Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19.

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.

Comparison of intubating conditions after induction with propofol and remifentanil or sufentanil : Randomized controlled REMIDENT trial for surgical tooth extraction.

PURPOSE: The aim of this study was to compare tracheal intubation conditions after induction of anesthesia with a bolus of propofol-sufentanil or propofol-remifentanil and a rapid induction technique. MATERIAL AND METHODS: A total of 70 patients (American Society of Anesthesiologists (ASA) classification I­II) undergoing outpatient surgery under general anesthesia with intubation for tooth extraction were randomly assigned to two groups in this double-blind study. Patients received either a bolus of remifentanil (3 µg/kg) or sufentanil (0.3 µg/kg) together with 2.5 mg/kg propofol for intubation. The primary outcome was the percentage of excellent intubation conditions and the secondary outcomes were the percentage of patients with a decrease of over 20% in mean arterial pressure (MAP) or heart rate (HR), time to achieve spontaneous respiration, time between the end of surgery and extubation and time to achieve an Aldrete score of 10. VAS pain score was >3 or having laryngeal pain 15 min after arriving in the postanesthesia care unit (PACU) were also analyzed. RESULTS: Intubating conditions (perfect + good conditions) were significantly better with remifentanil than with sufentanil (88.5% vs. 68.6%; p = 0.01). When using remifentanil, the hemodynamic conditions were good. Using remifentanil did not significantly increase the pain score or the laryngeal pain in the recovery room. This was confirmed by no significant differences between the groups for morphine consumption. Remifentanil significantly decreased the time to achieve an Aldrete score of 10. CONCLUSION: When intubation without muscle relaxants is required, intubating conditions are much better when a remifentanil bolus is used compared to a sufentanil bolus. The remifentanil/propofol rapid induction technique is a valuable technique to quickly intubate and achieve good conditions.

3-month prognostic impact of severe acute renal failure under veno-venous ECMO support: Importance of time of onset.

PURPOSE: Veno-venous ECMO is increasingly used for the management of refractory ARDS. In this context, acute kidney injury (AKI) is a major and frequent complication, often associated with poor outcome. We aimed to identify characteristics associated with severe renal failure (Kidney Disease Improving Global Outcome (KDIGO) 3) and its impact on 3-month outcome. METHODS: Between May 2009 and April 2016, 60 adult patients requiring VV-ECMO in our University Hospital were prospectively included. RESULTS: AKI occurrence was frequent (75%; n=45), 51% of patients (n=31) developed KDIGO 3 - predominantly prior to ECMO insertion - and renal replacement therapy was required in 43% (n=26) of cases. KDIGO 3 was associated with a lower mechanical ventilation weaning rate (24% vs 68% for patients with no AKI or other stages of AKI; p<0.001) and a higher 90-day mortality rate (72% vs 32%, p=0.002). Multivariate logistic regression suggested that KDIGO 3 occurrence prior to ECMO insertion, as well as PaCO2>57mmHg and mSOFA>12 were independent risks factors for 90-day mortality. CONCLUSION: KDIGO 3 AKI occurrence is correlated with the severity of patients' clinical condition prior to ECMO insertion and is negatively associated with 90-day survival.

Estimation of glomerular filtration rate to adjust vancomycin dosage in critically ill patients: superiority of the Chronic Kidney Disease Epidemiology Collaboration equation?

The purpose of this study was to determine the best estimate of glomerular filtration rate (GFR) to adjust vancomycin (VAN) dosage in critically ill patients. Seventy-eight adult intensive care unit patients received a 15 mg/kg loading dose of VAN plus a 30 mg/kg/day continuous infusion. Steady-state concentration was measured 48 hours later and the dose was adjusted to obtain a target concentration ranging from 20 to 25 mg/l. GFR was estimated by measured creatinine clearance (CLCR), Cockcroft, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. The required dose providing the target concentration was 36±17 mg/kg/day. The first dosage had to be increased in 51% of all patients and in 84% of trauma patients (highest GFR), but had to be decreased in 17% of patients. The closest relationship between clearances of vancomycin was observed with CKD-EPI to GFR. The correlation between clearances of vancomycin and measured CLCR was significant but was rather poor with Cockcroft and Modification of Diet in Renal Disease equation. On the Bland and Altman plots, measured CLCR provided a lower bias but a larger confidence interval and a weaker precision than CKD-EPI. For VAN dose adjustments in intensive care unit patients, Cockcroft formula and Modification of Diet in Renal Disease should be used with caution. In clinical practice, the physician does not have at their disposal the patient's measured CLCR when prescribing. The CKD-EPI appears to be the best predictor of clearances of vancomycin for calculation of a therapeutic VAN regimen.

[Patient with acute renal injury presenting dabigatran overdose: Hemodialysis for surgery]. / Surdosage en dabigatran chez un patient en insuffisance rénale : intérêt et limites de l'hémodialyse.

Dabigatran is a direct thrombin inhibitor indicated for stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation. No reversal agent exists, but hemodialysis has been proposed as dabigatran removal method. We report a case of an 80-year-old man presenting hemorrhage with dabigatran overdose caused by obstructive acute renal failure. Before nephrostomy, several hemodialysis sessions were necessary to remove dabigatran probably because of its large volume of distribution.

[Aspirin and its danger: Reye syndrome in young adult]. / L'aspirine et ses dangers: syndrome de Reye chez un adulte jeune.

We describe the case of a 19-year-old male diagnosed with Reye syndrome within the context of viral pericarditis and salicylate ingestion. He presented a fatal brain oedema without liver failure. Brain biopsies obtained during a decompressive craniectomy led to the diagnosis.

Study of agreement of aortic, radial and femoral blood pressures during aortic endografting.

PURPOSE: To estimate the agreement between radial or femoral, and ascending aortic invasive blood pressure values. PATIENTS AND METHODS: Prospective study on 32 patients who underwent an aortic endografting under general anesthesia. After deploying the prosthesis under controlled hypotension, a catheter was introduced in the aorta to measure the staged systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressures, in particular at the level of ascending aorta and femoral artery. RESULTS: No differences were observed between SAP, DAP or MAP measured in the aorta versus femoral or radial arteries. A better agreement was observed between the aortic and femoral MAP (bias of 1mmHg, limits of agreement between: -8.8mmHg and +10.8mmHg) than between the aortic and the radial MAP (bias of 1.7mmHg, limits of agreement between: -14.1mmHg and +17.5mmHg). The comparison between radial and femoral MAP was not satisfying (bias of -4.7mmHg and limits of agreement between -19.1mmHg and +9.7mmHg). CONCLUSION: The femoral MAP is more accurate to predict value of the aortic MAP than the radial MAP in a hypotensive setting. The clinician should be aware of these discrepancies in conditions of hemodynamic impairment to optimize the treatment.

[Use of ECMO (extracorporeal membrane oxygenation) in a traumatic brain injured patient with severe hypoxemia]. / Utilisation d'un ECMO (extracorporeal membrane oxygenation) dans un cas d'hypoxémie réfractaire associée à un traumatisme crânien grave.

Traumatic brain injuries are fairly sensitive to hypoxia. For patient with associated lung and brain traumas, different means used to improve oxygen blood level are poorly described. We report the use of ECMO in a refractory hypoxemia occurred to a multitrauma young patient with neurological lesions.

Cefepime in intensive care unit patients: validation of a population pharmacokinetic approach and influence of covariables.

AIM: The purpose of our study was to define and validate a population-pharmacokinetic model including the influence of patients' characteristics on the pharmacokinetics of cefepime. PATIENTS AND METHODS: A total of 55 patients were randomized in Group 1 (34 patients, 320 cefepime concentrations) for the model building and Group 2 (21 patients, 196 cefepime concentrations) for the validation group. They received cefepime as 2 g A 2 or as 4 g continuously. The population pharmacokinetic analysis was carried out using NONMEM and a baseline model was constructed for studying the influence of demographic and biological variables. The model was then validated by a comparison of the predicted and observed concentrations in Group 2. A final model was elaborated from the whole population. RESULTS: Total clearance (CL) was significantly correlated with the serum creatinine (CREA) and the central volume of distribution (V1) was correlated with the body weight (WT). The final model was: CL = 7.14 + (-0.0133 A CREA). V1 = (-16.8) + (0.475 A WT). Q (intercompartmental clearance) = 10.5. V2 = 18.1. The mean pharmacokinetic parameters and their individual variability were: CL (8.24 l/h, 45%), V1 (20.89 l, 60%), V2 (17.95 l, 49%), total volume (38.85 l, 42%) and Q (10.56 l/h, 9%). The bias (1.07 mg/l, IC 95% = -40.46 -+42.60), precision (21.19%) and AFE (1.15) demonstrated the performance of the model. CONCLUSION: We have developed and validated a pharmacokinetic model to estimate cefepime concentrations. We showed that serum creatinine and body weight are factors that may influence the standard dose of cefepime. Our model enabled us to predict cefepime concentrations in other patients.

Pharmacokinetics of ceftazidime and cefepime in burn patients: the importance of age and creatinine clearance.

AIM: The standard dosage recommendations for beta-lactam antibiotics can result in very low drug levels in intensive care (IC) patients and burn patients in the absence of renal dysfunction. We studied the pharmacokinetic parameters and serum concentrations of ceftazidime (CF) and cefepime (CE) in burn patients and analyzed the modifications according to clinical and biological parameters and in particular age and creatinine clearance. MATERIAL AND METHODS: Two pharmacokinetic studies were carried out with daily doses of 1 g x 6 for CF (n = 17) and 2 g x 3 for CE (n = 13). Creatinine clearance (CL(CR)) was both estimated and measured. Blood was sampled at steady state after an initial and a subsequent antibiotic dose. C(max) (maximal) and C(min) (minimal) concentrations were measured by HPLC. The influence of clinical and biological data was analyzed using ANOVA, ANCOVA and stepwise multiple linear regression. RESULTS: The ratio of C(min) to the low MIC break point (4 mg/l) was lower than 4 in 52% of subjects receiving CF and in 80% of subjects receiving CE. The C(min) of CF was correlated with measured CL(CR) and was higher in mechanically ventilated patients than in non-ventilated patients. The clearance of CF was correlated with age. The C(min) of CE was correlated with age and drug clearance with measured CL(CR). Therefore dosage adjustment of these drugs in burn patients needs to take into account age, measured creatinine clearance and the danger of low concentrations occurring when the creatinine clearance is greater than 120 ml x min(-1). CONCLUSION: In burn patients, the pharmacokinetic disposition of CF and CE was much more variable than in healthy subjects. Age and CL(CR) were predictors of the disposition of these antibiotics. Shortening the dosage interval or using continuous infusions will prevent low serum levels and keep trough levels above the MIC for longer periods of time. In view of the lack of a bedside measurement technique for ceftazidime and cefepime levels, we suggest a more frequent use of measured CL(CR) in order to attain efficacious clinical concentrations.

Intermittent administration of ceftazidime to burns patients: influence of glomerular filtration.

OBJECTIVE: The pharmacokinetics of ceftazidime, the antibiotic of choice for treating acute P. aeruginosa infections, may be modified in burns patients. The aim of this study was to identify the factors causing variations in the serum antibiotic concentrations in bums patients. METHODS: 30 patients with serious burns were randomly divided into two groups. Group 1 received a dose of ceftazidime of 2 x 3 g/24 hours. The second group received the same dose but divided into 6 administrations. Blood samples were taken at 24 (M1) and 48 hours (M2) after the start of treatment and the peak and trough serum concentrations of ceftazidime measured by HPLC. Depending on the results, frequency and/or dose was modified to obtain trough concentrations (Cmin) equal to 16 mg/l, i.e. 4 times the MIC. Either the same dose was maintained, but mostly divided up, or it was increased to 1 g x 8 administrations or it was decreased to 1 g x 4 or 1 g x 3. The serum concentrations of ceftazidime obtained were analyzed taking into account the characteristics of the burns patients (multivariate correlation). RESULTS: From the first sample (M1) Cmin was lower than the target concentration in 50% of the patients in Group 1 and 20% in Group 2. The modification of the dosing regimen put into place after the first analysis, led to the patients being further divided into four groups before the second blood sampling. Finally, 5 patients ended up in Group 1. In all patients and for all administration times, a negative correlation was found between Cmin and the creatinine clearance, calculated by using Cockcroft's formula. CONCLUSION: This study highlights the peculiarities of ceftazidime pharmacokinetics seen in burns patients with high interindividual variability. Based on Cmin monitoring and a predefined therapeutic range, dose adjustment was often required. Ceftazidime clearance is correlated with creatinine clearance (Cockcroft's formula), suggesting that this parameter could be used for a priori or a posteriori dose individualization. To respect the summary of the product characteristics (SPC) and reduce the variability in trough concentrations, the dose should be fractionated (1 g x 6) over a 24-hour period or even given as a continuous infusion. Trough concentrations must be evaluated to adapt the dosage regimen to attain target concentrations of 4 x the MIC.

[Multiresistant Escherichia coli meningitis after transrectal prostate biopsy]. / Méningite à Escherichia coli multirésistant après biopsie de prostate transrectale.

Transrectal prostate biopsy represents the most accurate technique to diagnose prostate cancer. More vigilance is necessary when fluoroquinolones are given as prophylactic agents because of the increase in Escherichia coli resistant strains. We report a case of multiresistant E. coli meningitis after transrectal biopsy resulting in the death of the patient.

Assessment of renal function in clinical practice at the bedside of burn patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In burn patients it has been shown ([2]), that there is a correlation between the creatinine clearance (CL(CR)) and the clearance of inulin. * The CL(CR) has never been studied in burn patients who have normal serum creatinine. * The Robert, Kirkpatrick and sMDRD formulae have never been evaluated in burn patients. WHAT THIS STUDY ADDS: * Despite burn patients having normal serum creatinine concentrations, the study showed that there are large variations in CL(CR) which cannot be detected by single serum creatinine measurements, and which have important implications for drug therapy. * It showed that the formulae currently used to calculate creatinine clearance on the basis of serum creatinine are inadequate for use in burn patients, and they should be abandoned in favour of direct measurement from a 24 h urine collection. AIMS: The aim of this study was to evaluate whether the renal function of burn patients could be correctly assessed using a single serum creatinine measurement, within normal limits, and three prediction equations of glomerular filtration taking into account, serum creatinine, age, weight and sex. METHODS: This was a prospective study comprising 36 adult burn patients with a serum creatinine <120 micromol l(-1), within the second or third week following the burn injury. Renal function was assessed using serum creatinine, 24 h urinary CL(CR), and the Cockcroft-Gault, Robert, Kirkpatrick and simplified MDRD equations. RESULTS: Despite normal serum creatinine concentrations in all patients, a significant number had a decreased CL(CR). The urinary CL(CR) was <80 ml(-1) min(-1) 1.73 m(-2) in nine patients (25%), and <60 ml(-1) min(-1) 1.73 m(-2) in five patients (14%). Between the groups having a CL(CR) lower or greater than 80 ml(-1) min(-1) 1.73 m(-2) there were no differences in gender, burn indices, percentage of mechanically ventilated patients or length of hospital stay, but a difference in age. The highest CL(CR) (>140 ml(-1) min(-1) 1.73 m(-2)) was found in 13 patients younger than 40 years. Regression analysis, residual and Bland-Altman plots revealed that neither the Cockcroft-Gault, Robert, Kirkpatrick nor sMDRD equations were specific enough for the assessment of renal function. CONCLUSIONS: In burn patients with normal serum creatinine during the hypermetabolic phase, serum creatinine and creatine based predictive equations are imprecise in assessing renal function.

Increased amikacin dosage requirements in burn patients receiving a once-daily regimen.

Altered pharmacokinetics in burn patients may affect antibiotic plasma concentrations. Typical once-daily dosing (ODD) of 15 mg/kg amikacin (AMK) in burn patients does not always produce peak concentrations (C(max)) reaching the therapeutic objective of six to eight times the minimal inhibitory concentration (MIC). We recorded plasma concentrations following administration of 20 mg/kg AMK in burn patients and studied factors affecting pharmacokinetics. Mean C(max) was 48.3+/-10.8 mg/L and the C(max)/MIC ratio was 6+/-1.35. Statistical analysis demonstrated a relationship between C(max) and the area of the burn and Unit Burn Standard, and between AMK clearance and creatinine clearance (Cl(CR)). We conclude that ODD regimens of AMK in patients with burns >15% body surface area and/or with Cl(CR) >120 mL/min could require doses >20 mg/kg to reach adequate C(max). In all cases, patient therapeutic drug monitoring is essential to ensure the safe usage of these dosing recommendations.

Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen.

The aim of this study was to compare the pharmacokinetic and pharmacodynamic parameters of a continuous infusion of cefepime vs. an intermittent regimen in critically ill adult patients with Gram-negative bacilli infection. The prospective randomized parallel study was carried out in 50 patients with severe pneumonia (n = 41) or bacteremia (n = 9). They received cefepime 4 g/d either as a continuous infusion or intermittent administration 2 x 2 g in combination with amikacin. Patient characteristics and the minimal inhibitory concentration (MIC) of the isolated bacteria were comparable. Clinical outcomes were assessed along with pharmacodynamic indices and compared in both groups (chi2 and Mann-Whitney U-tests). Mechanical ventilation, clinical outcome and bacteriological eradication did not significantly differ between the two groups. Also, the area under the plasma cefepime concentration curve at steady state (AUCss: 612 +/- 369 vs. 623 +/- 319 mg x 1(-1) x h), AUCss > MIC (595 +/- 364 vs. 606 +/- 316 mg x 1(-1) x h) and the area under the inhibitory concentration curve (AUICss: 4258 +/- 5819 vs. 5194 +/- 7465 mg x 1(-1) x h) were similar. If the time above MIC (t > MIC) was not significantly higher in Group 1 (100 +/- 0%) than in Group 2 (90 +/- 11%), t > five-fold MIC in Group 1 (100 +/- 0%) was significantly higher (p < 0.01) than in Group 2 (82 +/- 25%). The mean time over the French breakpoint (4 mg/l) was 100 +/- 0% and 72 +/- 27% in Group 1 and 2 (p < 0.001), respectively. In contrast to intermittent cefepime administration, continuous infusion of cefepime consistently maintained a serum concentration > 5 x the MIC of typical Gram-negative nosocomial pathogens. This results in greater bactericidal activity against organisms with a higher (2 mg/l) cefepime breakpoint even if the clinical outcome is not significantly modified.

[Importance of a cefpirome-vancomycin combination on bactericidal kinetics in severe MRSA infections in intensive care]. / Intérêt de l'association cefpirome-vancomycine sur la cinétique de bactéricidie dans les infections sévères à SAMR en réanimation.

UNLABELLED: Vancomycin is always the drug of choice for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in spite of his bactericidal kinetic. BACKGROUND: The aim of this study was to evaluate in vivo the improvement of bactericidal kinetic of vancomycin associated with cefpirome against MRSA infection in critically ill patients. METHODS: The prospective cross-over study was carried out in 20 patients with severe pneumonia or bacteremia. There were randomized to receive vancomycin 2 g per day (Group 1, n = 10) or vancomycin with cefpirome 2 g x 2 (Group 2, n = 10). Clinical recovery, bacteriologic parameters (bactericidal kinetic and bactericidal power in vivo at the peak and the valley), duration of ventilation and stay in ICU were comparatively explored in both groups. RESULTS: Clinical outcome did not significantly differ between Group 1 and 2. Bactericidal kinetics were better in the Group 2 (40% vs 60% after 6 hours to the dilution for 1/8e) but the difference was not significant. However, bactericidal power in sera was also better in the Group 2 with more bactericidal dilution at 1/16e (68% vs 88.8%: NS) and overall at 1/32e (10.5% vs 50%: p < 0.05) and CRP, an inflammatory marker, was significantly lower in the Group 2 than in the Group 1 (119.5 +/- 24 mg/l vs 198.6 +/- 78 mg/l: p < 0.05) on the third day.