Elise Dupuis-Lozeron

A model for dropout assessment of candidates with or without hepatocellular carcinoma on a common liver transplant waiting list

In many countries, the allocation of liver grafts is based on the Model of End‐stage Liver Disease (MELD) score and the use of exception points for patients with hepatocellular carcinoma (HCC). With this strategy, HCC patients have easier access to transplantation than non‐HCC ones. In addition, this system does not allow for a dynamic assessment, which would be required to picture the current use of local tumor treatment. This study was based on the Scientific Registry of Transplant Recipients and included 5,498 adult candidates of a liver transplantation for HCC and 43,528 for non‐HCC diagnoses. A proportional hazard competitive risk model was used. The risk of dropout of HCC patients was independently predicted by MELD score, HCC size, HCC number, and alpha‐fetoprotein. When combined in a model with age and diagnosis, these factors allowed for the extrapolation of the risk of dropout. Because this model and MELD did not share compatible scales, a correlation between both models was computed according to the predicted risk of dropout, and drop‐out equivalent MELD (deMELD) points were calculated. Conclusion: The proposed model, with the allocation of deMELD, has the potential to allow for a dynamic and combined comparison of opportunities to receive a graft for HCC and non‐HCC patients on a common waiting list. (HEPATOLOGY 2012;56:149–156)

Screening of Illegal Intracorporeal Containers (“Body Packing”): Is Abdominal Radiography Sufficiently Accurate? A Comparative Study with Low-Dose CT

PURPOSE To evaluate the diagnostic performance of abdominal radiography in the detection of illegal intracorporeal containers (hereafter, packets), with low-dose computed tomography (CT) as the reference standard. MATERIALS AND METHODS This study was approved by the institutional ethical review board, with written informed consent. From July 2007 to July 2010, 330 people (296 men, 34 women; mean age, 32 years [range, 18-55 years]) suspected of having ingested drug packets underwent supine abdominal radiography and low-dose CT. The presence or absence of packets at abdominal radiography was reported, with low-dose CT as the reference standard. The density and number of packets (≤ 12 or >12) at low-dose CT were recorded and analyzed to determine whether those variables influence interpretation of results at abdominal radiography. RESULTS Packets were detected at low-dose CT in 53 (16%) suspects. Sensitivity of abdominal radiography for depiction of packets was 0.77 (41 of 53), and specificity was 0.96 (267 of 277). The packets appeared isoattenuated to the bowel contents at low-dose CT in 16 (30%) of the 53 suspects with positive results. Nineteen (36%) of the 53 suspects with positive low-dose CT results had fewer than 12 packets. Packets that were isoattenuated at low-dose CT and a low number of packets (≤12) were both significantly associated with false-negative results at abdominal radiography (P = .004 and P = .016, respectively). CONCLUSION Abdominal radiography is mainly limited by low sensitivity when compared with low-dose CT in the screening of people suspected of carrying drug packets. Low-dose CT is an effective imaging alternative to abdominal radiography.

Pulse wave amplitude reduction: a surrogate marker of micro-arousals associated with respiratory events occurring under non-invasive ventilation?

INTRODUCTION Respiratory events occurring under non-invasive ventilation (NIV) may produce sleep fragmentation. Alternatives to polysomnography (PSG) should be validated for providing simple monitoring tools for patients treated at home with NIV. OBJECTIVES To study the value of pulse wave amplitude (PWA) reduction as a surrogate marker of cortical micro-arousals associated with respiratory events occurring during NIV. METHODS 27 PSG tracings under NIV recorded in 9 stable patients with Obesity Hypoventilation Syndrome (OHS), under 3 different ventilator modes (no back-up rate, low or high back-up rate) were analyzed. For all respiratory events (obstructive, central, or mixed event), the association with EEG-micro-arousals, PWA reduction of more than 30% and the presence of associated SpO2 desaturation ≥ 4% was recorded. RESULTS 2474 respiratory events during NREM sleep were analyzed. 73.6% were associated with an EEG-MA, 91.4% with a ≥ 4% decrease in SpO2, and 74.9% with a significant PWA reduction. Sensitivity of PWA for the detection of an EEG-micro-arousal related to a respiratory event was 89.1% [95%CI: 76.7-95.3]. Positive predictive value (PPV) was 87.0% [95%CI: 75.0-94.0]. Sensitivity of PWA was highest in the S mode, compared to both other S/T modes, p = <0.001. Sensitivity of PWA was also higher for central and mixed events, compared to obstructive respiratory events, p = <0.05. CONCLUSIONS PWA reduction is a sensitive marker with a high PPV for the detection of EEG-MA associated with respiratory events during NREM sleep in stable OHS patients treated by NIV. In this situation, PWA could be used to improve scoring of hypopneas and allow an appropriate assessment of sleep fragmentation related to respiratory events.

Comorbidities and Subgroups of Patients Surviving Severe Acute Hypercapnic Respiratory Failure in the Intensive Care Unit

&NA; Rationale: No methodical assessment of the lung, cardiac, and sleep function of patients surviving an acute hypercapnic respiratory failure episode requiring admission to the intensive care unit (ICU) has been reported in the literature. Objectives: To prospectively investigate the prevalence and impact of comorbidities in patients treated by mechanical ventilator support (invasive or noninvasive) for acute hypercapnic respiratory failure in the ICU. Methods: Seventy‐eight consecutive patients admitted for an episode of acute hypercapnic respiratory failure underwent an assessment of lung, cardiac, and sleep function by pulmonary function tests, transthoracic echocardiography, and polysomnography 3 months after ICU discharge. Measurements and Main Results: Sixty‐seven percent (52 of 78) of patients exhibited chronic obstructive pulmonary disease (COPD), although only 19 had been previously diagnosed. Patients without COPD were primarily obese. Prevalence of severe obstructive sleep apnea was 51% (95% confidence interval, 34‐69) in patients with COPD and 81% (95% confidence interval, 54‐96) in patients without COPD. Previously undiagnosed cardiac dysfunction with preserved ejection fraction was highly prevalent (44%), as was hypertension (67%). More than half of the population demonstrated at least three major comorbidities known to precipitate acute hypercapnic respiratory failure. Multimorbidity was associated with longer time to hospital discharge. Hospital readmission or death occurred in 46% of patients over an average of 3.5 months after discharge. Conclusions: Severe hypercapnic respiratory failure requiring ICU admission resulted primarily from COPD or obesity. Major comorbidities are highly prevalent in both cases and most often ignored. Surviving acute hypercapnic respiratory failure should be an opportunity to systematically evaluate lung, heart, and sleep functions to improve poor outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02111876).

Spirometer Replacement and Serial Lung Function Measurements in Population Studies: Results From the SAPALDIA Study

The Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), a population cohort study, used heated-wire spirometers in 1991 and 2002 and then ultrasonic spirometers in 2010 revealing measurement bias in healthy never smokers. To provide a practical method to control for measurement bias given the replacement of spirometer in long-term population studies, we built spirometer-specific reference equations from healthy never smokers participating in 1991, 2002, and 2010 to derive individualized corrections terms. We compared yearly lung function decline without corrections terms with fixed terms that were obtained from a quasi-experimental study and individualized terms. Compared with baseline reference equations, spirometer-specific reference equations predicted lower lung function. The mean measurement bias increased with age and height. The decline in forced expiratory volume in 1 second during the reference period of 1991-2002 was 31.5 (standard deviation (SD), 28.7) mL/year while, after spirometer replacement, uncorrected, corrected by fixed term, and individualized term, the declines were 47.0 (SD, 30.1), 40.4 (SD, 30.1), and 30.4 (SD, 29.9) mL/year, respectively. In healthy never smokers, ultrasonic spirometers record lower lung function values than heated-wire spirometers. This measurement bias is sizeable enough to be relevant for researchers and clinicians. Future reference equations should account for not only anthropometric variables but also spirometer type. We provide a novel method to address spirometer replacement in cohort studies.

Agreement between Spirometers: A Challenge in the Follow-Up of Patients and Populations?

Background: Long-term cohort studies and lung function laboratories are confronted with the need for replacement of spirometers. Lack of agreement between spirometers might affect the longitudinal comparison of data, notably when replacing conventional by portable spirometers. Objectives: To compare the handheld EasyOne (EO) with the conventional SensorMedics (SM) spirometer, and to analyze the interdevice reproducibility of EO spirometers. Methods: In total, 82 volunteers completed spirometry sessions with 1 SM and 2 of 3 EO spirometers following a Latin square design. Analyses of differences in forced vital capacity (FVC), forced expiratory flow in 1 s (FEV1), FEV1/FVC and mean forced expiratory flow calculated between 25 and 75% of the FVC between spirometers used a mixed effect model with a random intercept for each subject and the effect of the device as fixed effect adjusted for sex, age, height and order of spirometer tested. Bland-Altman plots show the 95% limits of agreement. Results: Comparisons between EO and SM showed relatively small mean differences of <3%, but systematically lower values for FVC and FEV1 in all EO devices. The 95% agreement exceeded the limits for FEV1 by 50 ml in 2 EO spirometers. The EO interdevice comparisons showed mean differences and limits of agreement within established thresholds, thus indicating fair accuracy when comparing devices. Repeats with the same spirometer did not result in statistically significant differences. Conclusions: This study suggests fair agreement between the handheld and the conventional spirometer. Differences slightly exceeding limits for FEV1 in 2 EO devices might be considered mostly irrelevant for clinical practice. However, the systematically lower FVC and FEV1 observed with EO may be significant for epidemiological studies, thus justifying inspection before replacing devices.

When Breathing Interferes with Cognition: Experimental Inspiratory Loading Alters Timed Up-and-Go Test in Normal Humans

Human breathing stems from automatic brainstem neural processes. It can also be operated by cortico-subcortical networks, especially when breathing becomes uncomfortable because of external or internal inspiratory loads. How the “irruption of breathing into consciousness” interacts with cognition remains unclear, but a case report in a patient with defective automatic breathing (Ondines curse syndrome) has shown that there was a cognitive cost of breathing when the respiratory cortical networks were engaged. In a pilot study of putative breathing-cognition interactions, the present study relied on a randomized design to test the hypothesis that experimentally loaded breathing in 28 young healthy subjects would have a negative impact on cognition as tested by “timed up-and-go” test (TUG) and its imagery version (iTUG). Progressive inspiratory threshold loading resulted in slower TUG and iTUG performance. Participants consistently imagined themselves faster than they actually were. However, progressive inspiratory loading slowed iTUG more than TUG, a finding that is unexpected with regard to the known effects of dual tasking on TUG and iTUG (slower TUG but stable iTUG). Insofar as the cortical networks engaged in response to inspiratory loading are also activated during complex locomotor tasks requiring cognitive inputs, we infer that competition for cortical resources may account for the breathing-cognition interference that is evidenced here.

Prognostication of Mortality in Critically Ill Patients With Severe Infections

BACKGROUND The purpose of this study was to confirm the prognostic value of pancreatic stone protein (PSP) in patients with severe infections requiring ICU management and to develop and validate a model to enhance mortality prediction by combining severity scores with biomarkers. METHODS We enrolled prospectively patients with severe sepsis or septic shock in mixed tertiary ICUs in Switzerland (derivation cohort) and Brazil (validation cohort). Severity scores (APACHE [Acute Physiology and Chronic Health Evaluation] II or Simplified Acute Physiology Score [SAPS] II) were combined with biomarkers obtained at the time of diagnosis of sepsis, including C-reactive-protein, procalcitonin (PCT), and PSP. Logistic regression models with the lowest prediction errors were selected to predict in-hospital mortality. RESULTS Mortality rates of patients with septic shock enrolled in the derivation cohort (103 out of 158) and the validation cohort (53 out of 91) were 37% and 57%, respectively. APACHE II and PSP were significantly higher in dying patients. In the derivation cohort, the models combining either APACHE II, PCT, and PSP (area under the receiver operating characteristic curve [AUC], 0.721; 95% CI, 0.632-0.812) or SAPS II, PCT, and PSP (AUC, 0.710; 95% CI, 0.617-0.802) performed better than each individual biomarker (AUC PCT, 0.534; 95% CI, 0.433-0.636; AUC PSP, 0.665; 95% CI, 0.572-0.758) or severity score (AUC APACHE II, 0.638; 95% CI, 0.543-0.733; AUC SAPS II, 0.598; 95% CI, 0.499-0.698). These models were externally confirmed in the independent validation cohort. CONCLUSIONS We confirmed the prognostic value of PSP in patients with severe sepsis and septic shock requiring ICU management. A model combining severity scores with PCT and PSP improves mortality prediction in these patients.

Simulation based bias correction methods for complex models

ABSTRACT Along with the ever increasing data size and model complexity, an important challenge frequently encountered in constructing new estimators or in implementing a classical one such as the maximum likelihood estimator, is the computational aspect of the estimation procedure. To carry out estimation, approximate methods such as pseudo-likelihood functions or approximated estimating equations are increasingly used in practice as these methods are typically easier to implement numerically although they can lead to inconsistent and/or biased estimators. In this context, we extend and provide refinements on the known bias correction properties of two simulation-based methods, respectively, indirect inference and bootstrap, each with two alternatives. These results allow one to build a framework defining simulation-based estimators that can be implemented for complex models. Indeed, based on a biased or even inconsistent estimator, several simulation-based methods can be used to define new estimators that are both consistent and with reduced finite sample bias. This framework includes the classical method of the indirect inference for bias correction without requiring specification of an auxiliary model. We demonstrate the equivalence between one version of the indirect inference and the iterative bootstrap, both correct sample biases up to the order n− 3. The iterative method can be thought of as a computationally efficient algorithm to solve the optimization problem of the indirect inference. Our results provide different tools to correct the asymptotic as well as finite sample biases of estimators and give insight on which method should be applied for the problem at hand. The usefulness of the proposed approach is illustrated with the estimation of robust income distributions and generalized linear latent variable models. Supplementary materials for this article are available online.

Obstructive sleep apnea in patients surviving acute hypercapnic respiratory failure is best predicted by static hyperinflation

Rationale Acute hypercapnic respiratory failure (AHRF) treated with non-invasive ventilation in the ICU is frequently caused by chronic obstructive pulmonary disease (COPD) exacerbations and obesity-hypoventilation syndrome, the latter being most often associated with obstructive sleep apnea. Overlap syndrome (a combination of COPD and obstructive sleep apnea) may represent a major burden in this population, and specific diagnostic pathways are needed to improve its detection early after ICU discharge. Objectives To evaluate whether pulmonary function tests can identify a high probability of obstructive sleep apnea in AHRF survivors and outperform common screening questionnaires to identify the disorder. Methods Fifty-three patients surviving AHRF (31 males; median age 67 years (interquartile range: 62–74) participated in the study. Anthropometric data were recorded and body plethysmography was performed 15 days after ICU discharge. A sleep study was performed 3 months after ICU discharge. Results The apnea-hypopnea index was negatively associated with static hyperinflation as measured by the residual volume to total lung capacity ratio in the % of predicted (coefficient = -0.64; standard error 0.17; 95% CI -0.97 to -0.31; p<0.001). A similar association was observed in COPD patients only: coefficient = -0.65; standard error 0.19; 95% CI -1.03 to -0.26; p = 0.002. Multivariate analysis with penalized maximum likelihood confirmed that the residual volume to total lung capacity ratio was the main contributor for apnea-hypopnea index variance in addition to classic predictors. Screening questionnaires to select patients at risk for sleep-disordered breathing did not perform well. Conclusions In AHRF survivors, static hyperinflation is negatively associated with the apnea-hypopnea index in both COPD and non-COPD patients. Measuring static hyperinflation in addition to classic predictors may help to increase the recognition of obstructive sleep apnea as common screening tools are of limited value in this specific population.