Elimination of cefotaxime using polysulfone and polyacrylonitrile-derived filters: An in vitro assessment.

Continuous renal replacement therapy (CCRT) efficiently eliminates cefotaxime. To our knowledge, there are no previous in vitro studies dealing with the disposition of cefotaxime. We studied the elimination of cefotaxime by two filters in a model mimicking a session of CRRT using the NeckEpur® technology. The ST150®-polyacrylonitrile filter with the Prismaflex, Baxter-Gambro, and the AV1000®-polysulfone filter with the Multifiltrate Pro, Fresenius, were studied. Continuous filtration used a flowrate of 1 L/h in post-dilution only. Simulated blood flowrate was set at 200 mL/min. Routes of elimination were assessed using the NeckEpur® technology. Cefotaxime concentrations were measured using ultra high-performance liquid chromatography, and tandem mass spectrometry. Two sessions were performed using the ST® filter and three using the AV® filter. Stability of cefotaxime during 6 h was assessed in triplicate with a mean variation of concentrations of 2.4 ± 1.5% at the end of the study. The mean measured initial concentration in the central compartment (CC) for the five sessions was 52.4 mg/L. The mean amount eliminated from the CC at the end of the sessions using the ST150®-polyacrylonitrile and the AV1000®-polysulfone filters were 72% and 73%, respectively. The clearances of cefotaxime from the central compartment (CC) were 1.1 and 1.2 L/h, respectively. The mean sieving coefficient were 0.99 and 0.99, respectively. The mean percentages of the amount eliminated from the CC by filtration/adsorption were 87/13% and 92/8%, respectively. Both adsorption percentages were below 15%. We conclude neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in clinically significant adsorption of cefotaxime.

Disposition of gentamicin and amikacin in extracorporeal membrane oxygenation using a heparin-coated filter: An in vitro assessment.

Disposition of gentamicin and amikacin during extracorporeal membrane oxygenation has not been addressed in in vitro models. The HLS Advanced 7.0® circuit with the Cardio Help® monitor, Getinge, was used. The 5-L central compartment (CC) was loaded with gentamicin and amikacin at a targeted concentration of 40 and 80 mg/L in the same bag prior connection to the circuit. Samples were collected in the CC, the inlet and outlet ports from 15 min to 6 h post-connection. Pharmacokinetic analyses were performed using the NeckEpur® method. Analysis of results of gentamicin and amikacin showed in the filter-pump block (i) the extremely low value of the extraction coefficients, (ii) similar values of the areas under the curve (AUCs) at the inlet and outlet ports, (iii) using the Wilcoxon matched pairs signed rank test no significant differences of the inlet-outlet concentrations in the filter-pump. In the whole system (i) the amounts recovered in the CC at the end of the 6-h session were not significantly different from the initial values, (ii) the extremely low values of the total clearance of gentamicin and amikacin from the CC in comparison with the measured simulated blood flowrate, (iii) the lack of significant time-concentration interactions in the CC and the inlet and outlet ports. These findings allow concluding no detectable adsorption of gentamicin and amikacin occurred in the HLS Advanced 7.0 circuit.

Elimination of three doses of gentamicin over three consecutive days using a polyacrylonitrile-derived filter: An in vitro assessment.

INTRODUCTION: Adsorption of gentamicin in a polyacrylonitrile filter was previously evidenced in a session lasting 6 h using the NeckEpur model. We extended the study over three consecutive days to mimic the 72-h life span of a filter. METHODS: Prismaflex® monitor and ST150® filter were used in the continuous diafiltration (CDF) mode at a 2.5 L/h flowrate. The daily session started with a 6-h session of CDF. Thereafter, the 5-L central compartment was changed using a bag free of gentamicin to assess gentamicin release over the following 18 h. Experiments were repeated on Day 2 and stopped at the end of the 6-h session of CDF on Day 3. The experiment was performed in duplicate. RESULTS: At a 2.5 L/h diafiltration flowrate, the mean daily clearances of gentamicin were 5.5, 4.0, and 3.3 L/h, respectively. The mean diafiltration and adsorption ratios in the daily elimination of gentamicin were 32/68%, 58/42%, and 88/12%, respectively. During days 1 and 2, the mean amount of gentamicin released from the ST150® filter were 14 and 34 mg, respectively. CONCLUSION: The pharmacokinetics of gentamicin over 3 days is strongly altered by adsorption in the same filter with a progressive decrease of elimination by adsorption, suggesting saturation of the filter. One limitation of our study results from the mode of administration using a bolus dose instead of an infusion over 30 min. Adsorption adds a clearance to those of diafiltration. The time-dependency of gentamicin clearance precludes using a constant dosage regimen over the filter's life span.

Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment.

INTRODUCTION: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied. METHODS: The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model. RESULTS: The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%-93% and 96%-94%, respectively; the clearances from the central compartment (CC) were 2.5-2.6 and 2.4-2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%-0.91% and 0.99%-0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%-95/5% and 100/0%-100/0%, respectively. CONCLUSION: Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole.

Are we correctly treating invasive candidiasis under continuous renal replacement therapy with echinocandins? Preliminary in vitro assessment.

There is major concern regarding the pharmacokinetics of drugs under continuous renal replacement therapy (CRRT), including anti-infectious agents and more especially antifungal agents. From a regulatory viewpoint, only dialysis and filtration are considered meanwhile there is growing evidence that adsorption may also significantly alter the pharmacokinetics of anti-infectious agents. Adsorption results from a complex drug-filter interaction and might be considered an unexpected adverse effect induced by CRRT. Measurement of total plasma concentrations instead of the unbound, free, active concentrations in in vitro as well as in clinical studies hides this major adverse effect, which may jeopardise the therapeutic effect and even result in treatment failure. Noteworthy, minimal inhibitory concentrations (MIC) of anti-infectious agents are performed using solid and liquid medium without proteins testing only the antimicrobial activity of the free fraction of drugs. In a new in vitro model using crystalloid solution instead of blood, we report data supporting the assumption that the assessment of the disposition of the free fraction of caspofungin and micafungin unveils adverse effects of ST150® filter, which might eventually result in non-detectable drug concentrations and treatment failure. From a technical viewpoint, we conclude the measurement of the free fraction of drugs that largely bound to plasma proteins, including caspofungin and micafungin, should be considered instead of total plasma concentrations to assess all effects induced by filters used in CRRT.

Alteration of the pharmacokinetics of aminoglycosides by adsorption in a filter during continuous renal replacement therapy. An in vitro assessment.

OBJECTIVES: Filters used in continuous renal replacement therapy (CRRT) induce elimination by filtration, dialysis, and adsorption. The worldwide used ST150® filter adsorbs cytokines. However, adsorption is a non-specific process which might alter the pharmacokinetics of drugs. Pharmacodynamic/pharmacokinetic relationship of aminoglycosides evidences the importance of the peak concentration at the first dose. We hypothesize an in vitro study may clarify the routes of elimination of aminoglycosides using the ST150® filter. METHODS: Prismaflex® and the STX150® filter, Baxter-Gambro were used. The diafiltration mode combined flowrates of dialysis and filtration at 2.5/1.5L/h, respectively, over 6h. One ionic solute was used in the different compartments. Pharmacokinetic analyses were performed using the NeckEpur® software. RESULTS: Percentages of gentamicin, tobramycin, and amikacin eliminated from the central compartment were 97±1, 95±3, and 94±6, %, respectively. The clearances were 8.4±2.3, 5.4±5, and 4.2±0.4L/h, respectively. The contributions of dialysis, filtration, and adsorption for gentamicin, tobramycin, and amikacin were 34.3±2.1, 0±0, and 67.7±2.1; 51.1±1.6, 6.3±3.1, and 46.3±2.0, and 37.8±6.3, 46.3±2.0, and 16.0±5.7%, respectively. Among physico-chemical properties, the rate of adsorption linearly and inversely correlated with the polar surface area of aminoglycosides (Y=-0.44X+161.7; R2=0.9993). DISCUSSION: Using the ST150® filter, dialysis, filtration, and adsorption play a role depending on the chemical structure of aminoglycosides. In the diafiltration mode, elimination of gentamicin and tobramycin by filtration is not detected or weak, respectively. Adsorption should be considered as a potential adverse effect of CRRT. Polar surface area of drugs is a physico-chemical parameter which should be considered regarding adsorption of drugs in filters. The risk needs to be systematically assessed.

Contribution of cutlery and serving dishes to the human daily intake of silver An in vitro assessment.

Silver cutlery and serving dishes are a potential source of exposure of humans that was never quantified. Release of silver was assessed in vitro in an acidic solution mimicking food fluid in two conditions: i] the JRC guidelines for hot fill conditions with stable high temperature over a 2 hour-period of time, and ii] a more realistic condition with spontaneous progressive decline from 90̊C to ambient temperature over the same period of time. Massive silver 95% strips were exposed to a 5% citric acid solution: i) cooling down from 90̊C to ambient or ii) 70̊C maintained, during 2 hours. Spectrometry with optical emission was used to measure silver in solution. In the spontaneous cooling down study, the time-course of temperature was close to the Newton's law of cooling and the released quantities were detected but too low to be measured. The 70̊C exposition resulted in a non-linear release that became quantifiable after one hour of heating up to an apparent plateau at 120 min with a mean concentration [extreme] of 24.6 [22.3-26.8] µg/L. The results of the present study allow concluding that 95% silver used for cutlery and serving dishes may be released in foods. However, the extent of release depends on the condition of use. At a stable 70̊C temperature over a 2 h-period of time, silver is released in a non-linear model up to a mean concentration of 24.6 µg/L. In contrast, in conditions fitting with the routine recommendations of use, infinitesimal detectable amounts of silver were released.

Prospective comparative assessment of buprenorphine overdose with heroin and methadone: clinical characteristics and response to antidotal treatment.

Buprenorphine is a partial opioid agonist with a "ceiling effect" for respiratory depression. Despite this, it has been associated with severe overdoses. Conflicting data exist regarding its response in overdose to naloxone. We compared clinical overdose characteristics of buprenorphine with heroin and methadone and assessed responses to naloxone and flumazenil. Patients admitted to two intensive care units with severe opioid overdoses were enrolled into this 4-year prospective study. Urine and blood toxicological screening were performed to identify overdoses involving predominantly buprenorphine, heroin, or methadone. Eighty-four patients with heroin (n = 26), buprenorphine (n = 39), or methadone (n = 19) overdoses were analyzed. In the buprenorphine group, sedative drug coingestions were frequent (95%), whereas in the methadone group, suicide attempts were significantly more often reported (p = .0007). Buprenorphine overdose induced an opioid syndrome not differing significantly from heroin and methadone in mental status (as measured by Glasgow Coma Score) or arterial blood gases. Mental status depression was not reversed in buprenorphine overdoses with naloxone (0.4-0.8 mg) but did improve with flumazenil (0.2-1 mg) if benzodiazepines were coingested. In conclusion, buprenorphine overdose causes an opioid syndrome clinically indistinguishable from heroin and methadone. Although mental status and respiratory depression are often unresponsive to low-dose naloxone, flumazenil may be effective in buprenorphine overdoses involving benzodiazepines.

Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure.

OBJECTIVE: To evaluate the use of antidotal therapy in patients with an elevated digitalis concentration following chronic or acute exposure. DESIGN AND SETTING: Retrospective review of patient records over 2 years in 20 city hospitals in France. PATIENTS: Overall 838 patients with an elevated serum digitalis concentration (digoxin > 1.95ng /ml or digitoxin > 23ng /ml) were included in the study. Of these, 67 (8%) had received antidotal therapy with Fab fragments. MEASUREMENTS AND RESULTS: The relationships between previously reported prognostic criteria and use of antidotal therapy were investigated. We identified five independent factors that were associated with the use of antidotal therapy: acute overdose (OR 15.74), Fab fragment availability in the hospital (11.06), serum potassium (1.81), and heart rate (0.96). Mortality was significantly lower in Fab-treated (6%, 4/67) than untreated patients (15%, 117/770). CONCLUSIONS: Antidotal therapy is underused in patients with an elevated digitalis concentration especially in patients with chronic digitalis exposure. These patients in our series presented a higher mortality rate than patients with acute poisoning. Although they were older and tended to have a history of cardiac disease, they did not differ from patients with acute poisoning with regard to the main severity criteria and prognostic factors. The use of identical criteria for antidotal treatment after acute and chronic poisoning should help optimize outcomes. Fab fragment availability is insufficient in France but ranks only second after type of poisoning (acute or chronic) in the multivariate association with Fab treatment.

Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning.

OBJECTIVE: To test the hypothesis that plasma lactate concentrations could be of confirmatory value in patients with histories consistent with acute pure cyanide poisoning because immediate laboratory confirmation of suspected cyanide poisoning is rarely possible and because clinicians must rapidly decide whether to administer specific antidotes, which may have severe side effects. DESIGN: Retrospective clinical study. SETTING: An intensive care unit in a university-affiliated teaching hospital. PATIENTS: All acute cyanide-poisoned patients admitted to our intensive care unit, excluding fire victims, from 1988 to 1999. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven patients were studied. Before antidotal treatment, the median plasma lactate concentration was 168 mg/dL, the median blood cyanide concentration was 4.2 mg/L. Using Spearman's test, there was a significant correlation between plasma lactate and blood cyanide concentrations ( =.74, =.017). Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH. During the course of cyanide poisonings, a plasma lactate concentration of >or=72 mg/d/L (8 mmol/L) was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration (>or=1.0 mg/L). The specificity was substantially improved in patients not receiving catecholamines (85%). CONCLUSIONS: The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning.