Sophie Perinel-Ragey

Aerosol delivery during invasive mechanical ventilation is influenced by multiple factors, including nebulizer type and ventilatory settings. Current intensive care unit (ICU) guidelines generally discourage modifying these parameters due to limited and conflicting evidence. This study evaluated the effects of inspiratory flow and inspiratory-to-expiratory (I:E) ratio on pulmonary aerosol deposition according to nebulizer technology using a controlled preclinical model.Using a validated ex vivo porcine respiratory model under volume-controlled ventilation, we assessed the impact of inspiratory flow (35 vs. 60 L/min) and I:E ratio (1:2 vs. 1:3) on regional aerosol deposition. Experiments were performed with a vibrating mesh nebulizer (VMN) and a jet nebulizer (JN) placed 15 cm upstream of the Y-piece, with active heated humidification. Deposition was measured by planar scintigraphy with radiolabeled aerosol and a mass balance approach.VMN showed significantly higher delivery efficiency than JN in all conditions. With VMN, lower inspiratory flow increased pulmonary deposition (57% ± 8% vs. 45% ± 5%, p = 0.022), and a longer expiratory phase (I:E 1:3 vs. 1:2) further improved deposition (60% ± 9% vs. 45% ± 5%, p < 0.0001), with reduced losses in the inspiratory limb. In contrast, JN had low output and no significant variation across settings.Ventilatory parameters significantly influence aerosol deposition with VMN but not JN in mechanical ventilation. Combining lower inspiratory flow and longer expiratory time may optimize delivery with VMN. These findings support a device-specific approach and require clinical confirmation.

Aerosol delivery during invasive mechanical ventilation is influenced by multiple factors, including nebulizer type and ventilatory settings. Current intensive care unit (ICU) guidelines generally discourage modifying these parameters due to limited and conflicting evidence. This study evaluated the effects of inspiratory flow and inspiratory-to-expiratory (I:E) ratio on pulmonary aerosol deposition according to nebulizer technology using a controlled preclinical model.Using a validated ex vivo porcine respiratory model under volume-controlled ventilation, we assessed the impact of inspiratory flow (35 vs. 60 L/min) and I:E ratio (1:2 vs. 1:3) on regional aerosol deposition. Experiments were performed with a vibrating mesh nebulizer (VMN) and a jet nebulizer (JN) placed 15 cm upstream of the Y-piece, with active heated humidification. Deposition was measured by planar scintigraphy with radiolabeled aerosol and a mass balance approach.VMN showed significantly higher delivery efficiency than JN in all conditions. With VMN, lower inspiratory flow increased pulmonary deposition (57% ± 8% vs. 45% ± 5%, p = 0.022), and a longer expiratory phase (I:E 1:3 vs. 1:2) further improved deposition (60% ± 9% vs. 45% ± 5%, p < 0.0001), with reduced losses in the inspiratory limb. In contrast, JN had low output and no significant variation across settings.Ventilatory parameters significantly influence aerosol deposition with VMN but not JN in mechanical ventilation. Combining lower inspiratory flow and longer expiratory time may optimize delivery with VMN. These findings support a device-specific approach and require clinical confirmation.

Background: Cotrimoxazole (trimethoprim/sulfamethoxazole) is a widely used antibiotic in ICU for the treatment of infections such as nosocomial or Pneumocystis jirovecii pneumonia. However, dosing in ICU patients is complicated by fluctuations in renal function, particularly acute kidney injury and augmented renal clearance, which affect drug elimination. This study investigated how renal function and body weight influence trimethoprim and sulfamethoxazole concentrations. Patients and methods: This retrospective bicentre observational study involved 116 ICU patients receiving cotrimoxazole therapy with routine therapeutic drug monitoring. The study focused on effects of estimated glomerular filtration rate (eGFR) and weight on concentrations and dosing. Results: Dosing of sulfamethoxazole and trimethoprim was significantly lower in patients with eGFR <30 mL/min/1.73 m2, as recommended. In these patients, sulfamethoxazole concentrations were reduced, suggesting underdosing, while trimethoprim increased with worsening renal function, indicating overdose risk when eGFR <60 mL/min/1.73 m2. Patients on renal replacement therapy (RRT) had lower sulfamethoxazole concentrations and a reduced dose-normalized C/D ratio, raising underdosing risk during RRT. trimethoprim was less affected by RRT, supporting dose reduction regardless of RRT status. No C/D ratio difference was seen between obese and non-obese patients. Weight influenced sulfamethoxazole but not trimethoprim. Conclusions: These findings underscore the need for individualized dosing in ICU patients, especially in patients with renal impairment or RRT. Current fixed-dose combination may not adequately reflect cotrimoxazole’s complex pharmacokinetics in critical illness, stressing the importance of tailored strategies.

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state.

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.

Background In order to rapidly achieve target concentrations and bactericidal efficacy, the administration of a loading dose (LD) is recommended before starting ceftazidime continuous infusion. However, the adequacy of the 2g-LD usually administered should be investigated considering the special pharmacokinetic characteristics of critically ill patients. Materials PK dataset for model development and external validation included patients hospitalized in 6 intensive care units (ICU) in the Saint-Etienne region (France) and in Paris, with ceftazidime continuous infusion and at least one measurement of plasma concentration [IRBN992021/CHUSTE]. Data were analysed with MONOLIX and R softwares. A review of the literature was performed to search for PK models developed in ICU patients, to compare our results with existing models. A simulation of the LD needed to reach a target concentration of 60mg/L was performed with all models. Results Ceftazidime was well described by a one-compartment model with allometrically scaled lognormalized e-glomerular filtration rate as a covariate of clearance, using a dataset of 86 patients/223 samples. Typical ceftazidime clearance and volume of distribution were 4.45L/h and 88L, respectively. The predicted individual ceftazidime concentrations were significantly lower at 24 ± 4hours than at 48 ± 4hours. Of the 8 publications of pharmacokinetics models developed in ICU populations, median volume of distribution was 37.2L. The simulated LD to achieve 60mg/L in 80% of the patients from the models found in the literature was higher than 2g in all but one study. Median LD was 4.9g. Conclusions Standard LD results in delay in achieving target ceftazidime concentration in ICU patients.

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.

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. 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. 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. 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.