role for TAS2R5, 10 and 14 in bitter taste agonist-induced relaxation. The mechanism of relaxation was independent of the signalling pathways modulated by conventional bronchodilators and may be partly explained by the inhibition of phosphatidylinositol-3-kinases. CONCLUSIONS: The TAS2Rs may constitute a new therapeutic target in chronic obstructive lung diseases such as asthma.

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.

Acetazolamide: a second wind for a respiratory stimulant in the intensive care unit?

Patients with chronic obstructive pulmonary disease (COPD) are affected by episodes of respiratory exacerbations, some of which can be severe and may necessitate respiratory support. Prolonged invasive mechanical ventilation is associated with increased mortality rates. Persistent failure to discontinue invasive mechanical ventilation is a major issue in patients with COPD. Pure or mixed metabolic alkalosis is a common finding in the intensive care unit (ICU) and is associated with a worse outcome. In patients with COPD, the condition is called post-hypercapnic alkalosis and is a complication of mechanical ventilation. Reversal of metabolic alkalosis may facilitate weaning from mechanical ventilation of patients with COPD. Acetazolamide, a non-specific carbonic anhydrase inhibitor, is one of the drugs employed in the ICU to reverse metabolic alkalosis. The drug is relatively safe, undesirable effects being rare. The compartmentalization of the different isoforms of the carbonic anhydrase enzyme may, in part, explain the lack of evidence of the efficacy of acetazolamide as a respiratory stimulant. Recent findings suggest that the usually employed doses of acetazolamide in the ICU may be insufficient to significantly improve respiratory parameters in mechanically ventilated patients with COPD. Randomized controlled trials using adequate doses of acetazolamide are required to address this issue.

Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients.

INTRODUCTION: Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation. METHODS: This observational, retrospective study included 68 invasively ventilated COPD patients who received one or multiple doses of 250 or 500 mg of acetazolamide during the weaning period. Among the 68 investigated patients, 207 time-serum bicarbonate observations were available for analysis. Population pharmacodynamics was modeled using a nonlinear mixedeffect model. The main covariates of interest were baseline demographic data, Simplified Acute Physiology Score II (SAPS II) at ICU admission, cause of respiratory failure, co-prescription of drugs interfering with the acid-base equilibrium, and serum concentrations of protein, creatinin, potassium and chloride. The effect of acetazolamide on serum bicarbonate levels at different doses and in different clinical conditions was subsequently simulated in silico. RESULTS: The main covariates interacting with acetazolamide pharmacodynamics were SAPS II at ICU admission (P = 0.01), serum chloride (P < 0.001) and concomitant administration of corticosteroids (P = 0.02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a dose-response relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 ± 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentrations > 5 mmol/L in the presence of high serum chloride levels or coadministration of systemic corticosteroids or furosemide. CONCLUSIONS: This study identified several covariates that influenced acetazolamide pharmacodynamics and could allow a better individualization of acetazolamide dosing when treating COPD patients with metabolic alkalosis.

Airway response to acute mechanical stress in a human bronchial model of stretch.

INTRODUCTION: Lung inflation may have deleterious effects on the alveoli during mechanical ventilation. However, the consequences of stretch during excessive lung inflation on basal tone and responsiveness of human bronchi are unknown. This study was undertaken to devise an experimental model of acute mechanical stretch in isolated human bronchi and to investigate its effect on airway tone and responsiveness. METHODS: Bronchi were removed from 48 thoracic surgery patients. After preparation and equilibration in an organ bath, bronchial rings were stretched for 5 min using a force (2.5 × basal tone) that corresponded to airway-inflation pressure > 30 cm H2O. The consequences of stretch were examined by using functional experiments, analysis of organ-bath fluid, and ribonucleic acid (RNA) isolation from tissue samples. RESULTS: Following removal of the applied force the airways immediately developed an increase in basal tone (P < 0.0001 vs. paired controls) that was sustained and it did so without significantly increasing responsiveness to acetylcholine. The spontaneous tone was abolished with a Rho-kinase inhibitor and epithelium removal, a leukotriene antagonist or nitric oxide synthase inhibitors reduced it, whereas indomethacin, sensory nerve inhibitors or antagonists for muscarinic, endothelin and histamine receptors had no effect. Stretch enhanced leukotriene-E4 production during the immediate spontaneous contraction of human bronchi (P < 0.05). Moreover, stretch up-regulated the early mRNA expression of genes involved in wingless-type mouse mammary tumor virus integration-site family (WNT)-signaling and Rho-kinase pathways. CONCLUSIONS: Stretching human bronchi for only 5 min induces epithelial leukotriene release via nitric oxide synthase activation and provokes a myogenic response dependent on Rho-kinase and WNT-signaling pathways. From a clinical perspective, these findings highlight the response of human airway to acute mechanical stress during excessive pulmonary inflation.

beta2-Agonist modulates epithelial gene expression involved in the T- and B-cell chemotaxis and induces airway sensitization in human isolated bronchi.

Regular use of beta(2)-adrenoceptor agonists may enhance non-specific airway responsiveness and inflammation. In earlier experimental studies, we showed that prolonged in vitro fenoterol exposure induced airway sensitization via perturbed epithelial regulation of bronchoconstriction. The aim of the present work was to examine the involvement of inflammatory mediator genes and proinflammatory cells and to investigate the role of the bronchial epithelium in these untoward effects. Bronchial tissues were surgically removed from 17 ex-smokers. Bronchial rings and primary cultures of bronchial epithelial cells were incubated with 0.1microM fenoterol for 15h. Levels of mRNA-expression were analyzed using a real-time quantitative reverse transcription-polymerase chain reaction array. Bronchial rings were contracted with endothelin-1 and immune cell infiltration was assessed by immunohistochemistry. Compared to paired controls, fenoterol up-regulated the mRNAs of cytokines/proteins implicated in the recruitment of T and B cells or the activation and proliferation of bronchial epithelial cells (CCL20/MIP-3alpha, FOXA2, PPAR-gamma) in isolated bronchi and in cultured epithelial cells. Fenoterol exposure significantly enhanced CD8(+)-T and differentiated CD138(+)-B-cells infiltration into the bronchi, especially the subepithelial area. Increase in CD8 or CD138 labeling-intensity strongly correlated with rise in maximal contraction to endothelin-1 induced by fenoterol exposure. In summary, our results show that fenoterol modulates the T and B cells chemotaxis possibly via the epithelial chemokine secretion in isolated bronchi from ex-smokers. They also suggest that the infiltration of resident T and B cells into the subepithelial area is associated with an increase in airway responsiveness due to fenoterol exposure.

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.

Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists.

BACKGROUND: Bitter-taste receptors (TAS2Rs) are involved in airway relaxation but are also expressed in human blood leukocytes. We studied TAS2R expression and the effects of TAS2R agonists on the lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs). METHODS: Lung macrophages were isolated from patients undergoing surgery for carcinoma. We used RT-qPCR to measure transcripts of 16 TAS2Rs (TAS2Rs 3/4/5/7/8/9/10/14/19/20/31/38/39/43/45 and 46) in unstimulated and LPS-stimulated (10 ng.mL-1) LMs. The macrophages were also incubated with TAS2R agonists for 24 h. Supernatant levels of the cytokines TNF-α, CCL3, CXCL8 and IL-10 were measured using ELISAs. RESULTS: The transcripts of all 16 TAS2Rs were detected in macrophages. The addition of LPS led to an increase in the expression of most TAS2Rs, which was significant for TAS2R7 and 38. Although the promiscuous TAS2R agonists, quinine and denatonium, inhibited the LPS-induced release of TNF-α, CCL3 and CXCL8, diphenidol was inactive. Partially selective agonists (dapsone, colchicine, strychnine, and chloroquine) and selective agonists [erythromycin (TAS2R10), phenanthroline (TAS2R5), ofloxacin (TAS2R9), and carisoprodol (TAS2R14)] also suppressed the LPS-induced cytokine release. In contrast, two other agonists [sodium cromoglycate (TAS2R20) and saccharin (TAS2R31 and 43)] were inactive. TAS2R agonists suppressed IL-10 production - suggesting that this anti-inflammatory cytokine is not involved in the inhibition of cytokine production. CONCLUSION: Human LMs expressed TAS2Rs. Experiments with TAS2R agonists' suggested the involvement of TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39 and 40 in the inhibition of cytokine production. TAS2Rs may constitute new drug targets in inflammatory obstructive lung disease.

Validation of a predictive method for an accurate assessment of resting energy expenditure in medical mechanically ventilated patients.

OBJECTIVE: Use comparison with indirect calorimetry to confirm the ability of our previously described equation to predict resting energy expenditure in mechanically ventilated patients. DESIGN: Prospective, validation study. SETTING: Eighteen-bed, medical intensive care unit at a teaching hospital. PATIENTS: All adult patients intubated >24 hrs were assessed for eligibility. Exclusion criteria were clinical situations that could contribute to erroneous calorimetric measurements. INTERVENTIONS: Resting energy expenditure was calculated using the original Harris-Benedict equations and those corrected for usual stress factors, the Swinamer equation, the Fusco equation, the Ireton-Jones equation, and our equation: resting energy expenditure (kcal/day) = 8 x weight (kg) + 14 x height (cm) + 32 x minute ventilation (L/min) + 94 x temperature (degrees C) - 4834. MEASUREMENTS AND MAIN RESULTS: Resting energy expenditure was measured by indirect calorimetry for the 45 included patients. Resting energy expenditure calculated with our predictive model correlated with the measured resting energy expenditure (r2 = .62, p < .0001), and Bland-Altman analysis showed a mean bias of -192 +/- 277 kcal/day, with limits of agreement ranging from -735 to 351 kcal/day. Resting energy expenditure calculated with the Harris-Benedict equations was more weakly correlated with measured resting energy expenditure (r2 = .41, p < .0001), with Bland-Altman analysis showing a mean bias of 279 +/- 346 kcal/day between them and the limits of agreement ranging from -399 to 957 kcal/day. Applying usual stress-correction factors to the Harris-Benedict equations generated wide variability, and the correlation with measured resting energy expenditure was poorer (r2 = .18, p < .0001), with Bland-Altman analysis showing a mean bias of -357 +/- 750 kcal/day and limits of agreement ranging from -1827 to 1113 kcal/day. The use of the Swinamer, Fusco, or Ireton-Jones predictive methods yielded weaker correlation between calculated and measured resting energy expenditure (r2 = .41, p < .0001; r2 = .38, p < .0001; r2 = .39, p < .0001, respectively) than our equation, and Bland-Altman analysis showed no improvement in agreement and variability between methods. CONCLUSIONS: The Faisy equation, based on static (height), less stable (weight), and dynamic biometric variables (temperature and minute ventilation), provided precise and unbiased resting energy expenditure estimations in mechanically ventilated patients.