Dosing Regimen for Cefotaxime Should Be Adapted to the Stage of Renal Dysfunction in Critically Ill Adult Patients-A Retrospective Study.

Cefotaxime administration is recommended in doses of 3-12 g/day in adults with a Glomerular Filtration Rate (GFR) > 5 mL/min. This study aimed to assess the impact of renal function and obesity on cefotaxime concentrations in intensive care unit (ICU) patients. A retrospective cohort study was conducted on consecutive ICU patients receiving continuous cefotaxime infusion between 2020 and 2022 [IRBN992021/CHUSTE]. Doses were not constant; consequently, a concentration-to-dose ratio (C/D) was considered. Statistical analysis was performed to assess the relationship between cefotaxime concentrations, renal function, and obesity. A total of 70 patients, median age 61 years, were included, with no significant difference in cefotaxime concentrations between obese and non-obese patients. However, concentrations varied significantly by GFR, with underdosing prevalent in patients with normal to increased renal function and overdosing in those with severely impaired renal function. Adjustment of cefotaxime dosing according to GFR was associated with improved target attainment. Cefotaxime dosing in critically ill patients should consider renal function, with higher initial doses required in patients with normal to increased GFR and lower doses in those with severely impaired renal function. Therapeutic drug monitoring may aid in optimising dosing regimens. Prospective studies are warranted to validate these findings and inform clinical practice.

Development of a Novel Bronchodilator Vaping Drug Delivery System Based on Thermal Degradation Properties.

This work aims to investigate bronchodilator delivery with the use of different vaping drug delivery systems (VDDS) by determining the dose equivalence delivered in relation to different references: a clinical jet nebulizer, a pMDI (pressurized metered dose inhaler) and a DPI (dry powder inhaler). Three different bronchodilators were used (terbutaline, salbutamol hemisulfate, ipratropium bromide). The e-liquids contained the active pharmaceutical ingredient (API) in powder form. Two different VDDS were tested (JUUL and a GS AIR 2 atomizer paired with a variable lithium-ion battery (i-stick TC 40 W), 1.5 ohm resistance, and 15 W power). Samples were collected using a glass twin impinger (GTI). High-performance liquid chromatography (HPLC) was used to quantify the drugs. A next-generation impactor (NGI) was used to measure the particle size distribution. Terbutaline emerged as the optimal API for bronchodilator delivery in both VDDS devices. It achieved the delivery of a respirable dose of 20.05 ± 4.2 µg/puff for GS AIR 2 and 2.98 ± 0.52 µg/puff for JUUL. With these delivered doses, it is possible to achieve a dose equivalence similar to that of a jet nebulizer and DPI, all while maintaining a reasonable duration, particularly with the GS AIR 2. This study is the first to provide evidence that vaping bronchodilators work only with appropriate formulation, vaping technology, and specific drugs, depending on their thermal degradation properties.

Towards optimization of ceftazidime dosing in obese ICU patients: the end of the 'one-size-fits-all' approach?

BACKGROUND: Ceftazidime is commonly used as a key antibiotic against Pseudomonas aeruginosa in critically ill patients. ICU patients have severely altered and variable antibiotic pharmacokinetics, resulting in lower antimicrobial concentrations and potentially poor outcome. Several factors, including obesity and renal function, may influence pharmacokinetics. Thus, the objective of the study was to evaluate the impact of obesity and renal function on ceftazidime plasma concentrations and dosing regimen in ICU patients. METHODS: All consecutive adult patients from six ICUs, treated with continuous ceftazidime infusion and under therapeutic drug monitoring evaluation, were included. Obesity was defined as BMI ≥30 kg/m². Glomerular filtration rate (GFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration formula. The ceftazidime recommended target for plasma concentrations was between 35 and 80 mg/L. RESULTS: A total of 98 patients (45 obese), with an average weight of 90 (±25) kg, were included. Mean GFR was 84.1 (±40.4) mL/min/1.73 m2. Recommended ceftazidime plasma concentrations were achieved for only 48.0% of patients, with median dosing regimen of 6 g/day. Obese patients had lower ceftazidime plasma concentrations compared with non-obese patients (37.8 versus 56.3 mg/L; P = 0.0042) despite similar dosing regimens (5.83 g/day versus 5.52 g/day, P = 0.2529). Almost all augmented renal clearance patients were underdosed despite ceftazidime dosing of 6.6 (±0.8) g/day. Weight-based ceftazidime dosing seemed to attenuate such obesity-related discrepancies, regardless of GFR. CONCLUSIONS: Obese ICU patients required significantly greater ceftazidime doses to achieve the target range. A tailored dosing regimen may be considered based on weight and GFR. Future prospective studies should be performed to confirm this individualized dosing approach.

Long-term outcomes of COVID-19 intensive care unit survivors and their family members: a one year follow-up prospective study.

Purpose: To describe the long-term physical, functional and mental status of COVID-19 intensive care unit (ICU) patients and their family members 1 year after ICU discharge. Methods: We performed a prospective observational cohort study among patients admitted to the ICU for COVID-19-associated respiratory failure and their family members. Patients attended a one-year follow-up consultation with family members. Physical, functional and respiratory outcomes were collected. In addition, participants completed the Hospital Anxiety and Depression Scale and the Revised Impact of Event Scale. Qualitative components were collected during a 2-h face-to-face interview. Results: Fifty-four patients and 42 family members were included. Thirty-four (63%) patients reported chronic fatigue and 37 (68.5%) dyspnea. Computed tomography scans were abnormal in 34 patients (72.3%). Anxiety symptoms were present in 23 (48%) patients and 26 (66%) family members, depression in 11 (23%) and 13 (33%), and post-traumatic stress disorder in 12 (25%) and 23 (55%), respectively. Visit limitation was reported as the most painful experience for family members. Numerous patients recalled nightmares that contributed to the anxiety. Long-term reconstruction was difficult for both patients and family members. Conclusion: The vast majority of patients and their relatives reported long-term consequences on various physical and mental components, leading to a profound impact on their well-being.

Impact of gas humidification and nebulizer position under invasive ventilation: preclinical comparative study of regional aerosol deposition.

Successful aerosol therapy in mechanically ventilated patients depends on multiple factors. Among these, position of nebulizer in ventilator circuit and humidification of inhaled gases can strongly influence the amount of drug deposited in airways. Indeed, the main objective was to preclinically evaluate impact of gas humidification and nebulizer position during invasive mechanical ventilation on whole lung and regional aerosol deposition and losses. Ex vivo porcine respiratory tracts were ventilated in controlled volumetric mode. Two conditions of relative humidity and temperature of inhaled gases were investigated. For each condition, four different positions of vibrating mesh nebulizer were studied: (i) next to the ventilator, (ii) right before humidifier, (iii) 15 cm to the Y-piece adapter and (iv) right after the Y-piece. Aerosol size distribution were calculated using cascade impactor. Nebulized dose, lung regional deposition and losses were assessed by scintigraphy using 99mtechnetium-labeled diethylene-triamine-penta-acetic acid. Mean nebulized dose was 95% ± 6%. For dry conditions, the mean respiratory tract deposited fractions reached 18% (± 4%) next to ventilator and 53% (± 4%) for proximal position. For humidified conditions, it reached 25% (± 3%) prior humidifier, 57% (± 8%) before Y-piece and 43% (± 11%) after this latter. Optimal nebulizer position is proximal before the Y-piece adapter showing a more than two-fold higher lung dose than positions next to the ventilator. Dry conditions are more likely to cause peripheral deposition of aerosols in the lungs. But gas humidification appears hard to interrupt efficiently and safely in clinical use. Considering the impact of optimized positioning, this study argues to maintain humidification.

Technical features of vaping drug delivery system for bronchodilator delivery.

PURPOSE: Several technical features influencing bronchodilator delivery were evaluated using different vaping drug delivery systems (VDDS). METHODS: Terbutaline in powder form, combined with 1, 3- propanediol used as e-liquid was tested at different concentrations (1 and 2.5 mg/mL), power levels (15 W and 30 W), and set applied resistances (0.15 to 1.5 O) to compare the efficiency of three VDDS (GS AIR2, GS TANK, CUBIS). Samples were collected with a Glass Twin Impinger (GTI). A High Performance Liquid Chromatography (HPLC) was used for drug quantification. The Next Generation Impactor (NGI) measured particle size distribution. Results were also considered with a clinical jet nebulizer (Cirrus TM 2, 2 mL of terbutaline at 2.5 mg/mL). RESULTS: GS AIR2 with resistance = 1.5 O; power = 15 W, and [Terbutaline] = 2.5 mg/mL represents the optimal VDDS conditions to deliver a respirable dose of 20.05 ± 4.2 µg/puff with a mass median aerodynamic diameter (MMAD) of 1.41 ± 0.03 µm. Thus, 52 puffs were required (lasting approximately 15 min of vaping) to reach similar respirable dose and MMAD compared to nebulization. CONCLUSION: We proved that several crucial VDDS technical parameters govern the performance of respiratory bronchodilator delivery including the resistance, power level and atomizer design.

Ceftazidime dosing in obese patients: is it time for more?

INTRODUCTION: Ceftazidime is used for the treatment of many bacterial infections, including severe P. aeruginosa infections. Like other beta-lactams, inter-individual variability in ceftazidime pharmacokinetics has been described. Due to its related pathophysiological modifications, obesity might influence ceftazidime pharmacokinetics. AREAS COVERED: The objective of this review is to assess the current state of knowledge about the impact of obesity on ceftazidime treatment. A literature search was conducted on PubMed-MEDLINE (2016-2021) to retrieve pharmacokinetic studies published in English, matching the terms 'ceftazidime' AND 'pharmacokinetics.' EXPERT OPINION: The impact of obesity on pharmacokinetics is generally poorly known, mainly because obese patients are often excluded from clinical studies. However, the published literature clearly shows that obese patients have significantly lower ceftazidime concentrations. This could be explained by increased volume of distribution and clearance. This low exposure represents a major factor of therapeutic failure, potentially fatal for critically ill patients. While further studies would be useful to better assess the magnitude and understanding of this variability, the use of higher doses of ceftazidime is needed in obese patients. Moreover, therapeutic drug monitoring for dose adaptation is of major interest for these patients, as the efficacy of ceftazidime seems to be directly related to its plasma concentration.

Assessment of High-Power Electronic Nicotine Delivery System as an Alternative Aerosol Device for Terbutaline Delivery.

PURPOSE: The performance of new-generation high-power electronic nicotine delivery system (ENDS) for the administration of inhaled terbutaline was assessed. METHODS: The formulation of e-liquid was carried out using terbutaline in combination with 1, 3- propanediol. Several terbutaline concentrations (from 0.3125 to 2.500 mg / mL) and power levels (from 15 to 35 W) were assessed using a box type ENDS. The respirable drug dose was determined using a Glass Twin Impinger and quantified by liquid chromatography coupled with a UV-detector. The Next Generation Impactor and the Dekati Low Pressure Impactor were used to measure the aerosol particle size distribution in drug mass. The results were compared with a jet nebulizer (Cirrus TM 2) similar to the usual clinical conditions (2 mL at [terbutaline] of 2.5 mg / mL). RESULTS: The optimal conditions to maximize terbutaline delivery using ENDS are a drug concentration at 1 mg/mL, and a power level at 30 W, to reach a respirable dose of 8.73 ± 0.90 µg/puff. By contrast, during a 5 min nebulization, the respirable dose of terbutaline was 1040 ± 33 µg whatever the cascade impactors and the aerosol devices used. The mass median aerodynamic diameter (MMAD) remains similar for jet nebulizer and ENDS in the 1.74-2.07 µm range. CONCLUSION: Compared to the jet nebulizer, a same respirable dose of terbutaline at the same range of aerosol size distribution was delivered by ENDS if 120 puffs were performed. The ENDS can be considered as an alternative aerosol device for terbutaline delivery.

Aerosol delivery during invasive mechanical ventilation: development of a preclinical ex vivo respiratory model for aerosol regional deposition.

In intensive care units, nebulization is a usual route for drug administration to patients under mechanical ventilation (MV). The effectiveness of inhalation devices as well as depositions sites of aerosols for ventilated patients remain poorly documented. In vivo human inhalation studies are scarce due to ethical restrictions because imaging techniques require radioaerosols to assess regional aerosol deposition. Thus, we developed an ex vivo respiratory model under invasive MV for preclinical aerosol deposition studies. The model was composed of ex vivo porcine respiratory tracts. MV was achieved thanks to a tracheal intubation and a medical ventilator under controlled conditions. Respiratory features were studied using analogical sensors. Then regional homogeneity of gas-ventilation was assessed with 81mKrypton scintigraphies. Finally, a proof of concept study for aerosol deposition was performed. Obtained respiratory features as well as gamma-imaging techniques, which demonstrated a homogenous regional ventilation and about 18% ± 4% of the nebulized dose deposited the respiratory tract, were in good agreement with human data available in the literature. This original ex vivo respiratory model provides a feasible, reproducible and cost-effective preclinical tool to achieve aerosol deposition studies under MV.

Development of an ex vivo preclinical respiratory model of idiopathic pulmonary fibrosis for aerosol regional studies.

Idiopathic pulmonary fibrosis is a progressive disease with unsatisfactory systemic treatments. Aerosol drug delivery to the lungs is expected to be an interesting route of administration. However, due to the alterations of lung compliance caused by fibrosis, local delivery remains challenging. This work aimed to develop a practical, relevant and ethically less restricted ex vivo respiratory model of fibrotic lung for regional aerosol deposition studies. This model is composed of an Ear-Nose-Throat replica connected to a sealed enclosure containing an ex vivo porcine respiratory tract, which was modified to mimic the mechanical properties of fibrotic lung parenchyma - i.e. reduced compliance. Passive respiratory mechanics were measured. 81mKr scintigraphies were used to assess the homogeneity of gas-ventilation, while regional aerosol deposition was assessed with 99mTc-DTPA scintigraphies. We validated the procedure to induce modifications of lung parenchyma to obtain aimed variation of compliance. Compared to the healthy model, lung respiratory mechanics were modified to the same extent as IPF-suffering patients. 81mKr gas-ventilation and 99mTc-DTPA regional aerosol deposition showed results comparable to clinical studies, qualitatively. This ex vivo respiratory model could simulate lung fibrosis for aerosol regional deposition studies giving an interesting alternative to animal experiments, accelerating and facilitating preclinical studies before clinical trials.

Hemodynamic effects of extended prone position sessions in ARDS.

BACKGROUND: Hemodynamic response to prone position (PP) has never been studied in a large series of patients with acute respiratory distress syndrome (ARDS). The primary aim of this study was to estimate the rate of PP sessions associated with cardiac index improvement. Secondary objective was to describe hemodynamic response to PP and during the shift from PP to supine position. METHODS: The study was a single-center retrospective observational study, performed on ARDS patients, undergoing at least one PP session under monitoring by transpulmonary thermodilution. PP sessions performed more than 10 days after ARDS onset, or with any missing cardiac index measurements before (T1), at the end (T3), and after the PP session (T4) were excluded. Changes in hemodynamic parameters during PP were tested after statistical adjustment for volume of fluid challenges, vasopressor and dobutamine dose at each time point to take into account therapeutic changes during PP sessions. RESULTS: In total, 107 patients fulfilled the inclusion criteria, totalizing 197 PP sessions. Changes in cardiac index between T1 and T2 (early response to PP) and between T1 and T3 (late response to PP) were significantly correlated (R2 = 0.42, p < 0.001) with a concordance rate amounting to 85%. Cardiac index increased significantly between T1 and T3 in 49 sessions (25% [95% confidence interval (CI95%) 18-32%]), decreased significantly in 46 (23% [CI95% 16-31%]), and remained stable in 102 (52% [CI95% 45-59%]). Global end-diastolic volume index (GEDVI) increased slightly but significantly from 719 ± 193 mL m-2 at T1 to 757 ± 209 mL m-2 at T3 and returned to baseline values at T4. Cardiac index and oxygen delivery decreased slightly but significantly from T3 to T4, without detectable increase in lactate level. Patients who increased their cardiac index during PP had significantly lower CI, GEDVI, global ejection fraction at T1, and received significantly more fluids than patients who did not. CONCLUSION: PP is associated with an increase in cardiac index in 18% to 32% of all PP sessions and a sustained increase in GEDVI reversible after return to supine position. Return from prone to supine position is associated with a slight hemodynamic impairment.

Change in cardiac output during Trendelenburg maneuver is a reliable predictor of fluid responsiveness in patients with acute respiratory distress syndrome in the prone position under protective ventilation.

BACKGROUND: Predicting fluid responsiveness may help to avoid unnecessary fluid administration during acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the diagnostic performance of the following methods to predict fluid responsiveness in ARDS patients under protective ventilation in the prone position: cardiac index variation during a Trendelenburg maneuver, cardiac index variation during an end-expiratory occlusion test, and both pulse pressure variation and change in pulse pressure variation from baseline during a tidal volume challenge by increasing tidal volume (VT) to 8 ml.kg-1. METHODS: This study is a prospective single-center study, performed in a medical intensive care unit, on ARDS patients with acute circulatory failure in the prone position. Patients were studied at baseline, during a 1-min shift to the Trendelenburg position, during a 15-s end-expiratory occlusion, during a 1-min increase in VT to 8 ml.kg-1, and after fluid administration. Fluid responsiveness was deemed present if cardiac index assessed by transpulmonary thermodilution increased by at least 15% after fluid administration. RESULTS: There were 33 patients included, among whom 14 (42%) exhibited cardiac arrhythmia at baseline and 15 (45%) were deemed fluid-responsive. The area under the receiver operating characteristic (ROC) curve of the pulse contour-derived cardiac index change during the Trendelenburg maneuver and the end-expiratory occlusion test were 0.90 (95% CI, 0.80-1.00) and 0.65 (95% CI, 0.46-0.84), respectively. An increase in cardiac index ≥ 8% during the Trendelenburg maneuver enabled diagnosis of fluid responsiveness with sensitivity of 87% (95% CI, 67-100), and specificity of 89% (95% CI, 72-100). The area under the ROC curve of pulse pressure variation and change in pulse pressure variation during the tidal volume challenge were 0.52 (95% CI, 0.24-0.80) and 0.59 (95% CI, 0.31-0.88), respectively. CONCLUSIONS: Change in cardiac index during a Trendelenburg maneuver is a reliable test to predict fluid responsiveness in ARDS patients in the prone position, while neither change in cardiac index during end-expiratory occlusion, nor pulse pressure variation during a VT challenge reached acceptable predictive performance to predict fluid responsiveness in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01965574 . Registered on 16 October 2013. The trial was registered 6 days after inclusion of the first patient.

Variability of Tidal Volume in Patient-Triggered Mechanical Ventilation in ARDS.

BACKGROUND: Limiting tidal volume (VT) in patients with ARDS may not be achieved once patient-triggered breaths occur. Furthermore, ICU ventilators offer numerous patient-triggered modes that work differently across brands. We systematically investigated, using a bench model, the effect of patient-triggered modes on the size and variability of VT at different breathing frequencies (f), patient effort, and ARDS severity. METHODS: We used a V500 Infinity ICU ventilator connected to an ASL 5000 lung model whose compliance was mimicking mild, moderate, and severe ARDS. Thirteen patient-triggered modes were tested, falling into 3 categories, namely volume control ventilation with mandatory minute ventilation; pressure control ventilation, including airway pressure release ventilation (APRV); and pressure support ventilation. Two levels of f and effort were tested for each ARDS severity in each mode. Median (first-third quartiles) VT was compared across modes using non-parametric tests. The probability of VT > 6 mL/kg ideal body weight was assessed by binomial regression and expressed as the odds ratio (OR) with 95% CI. VT variability was measured from the coefficient of variation. RESULTS: VT distribution over all f, effort, and ARDS categories significantly differed across modes (P < .001, Kruskal-Wallis test). VT was significantly greater with pressure support (OR 420 mL, 95% CI 332-527 mL) than with any other mode except for variable pressure support level. Risk for VT to be > 6 mL/kg was significantly increased with spontaneous breaths patient-triggered by pressure support (OR 19.36, 95% CI 12.37-30.65) and significantly reduced in APRV (OR 0.44, 95% CI 0.26-0.72) and pressure support with guaranteed volume mode. The risk increased with increasing effort and decreasing f. Coefficient of variation of VT was greater for low f and volume control-mandatory minute ventilation and pressure control modes. APRV had the greatest within-mode variability. CONCLUSIONS: Risk of VT > 6 mL/kg was significantly reduced in APRV and pressure support with guaranteed volume mode. APRV had the highest variability. Pressure support with guaranteed volume could be tested in patients with ARDS.

Nicotine delivery from the refill liquid to the aerosol via high-power e-cigarette device.

To offer an enhanced and well-controlled nicotine delivery from the refill liquid to the aerosol is a key point to adequately satisfy nicotine cravings using electronic nicotine delivery systems (ENDS). A recent high-power ENDS, exhibiting higher aerosol nicotine delivery than older technologies, was used. The particle size distribution was measured using a cascade impactor. The effects of the refill liquid composition on the nicotine content of each size-fraction in the submicron range were investigated. Nicotine was quantified by liquid chromatography coupled with tandem mass spectrometry. Particle size distribution of the airborne refill liquid and the aerosol nicotine demonstrated that the nicotine is equally distributed in droplets regardless of their size. Results also proved that the nicotine concentration in aerosol was significantly lower compared to un-puffed refill liquid. A part of the nicotine may be left in the ENDS upon depletion, and consequently a portion of the nicotine may not be transferred to the user. Thus, new generation high-power ENDS associated with propylene glycol/vegetable glycerin (PG/VG) based solvent were very efficient to generate carrier-droplets containing nicotine molecules with a constant concentration. Findings highlighted that a portion of the nicotine in the refill liquid may not be transferred to the user.

Assessment of new-generation high-power electronic nicotine delivery system as thermal aerosol generation device for inhaled bronchodilators.

PURPOSE: A need remains for alternative devices for aerosol drug delivery that are low cost, convenient and easy to use for the patient, but also capable of producing small-sized aerosol particles. This study investigated the potential of recent high power electronic nicotine delivery systems (ENDS) as aerosol generation devices for inhaled bronchodilators. METHODS: The particle size distribution was measured using a cascade impactor. The delivery of terbutaline sulfate, a current bronchodilator used for asthma or COPD therapy by inhalation, was studied. This drug was quantified by liquid chromatography coupled with tandem mass spectrometry. RESULTS: The particle size distribution in terms of mass frequency (in two ways, gravimetrically and quantitatively through drug assay on each stage) and the terbutaline sulfate concentration in the aerosol were elucidated. The mass median aerodynamic diameter (MMAD) and the drug delivery rose when the power level increased, to reach 5.6±0.4µg/puff with a MMAD of 0.78±0.03µm at 25W. CONCLUSION: New generation high-power ENDS are very efficient to generate carrier-droplets in the submicron range containing drug molecules with a constant drug concentration whatever the size-fractions. ENDS appear to be highly patient-adaptive.