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.

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.

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.

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.

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.

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.

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.

[Interaction between electrocautery and a pacemaker]. / Interaction entre bistouri électrique et stimulateur cardiaque.

Following a new case of inhibition of a sentinel pacemaker by the cutting current of an electrocoagulator during endoscopic urologic surgery, the mechanism of this complication is recalled. The non-selectivity of the pacemaker detector circuit is responsible for interpreting the electrical disturbances due to the electrocoagulator as cardiac activity. The problems seen with other types of stimulators are discussed, especially programmable stimulation where the use of a magnet can lead to variations in the stimulator frequency. The stimulating wire can also be responsible for accidents, such as myocardial burns, and rhythm disturbances. The safety rules for the use of the electrocoagulator in patients with a non programmable sentinel pacemaker.

[Anaphylactic shock caused by pancuronium and vecuronium]. / Choc anaphylactique au pancuronium et au vécuronium.

A case is reported of anaphylactic shock due to vecuronium occurring in a patient who had already had such a shock, due then to pancuronium, during a previous general anaesthesia. The need for a full immuno-allergological investigation, the occasional efficiency of the anti-histamine premedication, and crossed allergies between muscle relaxants are stressed. It is noted that an anaphylactic shock can be seen on first using a new molecule, as the patient can have been sensitized to it by other muscle relaxants. This case was the first to be described of an anaphylactic shock due to vecuronium bromide.

[Continuous administration of vancomycin in patients with severe burns]. / Vancomycine en administration continue chez le grand brûlé.

OBJECTIVES: In the severely burned patient, a marked, rapid fall in serum concentrations is often observed after intermittent infusion of vancomycin at the usual dose of 30 mg/kg. This specific "jagged" pharmokinetic course with inadequate residual concentrations raises the problem of the efficacy of this time-dependent antibiotic. Studies in patients in general resuscitation units have shown the interest of vancomycin administration in continuous infusion. METHODS: We analyzed variations in serum concentrations of vancomycin during continuous infusion in 18 patients with burns involving a mean of 40% total body surface and reported the doses necessary to maintain serum vancomycin at therapeutic levels; the possible correlations between serum vancomycin concentrations, burn parameters, age and renal function; and clinical and biological tolerance. RESULTS: Higher initial doses were required in burn patients (40 mg/kg in patients aged under 60) than in other patients. Impairment of renal function is a contra-indication of continuous infusion. CONCLUSION: This mode of administration has the advantage of ensuring greater efficacy by preventing fluctuations in serum concentrations.

[Double-blind randomized clinical study of a droperidol-fentanyl combination]. / Etude clinique randomisée en double aveugle de l'association dropéridol-Fentanyl.

Droperidol 1:50 given with Fentanyl increases the analgetic action of the latter by one third. This effect is not enhanced by increasing the dosage of droperidol.

[Induced normovolemic hemodilution. Calculation of the amount of blood to be withdrawn]. / Hémodilution normovolémique intentionnelle. Calcul de la masse de sang à soustraire.

The authors study the variation of the hematocrit during a provoked normovolemic hemodilution. To get a predetermined hematocrit rate they use a simple and original biophysical model which gives the exact blood volume to be extracted. Then they use the same method to evaluate the hematocrit of the extracted blood after its conditionnement in packs.

[Use of vecuronium bromide administered at a constant rate during renal transplantation]. / Utilisation du bromure de vécuronium administré à débit constant lors des transplantations rénales.

The authors describe a technique of vecuronium bromide perfusion at constant flow used to obtain curarisation during 50 renal transplantations. The muscular effects of the drug were monitored through an electromyographical recorder, so as to adjust the perfusion rate. The dose of vecuronium bromide was 47.7 +/- 0.74 micrograms X kg-1 X h-1 (mean +/- SEM), this being lower than the dose recommended by D'Hollander (60 micrograms X kg-1 X h-1) for patients with normal renal function. Furthermore, no recurarisation was observed. Therefore, vecuronium can be considered as a satisfactory muscle relaxant in patients with renal failure, but neuromuscular monitoring appears to be a most important safety factor.

[Constant-flow drug administration in anesthesia]. / Administration médicamenteuse à débit constant en anesthésie.

The authors describe a technique of constant flow perfusion of several anaesthetic drugs, using a simple formula to adjust the perfusion rate to the weight of the patients. Calculation of dilutions is easy: the drug concentration is equal to ten times the rate, per hour and per kg, in practical cases. The flow rate is then a tenth of the patient's weight. This method is easy to apply to several drugs, of which pharmacokinetic parameters justify this administration mode: alfentanil, etomidate, vecuronium bromide... but clinical and instrumental observations should be taken into account for the adjustment of the flow.

[Use of netilmicin for antibiotic prevention of urinary infections after endoscopic surgery in urology]. / Antibioprophylaxie par la nétilmicine des infections urinaires après chirurgie endoscopique en urologie.

We studied for one year 60 patients separated in 3 groups of 20: first reference group without treatment; second group receiving netilmicin in premedication; third group treated by netilmicin for 2 days postoperatively. This series clearly demonstrates the high urinary tract infection rate after transurethral surgery, the benefit of antibioprophylaxis with netilmicin and the efficiency of one dose of this aminosid given one hour preoperatively.

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.

[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.