Evaluating lactate prognostic value in children suspected of acetaminophen-induced liver failure in Liberia.

BACKGROUND: The prognostic significance of hyperlactatemia in young children with liver injury suspected to be attributed to repeated supratherapeutic doses of acetaminophen remain understudied. METHODS: We conducted a retrospective medical chart review including children aged <5 years admitted with hepatocellular injury. The study was conducted in Bardnesville Junction Hospital operated by Médecins Sans Frontières in Monrovia, Liberia. RESULTS: We analyzed 95 children with liver injury in whom a blood lactate measurement on admission was available. Eighty children (84%) were aged <2 years; 49 children (52%) died during hospitalization. The median acetaminophen concentration on admission was 20 mg/L with 60 (70%) children presenting concentrations exceeding 10 mg/L. Median lactate was significantly higher in children who died (10.7 mmol/L; interquartile range (IQR): 8.5-15.7) than those who survived (6.1 mmol/L; IQR: 4.1-8.5), P value < 0.001). The optimal threshold obtained was 7.2 mmol/L with a sensitivity of 84% and specificity 70% (area under curve = 0.80). The previously established thresholds of 3.5 and 4 mmol/L lactate had very low specificity identifying non-survival in children included in this study. CONCLUSION: In this setting, young children with ALF possibly attributed to acetaminophen toxicity were unlikely to survive if the venous blood lactate concentration exceeded 7.2 mmol/L.

Correction to: Suspected paracetamol overdose in Monrovia, Liberia: a matched case-control Study.

An amendment to this paper has been published and can be accessed via the original article.

Suspected paracetamol overdose in Monrovia, Liberia: a matched case-control study.

BACKGROUND: A cluster of cases of unexplained multi-organ failure was reported in children at Bardnesville Junction Hospital (BJH), Monrovia, Liberia. Prior to admission, children's caregivers reported antibiotic, antimalarial, paracetamol, and traditional treatment consumption. Since we could not exclude a toxic aetiology, and paracetamol overdose in particular, we implemented prospective syndromic surveillance to better define the clinical characteristics of these children. To investigate risk factors, we performed a case-control study. METHODS: The investigation was conducted in BJH between July 2015 and January 2016. In-hospital syndromic surveillance identified children with at least two of the following symptoms: respiratory distress with normal pulse oximetry while breathing ambient air; altered consciousness; hypoglycaemia; jaundice; and hepatomegaly. After refining the case definition to better reflect potential risk factors for hepatic dysfunction, we selected cases identified from syndromic surveillance for a matched case-control study. Cases were matched with in-hospital and community-based controls by age, sex, month of illness/admission, severity (in-hospital), and proximity of residence (community). RESULTS: Between July and December 2015, 77 case-patients were captured by syndromic surveillance; 68 (88%) were under three years old and 35 (46%) died during hospitalisation. Of these 77, 30 children met our case definition and were matched with 53 hospital and 48 community controls. Paracetamol was the most frequently reported medication taken by the cases and both control groups. The odds of caregivers reporting supra-therapeutic paracetamol consumption prior to admission was higher in cases compared to controls (OR 6.6, 95% CI 2.1-21.3). Plasma paracetamol concentration on day of admission was available for 19 cases and exceeded 10 µg/mL in 10/13 samples collected on day one of admission, and 4/9 (44%) collected on day two. CONCLUSIONS: In a context with limited diagnostic capacity, this study highlights the possibility of supratherapeutic doses of paracetamol as a factor in multi-organ failure in a cohort of children admitted to BJH. In this setting, a careful history of pre-admission paracetamol consumption may alert clinicians to the possibility of overdose, even when confirmatory laboratory analysis is unavailable. Further studies may help define additional toxicological characteristics in such contexts to improve diagnoses.

Safety and Efficacy of New Oximes to Reverse Low Dose Diethyl-Paraoxon-Induced Ventilatory Effects in Rats.

BACKGROUND: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new oximes has not been assessed in vivo. METHODS: The aim of this work was to assess the safety and efficiency of new oximes compared to pralidoxime in a rat model of diethyl paraoxon-induced non-lethal respiratory toxicity. RESULTS: Safety study of oximes showed no adverse effects on ventilation in rats. KO-33, KO-48, KO-74 oximes did not exhibit significant antidotal effect in vivo. In contrast, KO-27 and BI-6 showed evidence of antidotal activity by normalization of respiratory frequency and respiratory times. KO-27 became inefficient only during the last 30 min of the study. In contrast, pralidoxime demonstrated to be inefficient at 30 min post injection. Inversely, the antidotal activity of BI-6 occurred lately, within the last 90 min post injection. CONCLUSION: This study showed respiratory safety of new oximes. Regarding, the efficiency, KO-27 revealed to be a rapid acting antidote toward diethylparaoxon-induced respiratory toxicity, meanwhile BI-6 was a late-acting antidote. Simultaneous administration of these two oximes might result in a complete and prolonged antidotal efficiency.

Determinants of Lactic Acidosis in Acute Cyanide Poisonings.

OBJECTIVES: To investigate the magnitude of lactic acidosis in response to cyanide poisoning compared with the secondary response caused by cardiovascular shock. DESIGN: Retrospective case-control observational study. SETTING: University Hospital of Assistance Publique - Hôpitaux de Paris. SUBJECTS: Patients admitted for suspicion of cyanide poisoning or drug overdose. Medical charts provided by Assistance Publique - Hôpitaux de Paris of patients between January 1988 and December 2015. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Twelve cyanide poisoned patients were matched to 48 controls by age, sex, systolic blood pressure, catecholamine administration, and outcome at discharge from ICU. Extracted data included age, sex, vital signs, symptoms, biochemical parameters, toxicological analysis, treatment, and outcome. Non-parametric tests were used. Multivariable analysis was used to adjust for confounders causing hyperlactacidemia. The median blood lactate concentration was significantly greater in the cyanide group (15.6 mmol/L) compared to the control group (4.1 mmol/L; p = 0.0003). Similarly, blood lactate concentration greater than or equal to 8 mmol/l was observed in 83% of the cyanide cases versus 27% of the matched controls. Multivariate analysis conferred hyperlactacidemia as the lone factor which significantly predicted cyanide poisoning at an odds of 73.0 (5.7-936.1). Moreover, blood cyanide level significantly correlated with the increase of blood lactate (p = 0.0033). CONCLUSIONS: This study supports the hypothesis lactic acidosis primarily results from the direct toxicity of cyanide.

Hemorrhagic infarct of basal ganglia in cardiac arrest. CT and MRI findings. 2 cases.

We report the CT and MRI findings in two cases of hemorrhagic infarct of the basal ganglia (BG), following out-of-hospital cardiac arrest (CA). In case 1, Brain-CT realized at day 2 showed bilateral and almost symmetric hemorrhagic infarct of the BG and infarct of the tectum of the mesencephalon. In case 2, MRI realized at day 6 showed hemorrhagic infarct of both lenticular nuclei on T2 GE images. In both cases there was no medical history and the cardiovascular and the coagulation profile were normal. In these cases, the lesions are observed earlier than reported in a few previous radiological cases. Similar lesions have been reported in pathological studies. These lesions seem occur early after CA. Reperfusion is probably responsible for the hemorrhagic transformation. The reason why some patients present either BG or brainstem infarct or both remains unclear. Bilateral and symmetric hemorrhagic infarct of the BG, especially of the Lenticular nuclei, and infarct of the dorsal pons and mesencephalic tegmentum seem to be a characteristic feature of profound and prolonged hypotension or of CA.

Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study.

BACKGROUND: Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling. METHODS AND RESULTS: Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1-2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93-2.16; P=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96-2.35; P=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (P<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (P=0.009). CONCLUSION: Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00392639.

Influence of α-stat and pH-stat blood gas management strategies on cerebral blood flow and oxygenation in patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest: a crossover study.

OBJECTIVES: In patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest, two blood gas management strategies are used regarding the PaCO2 target: α-stat or pH-stat. We aimed to compare the effects of these strategies on cerebral blood flow and oxygenation. DESIGN: Prospective observational single-center crossover study. SETTING: ICU of University hospital. PATIENTS: Twenty-one therapeutic hypothermia-treated patients after out-of-hospital cardiac arrest more than 18 years old without history of cerebrovascular disease were included. INTERVENTIONS: Cerebral perfusion and oxygenation variables were compared in α-stat (PaCO2 measured at 37 °C) versus pH-stat (PaCO2 measured at 32-34 °C), both strategies maintaining physiological PaCO2 values: 4.8-5.6 kPa (36-42 torr). MEASUREMENTS AND MAIN RESULTS: Bilateral transcranial middle cerebral artery flow velocities using Doppler and jugular vein oxygen saturation were measured in both strategies 18 hours (14-23 hr) after the return of spontaneous circulation. Pulsatility and resistance indexes and cerebral oxygen extraction were calculated. Data are expressed as median (interquartile range 25-75) in α-stat versus pH-stat. No differences were found in temperature, arterial blood pressure, and oxygenation between α-stat and pH-stat. Significant differences were found in minute ventilation (p = 0.006), temperature-corrected PaCO2 (4.4 kPa [4.1-4.6 kPa] vs. 5.1 kPa [5.0-5.3 kPa], p = 0.0001), and temperature-uncorrected PaCO2 (p = 0.0001). No differences were found in cerebral blood velocities and pulsatility and resistance indexes in the overall population. Significant differences were found in jugular vein oxygen saturation (83.2% [79.2-87.6%] vs. 86.7% [83.2-88.2%], p = 0.009) and cerebral oxygen extraction (15% [11-20%] vs. 12% [10-16%], p = 0.01), respectively. In survivors, diastolic blood velocities were 25 cm/s (19-30 cm/s) versus 29 cm/s (23-35 cm/s) (p = 0.004), pulsatility index was 1.10 (0.97-1.18) versus 0.94 (0.89-1.05) (p = 0.027), jugular vein oxygen saturation was 79.2 (71.1-81.8) versus 83.3% (76.6-87.8) (p = 0.033), respectively. However, similar results were not found in nonsurvivors. CONCLUSIONS: In therapeutic hypothermia-treated patients after out-of-hospital cardiac arrest at physiological PaCO2, α-stat strategy increases jugular vein blood desaturation and cerebral oxygen extraction compared with pH-stat strategy and decreases cerebral blood flow velocities in survivors.

Vancomycin Sequestration in ST Filters: An In Vitro Study.

BACKGROUND: Sequestration of vancomycin in ST® filters used in continuous renal therapy is a pending question. Direct vancomycin-ST® interaction was assessed using the in vitro NeckEpur® technology. METHOD: ST150® filter and Prismaflex dialyzer, Baxter-Gambro, were used. Two modes were assessed in duplicate: (i) continuous diafiltration (CDF): 4 L/h, (ii) continuous dialysis (CD): 2.5 L/h post-filtration. RESULTS: The mean initial vancomycin concentration in the central compartment (CC) was 51.4 +/- 5.0 mg/L. The mean percentage eliminated from the CC over 6 h was 91 +/- 4%. The mean clearances from the CC by CDF and CD were 2.8 and 1.9 L/h, respectively. The mean clearances assessed using cumulative effluents were 4.4 and 2.2 L/h, respectively. The mean percentages of the initial dose eliminated in the effluents from the CC by CDF and CD were 114 and 108% with no detectable sequestration of vancomycin in both modes of elimination. DISCUSSION: Significant sequestration adds a clearance to that provided by CDF and CD. The study provides multiple evidence from the CC, the filter, and the effluents of the lack of an increase in total clearance in comparison with the flow rates without significant sequestration in the ST® filter comparing cumulative effluents to the initial dose in the CC. CONCLUSIONS: There is no evidence ST® filters directly sequestrate vancomycin.

Caspofungin sequestration in a polyacrylonitrile-derived filter: Increasing the dose does not mitigate sequestration.

OBJECTIVES: Critically ill patients frequently require continuous renal replacement therapy. Echinocandins are recommended as first-line treatment of candidemia. Preliminary results suggested echinocandin sequestration in a polyacrylonitrile filter. The present study aimed to determine whether increasing the dose might balance sequestration. METHODS: An STX filter (Baxter-Gambro) was used. A liquid chromatography-mass spectrometry method was used for dosage of caspofungin. In vitro drug disposition was evaluated by NeckEpur (Neckepur, Versailles, France) technology using a crystalloid medium instead of diluted/reconstituted blood, focusing on the disposition of the unbound fraction of drugs. Two concentrations were assessed. RESULTS: At the low dose, the mean measured initial concentration in the central compartment (CC) was 5.1 ± 0.6 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.6 ± 2.5 L/h. The mean percentages of elimination resulting from sequestration and diafiltration were 96.0 ± 5.0 and 4.0 ± 5.2%, respectively. At high dose, the mean measured initial concentration in the CC was 13.1 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.5 L/h. The mean percentages of elimination resulting from sequestration and filtration were 88.5% and 11.5%, respectively. CONCLUSION: Increasing the dose does not mitigate caspofungin sequestration in the STX filter. The results raise caution about the simultaneous use of caspofungin and polyacrylonitrile-derived filters. Intermittent modes of renal replacement therapy might be considered. For sensitive species, fluconazole might be an alternative.

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.

Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice.

OBJECTIVES: Deaths due to asphyxia as well as following acute poisoning with severe respiratory depression have been attributed to buprenorphine in opioid abusers. However, in human and animal studies, buprenorphine exhibited ceiling respiratory effects, whereas its metabolite, norbuprenorphine, was assessed as being a potent respiratory depressor in rodents. Recently, norbuprenorphine, in contrast to buprenorphine, was shown in vitro to be a substrate of human P-glycoprotein, a drug-transporter involved in all steps of pharmacokinetics including transport at the blood-brain barrier. Our objectives were to assess P-glycoprotein involvement in norbuprenorphine transport in vivo and study its role in the modulation of buprenorphine-related respiratory effects in mice. SETTING: University-affiliated research laboratory, INSERM U705, Paris, France. SUBJECTS: Wild-type and P-glycoprotein knockout female Friend virus B-type mice. INTERVENTIONS: Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion. MEASUREMENTS AND MAIN RESULTS: Norbuprenorphine(≥ 1 mg/kg) and to a lesser extent buprenorphine (≥ 10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (TI) and expiratory times (TE). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on TI (p < .01) and TE (p < .05) and norbuprenorphine-related effects on minute volume (VE, p < .05), TI, and TE (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on VE (p < .01), TE (p < .001), and TI (p < .05) and norbuprenorphine-related effects on VE (p < .05) and TI (p < .001) were significantly enhanced. Plasma norbuprenorphine concentrations were significantly increased in PSC833-treated mice (p < .001), supporting a P-glycoprotein role in norbuprenorphine pharmacokinetics. Brain norbuprenorphine efflux was significantly reduced in PSC833-treated and P-glycoprotein-knockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood-brain barrier. CONCLUSIONS: P-glycoprotein plays a key-protective role in buprenorphine-related respiratory effects, by allowing norbuprenorphine efflux at the blood-brain barrier. Our findings suggest a major role for drug-drug interactions that lead to P-glycoprotein inhibition in buprenorphine-associated fatalities and respiratory depression.

Tuberculosis in the intensive care unit: A retrospective descriptive cohort study with determination of a predictive fatality score.

BACKGROUND: Despite effective treatments, tuberculosis-related mortality remains high among patients requiring admission to the intensive care unit (ICU). OBJECTIVE: To determine prognostic factors of death in tuberculosis patients admitted to the ICU, and to develop a simple predictive scoring system. METHODS: A 10-year, retrospective study of 53 patients admitted consecutively to the Hôpitaux de Paris, Hôpital Lariboisière (Paris, France) ICU with confirmed tuberculosis, was conducted. A multivariate analysis was performed to identify risk factors for death. A predictive fatality score was determined. RESULTS: Diagnoses included pulmonary tuberculosis (96%) and tuberculous encephalomeningitis (26%). Patients required mechanical ventilation (45%) and vasopressor infusion (28%) on admission. Twenty patients (38%) died, related to direct tuberculosis-induced organ failure (n=5), pulmonary bacterial coinfections (n=14) and pulmonary embolism (n=1). Using a multivariate analysis, three independent factors on ICU admission were predictive of fatality: miliary pulmonary tuberculosis (OR 9.04 [95% CI 1.25 to 65.30]), mechanical ventilation (OR 11.36 [95% CI 1.55 to 83.48]) and vasopressor requirement (OR 8.45 [95% CI 1.29 to 55.18]). A score generated by summing these three independent variables was effective at predicting fatality with an area under the ROC curve of 0.92 (95% CI 0.85 to 0.98). CONCLUSIONS: Fatalities remain high in patients admitted to the ICU with tuberculosis. Miliary pulmonary tuberculosis, mechanical ventilation and vasopressor requirement on admission were predictive of death.

HISTORIQUE: Malgré des traitements efficaces, la mortalité liée à la tuberculose demeure élevée chez les patients qui doivent être hospitalisés à l'unité de soins intensifs (USI). OBJECTIF: Déterminer les facteurs pronostiques de décès chez les patients tuberculeux admis à l'USI et élaborer un système d'indice prédictif simple. MÉTHODOLOGIE: Les chercheurs ont mené une étude rétrospective d'une durée de dix ans auprès de 53 patients hospitalisés consécutivement à l'USI de l'Hôpital Lariboisière des Hôpitaux de Paris, en France, en raison d'une tuberculose confirmée. Ils ont procédé à une analyse multivariée pour déterminer les facteurs de risque de décès et ont établi un indice prédictif de fatalité. RÉSULTATS: Les diagnostics incluaient une tuberculose pulmonaire (96 %) et une encéphaloméningite tuberculeuse (26 %). Les patients avaient besoin d'une ventilation mécanique (45 %) et d'une perfusion de vasopresseur (28 %) à l'admission. Vingt patients (38 %) sont décédés en raison d'une insuffisance organique liée directement à la tuberculose (n=5), de co-infections bactériennes pulmonaires (n=14) et d'une embolie pulmonaire (n=1). Selon l'analyse multivariée, trois facteurs indépendants à l'admission à l'USI étaient prédictifs d'une fatalité : une tuberculose miliaire (RRR 9,04 [95 % IC 1,25 à 65,30]), une ventilation mécanique (RRR 11,36 [95 % IC 1,55 à 83,48]) et des besoins vasopressifs (RRR 8,45 [95 % IC 1,29 à 55,18]). Un indice conforme à la somme de ces trois variables indépendantes était efficace pour prévenir la fatalité, avec une zone sous la courbe ROC de 0,92 (95 % IC 0,85 à 0,98). CONCLUSIONS: Les décès demeurent élevés chez les patients tuberculeux admis à l'USI. La tuberculose miliaire, la ventilation mécanique et les besoins vasopressifs à l'admission sont prédictifs d'un décès.

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.

Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning?

OBJECTIVES: Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2⁻/⁻; Oct3⁻/⁻). 2) Assess whether sustained high plasma concentrations increase pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity. SETTING: INSERM U705, Faculté de Pharmacie, Université Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. SUBJECTS: Rodents: Knockout mice (Oct1/2⁻/⁻; Oct3⁻/⁻) and Sprague-Dawley rats. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In rats, the renal clearance of pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/2⁻/⁻) resulted in a significant increase in plasma pralidoxime concentrations. Lack of Oct3 did not alter plasma pralidoxime concentrations. The antidotal activity of pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium. CONCLUSIONS: Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma pralidoxime concentrations and the antidotal effect of pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of pralidoxime. However, further studies are needed before these results are extended to human poisoning.

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.

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.