RESUMO
BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). OBJECTIVES: The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. METHODS: Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). RESULTS: Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was - 57.5%, and mean change in Patient-Oriented Eczema Measure total score was - 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years. CONCLUSIONS: In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years. CLINICAL TRIAL REGISTRATION: NCT03356977.
Atopic dermatitis (AD) is a skin disease that causes inflamed and itchy skin. Crisaborole is an ointment that is approved to treat patients aged 2 years and older with mild-to-moderate AD. This clinical trial studied crisaborole in infants with mild-to-moderate AD who were 3 to under 24 months old. These infants were treated with crisaborole twice a day for 28 days. The trial studied crisaborole's safety, effectiveness, and absorption into the bloodstream. In total, 137 infants were treated. Although side effects of some sort occurred in about two-thirds of patients, only 1 in 6 patients experienced side effects that were attributed to crisaborole. When these side effects did occur, these were mainly pain, discomfort, or redness where crisaborole was applied. Fewer than 1 in 25 patients experienced each side effect where crisaborole was applied. The doctors saw improvement in the AD symptoms of some patients at day 29 of the study compared to the beginning of the study. Crisaborole blood-level measurements in this age group were consistent with those seen in patients aged 2 years and older. Overall, crisaborole was considered well tolerated and effective in infants (3 to under 24 months old) with mild-to-moderate AD. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: An Open-Label, Phase 4 Study (MP4 40891 MB).
Assuntos
Compostos de Boro/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Dermatite Atópica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/efeitos adversos , Compostos de Boro/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Feminino , Humanos , Lactente , Masculino , Inibidores da Fosfodiesterase 4/farmacocinética , Propilenoglicol/sangue , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: While some case reports indicate that high doses of propylene glycol (PG) may result in metabolic acidosis, there has been no large-scale study that evaluated the risk of metabolic acidosis in patients receiving PG-containing benzodiazepines for acute alcohol withdrawal. This study was undertaken to evaluate the potential toxicity of PG in patients with acute alcohol withdrawal treated with intermittent intravenous bolus doses of diazepam and/or lorazepam. METHODS: This is a retrospective case study using data collected from 18 randomly selected patients receiving one or both of these medications per a modified Clinical Institute Withdrawal Assessment for Alcohol (CIWA) Class 3 protocol. Plasma levels of PG were estimated using a one-compartment pharmacokinetic model. RESULTS: Only two patients had an elevated anion gap compared to their baseline value with one also experiencing a significant increase in serum creatinine. No increases in serum osmolarity were noted. Analysis showed that the benzodiazepine dose received was a good predictor of the estimated PG concentration (r = 0.6), but was poorly correlated with the anion gap. No significant correlation was found with the creatinine clearance or serum creatinine. Patients receiving several daily doses were at higher risk of developing an anion gap (r = 0.33), but the estimated maximum PG concentration did not correlate with the anion gap or serum concentration. CONCLUSION: It does not appear that intermittent bolus administration of intravenous benzodiazepines for alcohol withdrawal influenced renal function or anion gap regardless of number of administered doses, amount of PG received, or the estimated PG concentration.
Assuntos
Acidose/induzido quimicamente , Propilenoglicol/efeitos adversos , Propilenoglicol/farmacocinética , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Equilíbrio Ácido-Base/efeitos dos fármacos , Alcoolismo/complicações , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Diazepam/administração & dosagem , Diazepam/uso terapêutico , Feminino , Humanos , Injeções Intravenosas , Lorazepam/administração & dosagem , Lorazepam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Propilenoglicol/sangue , Propilenoglicol/farmacologia , Insuficiência Renal/induzido quimicamente , Estudos RetrospectivosRESUMO
Ethylene glycol (EG) is a common cause of toxic ingestions. Gas chromatography (GC)-based laboratory assays are the gold standard for diagnosing EG intoxication. However, GC requires specialized instrumentation and technical expertise that limits feasibility for many clinical laboratories. The objective of this retrospective study was to determine the utility of incorporating a rapid EG assay for management of cases with suspected EG poisoning. The University of Iowa Hospitals and Clinics core clinical laboratory adapted a veterinary EG assay (Catachem, Inc.) for the Roche Diagnostics cobas 8000 c502 analyzer and incorporated this assay in an osmolal gap-based algorithm for potential toxic alcohol/glycol ingestions. The main limitation is that high concentrations of propylene glycol (PG), while readily identifiable by reaction rate kinetics, can interfere with EG measurement. The clinical laboratory had the ability to perform GC for EG and PG, if needed. A total of 222 rapid EG and 24 EG/PG GC analyses were documented in 106 patient encounters. Of ten confirmed EG ingestions, eight cases were managed entirely with the rapid EG assay. PG interference was evident in 25 samples, leading to 8 GC analyses to rule out the presence of EG. Chart review of cases with negative rapid EG assay results showed no evidence of false negatives. The results of this study highlight the use of incorporating a rapid EG assay for the diagnosis and management of suspected EG toxicity by decreasing the reliance on GC. Future improvements would involve rapid EG assays that completely avoid interference by PG.
Assuntos
Etilenoglicol/sangue , Intoxicação/sangue , Padrões de Prática Médica , Kit de Reagentes para Diagnóstico , Centros Médicos Acadêmicos , Adulto , Algoritmos , Diagnóstico Diferencial , Registros Eletrônicos de Saúde , Etilenoglicol/intoxicação , Feminino , Ionização de Chama/economia , Custos Hospitalares , Humanos , Iowa , Masculino , Pessoa de Meia-Idade , Intoxicação/diagnóstico , Intoxicação/economia , Intoxicação/terapia , Padrões de Prática Médica/economia , Propilenoglicol/sangue , Propilenoglicol/intoxicação , Kit de Reagentes para Diagnóstico/economia , Kit de Reagentes para Diagnóstico/veterinária , Estudos Retrospectivos , Fatores de Tempo , ToxicocinéticaRESUMO
CONTEXT: Methanol, ethylene glycol, diethylene glycol, and propylene glycol intoxications are associated with cellular dysfunction and an increased risk of death. Adverse effects can develop quickly; thus, there is a need for methods for rapidly detecting their presence. OBJECTIVE: To examine the value and limitations of present methods to diagnose patients with possible toxic alcohol exposure. METHODS: I searched MEDLINE for articles published between 1969 and 2014 using the terms: toxic alcohols, serum osmolality, serum osmol gap, serum anion gap, metabolic acidosis, methanol, ethylene glycol, diethylene glycol, propylene glycol, and fomepizole. Each article was reviewed for additional references. RESULTS: The diagnosis of toxic alcohol exposure is often made on the basis of this history and physical findings along with an increase in the serum osmol and anion gaps. However, an increase in the osmol and/or anion gaps is not always present. Definitive detection in blood requires gas or liquid chromatography, laborious and expensive procedures which are not always available. Newer methods including a qualitative colorimetric test for detection of all alcohols or enzymatic tests for a specific alcohol might allow for more rapid diagnosis. CONCLUSIONS: Exposure to toxic alcohols is associated with cellular dysfunction and increased risk of death. Treatment, if initiated early, can markedly improve outcome, but present methods of diagnosis including changes in serum osmol and anion gap, and use of gas or liquid chromatography have important limitations. Development of more rapid and effective tests for detection of these intoxications is essential for optimal care of patients.
Assuntos
Álcoois/intoxicação , Etilenoglicol/sangue , Etilenoglicóis/sangue , Metanol/sangue , Propilenoglicol/sangue , Equilíbrio Ácido-Base , Acidose/sangue , Fomepizol , Humanos , Concentração Osmolar , Pirazóis/sangueRESUMO
A simple, cost effective, and fast gas chromatography method with flame ionization detection (GC-FID) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. This new method employs a relatively less used class of derivatization agents - alkyl chloroformates, allowing the efficient and rapid derivatization of carboxylic acids within seconds while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. To avoid possible interference from naturally occurring endogenous acids and quantitation errors 3-(4-chlorophenyl) propionic acid was chosen as an internal standard. The significant parameters of the derivatization have been found using chemometric procedures and these parameters were optimized using the face-centered central composite design. The calibration dependence of the method was proved to be quadratic in the range of 50-5000 mg mL(-1), with adequate accuracy (92.4-108.7%) and precision (9.4%). The method was successfully applied to quantify the selected compounds in serum of patients from emergency units.
Assuntos
Serviços Médicos de Emergência , Etilenoglicol/sangue , Etilenoglicol/urina , Glicolatos/sangue , Glicolatos/urina , Propilenoglicol/sangue , Propilenoglicol/urina , Estudos de Casos e Controles , Cromatografia Gasosa/métodos , Etilenoglicol/intoxicação , Feminino , Ionização de Chama/métodos , Glicolatos/intoxicação , Humanos , Masculino , Propilenoglicol/intoxicação , Soro/química , Toxicologia/métodosRESUMO
BACKGROUND: Despite limited information being available on the pharmacokinetics of excipients, propylene glycol (PG) is often used as an excipient in both adults and children. The aim of this study is to characterize the renal and hepatic elimination of PG in preterm and term neonates. METHODS: The pharmacokinetic analysis of PG was performed in NONMEM 6.2. on the basis of PG concentrations in plasma and/or urine samples for a total of 69 (pre)term neonates (birth weight 630-3980 g, gestational age 24-41 weeks, postnatal age 1-29 days) who received PG coadministered with intravenous paracetamol (5-10 mg/kg per 6 hours), phenobarbital (5 mg·kg(-1)·d(-1)), or both. To capture the time-dependent trend in the renal excretion of PG, different models based on time after the first dose, urine volume, and creatinine amount in urine were tested. RESULTS: A one-compartment model parameterized in terms of renal clearance, hepatic clearance, and volume of distribution was found to adequately describe the observations in both plasma and urine. After the first dose was administered, the renal elimination of PG was 15% of total clearance, which increased over time to 25% at 24 hours after the first dose of PG. This increase was best described using a hyperbolic function based on time after the first dose. CONCLUSIONS: Renal elimination of PG in (pre)term neonates is low, particularly compared with the reported percentage of 45% in adults, but it may increase with time after the first dose of PG. To study whether this increase is caused by an autoinduced increase in the renal secretion or a reduction of tubular reabsorption of PG, further research is needed.
Assuntos
Excipientes/farmacocinética , Recém-Nascido Prematuro/fisiologia , Propilenoglicol/farmacocinética , Acetaminofen/farmacologia , Simulação por Computador , Excipientes/análise , Feminino , Idade Gestacional , Eliminação Hepatobiliar , Humanos , Recém-Nascido , Masculino , Modelos Biológicos , Fenobarbital/farmacologia , Propilenoglicol/sangue , Propilenoglicol/urina , Eliminação RenalRESUMO
Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.
Assuntos
Acetaminofen/farmacocinética , Anti-Inflamatórios não Esteroides/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Inibidores do Citocromo P-450 CYP2E1 , Excipientes/administração & dosagem , Propilenoglicol/administração & dosagem , Acetaminofen/análogos & derivados , Acetaminofen/metabolismo , Adulto , Área Sob a Curva , Estudos Cross-Over , Formas de Dosagem , Feminino , Humanos , Masculino , Propilenoglicol/sangue , Sulfatos/metabolismoRESUMO
Many laboratories in Poland do not use gas chromatography (GC) method for determination of ethylene glycol (EG) and methanol in blood of poisoned patients, they use non specific spectrophotometry methods. One of the interfering substances is propylene glycol (PG)--compound present in many medical and cosmetic products: drops, air freshens, disinfectants, electronic cigarettes and others. In Laboratory of Analytical Toxicology and Drug Monitoring in Krakow determination of EG is made by GC method. The method enables to distinguish and make resolution of (EG) and (PG) in biological samples. In the years 2011-2012 in several serum samples from diagnosed patients PG was present in concentration from several to higher than 100 mg/dL. The aim of the study was to estimate PG interferences of serum EG determination by spectrophotometry method. Serum samples containing PG and EG were used in the study. The samples were analyzed by two methods: GC and spectrophotometry. Results of serum samples spiked with PG with no EG analysed by spectrophotometry method were improper ("false positive"). The results were correlated to PG concentration in samples. Calculated cross-reactivity of PG in the method was 42%. Positive results of EG measured by spectrophotometry method must be confirmed by reference GC method. Spectrophotometry method shouldn't be used for diagnostics and monitoring of patients poisoned by EG.
Assuntos
Etilenoglicol/sangue , Propilenoglicol/sangue , Etilenoglicol/química , Etilenoglicol/urina , Humanos , Propilenoglicol/química , Propilenoglicol/urina , Reprodutibilidade dos Testes , EspectrofotometriaRESUMO
Ethylene glycol ingestion, accidental or intentional, can be a life-threatening emergency. Assays are not available from most clinical laboratories, and, thus, results often require many hours or days to obtain. Enzymatic assays, adaptable to automated chemistry analyzers, have been evaluated, but they have been plagued by analytic problems. With an alternative method of data analysis applied to an existing enzymatic assay, a modified assay was developed and validated on 2 different automated chemistry systems. Compared with a previously validated method based on gas chromatography with flame ionization detection, the modified enzymatic assay showed excellent agreement on patient samples (y = 1.0227x -1.24; r(2) = 0.9725), with a large analytic measuring range (2.5-300 mg/dL [0.4-48.4 mmol/L]). Interferences from propylene glycol, various butanediols, and other related compounds were almost entirely eliminated; when present, they generated error flags rather than falsely elevated ethylene glycol results. This modified assay should make it possible for more clinical laboratories to offer ethylene glycol measurements.
Assuntos
Análise Química do Sangue/métodos , Ensaios Enzimáticos/métodos , Etilenoglicol/análise , Intoxicação/diagnóstico , Cromatografia Gasosa/métodos , Etilenoglicol/sangue , Humanos , Intoxicação/sangue , Propilenoglicol/sangue , Sensibilidade e EspecificidadeAssuntos
Acidose/diagnóstico , Acidose/etiologia , Acidose/sangue , Idoso , Alcoolismo/complicações , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Lorazepam/efeitos adversos , Pneumonia Associada à Ventilação Mecânica/sangue , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Propilenoglicol/sangue , Diálise RenalRESUMO
Double gap metabolic acidosis occurs in the setting of unmeasured active osmoles in the serum (osmolal gap) and anion gap (AG) metabolic acidosis. We describe a 67-year-old woman with acute respiratory failure on mechanical ventilator from pneumonia and anuric acute on chronic renal failure (urea nitrogen 21.4 mmol/L, creatinine 530.4 micromol/L) requiring haemodialysis (HD). On hospital day 5, she was found to have progressive metabolic acidosis (serum pH 7.16, PCO(2) 4.38 kPa, HCO(3)(-) 12.1 mmol/L and AG 21 mmol/L). There was no evidence of hypoxaemia, hypoperfusion or haemodynamic instability. Normal serum ketone and L-lactate but high serum osmolal gap (89.4 mmol/kg) was detected. A search for toxic alcohols revealed a high serum propylene glycol (PG 32.9 mmol/L), a stabilizing solvent for intravenous formulations of lorazepam, which was being used as sedation for mechanical ventilation. Unexpectedly, serum L- and D-lactate as metabolites of PG were not elevated. Although extended HD for eight hours completely removed serum PG and the osmolal gap, the predialysis high AG metabolic acidosis persisted, potentially related to hypercatabolism and anuric renal failure. PG should be in the differential diagnosis of the disorders with high osmolar gap and may not always be associated with L- or D-lactic acidosis.
Assuntos
Acidose/diagnóstico , Acidose/etiologia , Acidose/sangue , Idoso , Alcoolismo/complicações , Evolução Fatal , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Lorazepam/efeitos adversos , Pneumonia Associada à Ventilação Mecânica/sangue , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Propilenoglicol/sangue , Diálise RenalRESUMO
Propylene glycol is a diluent found in many intravenous and oral drugs, including phenytoin, diazepam, and lorazepam. Propylene glycol is eliminated from the body by oxidation through alcohol dehydrogenase to form lactic acid. Under normal conditions, the body converts lactate to pyruvate and metabolizes pyruvate through the Krebs cycle. Lactic acidosis has occurred in patients, often those with renal dysfunction, who were receiving prolonged infusions of drugs that contain propylene glycol as a diluent. We describe a 50-year-old man who experienced severe lactic acidosis after receiving an accidental overdose of lorazepam, which contains propylene glycol. The patient was acutely intoxicated, with a serum ethanol concentration of 406 mg/dl. He had choked on a large piece of meat and subsequently experienced pulseless electrical activity with ventricular fibrillation cardiac arrest. He was brought to the emergency department; within 2 hours, he was admitted to the intensive care unit for initiation of the hypothermia protocol. The patient began to experience generalized tonic-clonic seizures 12 hours later, which resolved after several boluses of lorazepam. A lorazepam infusion was started; however, it was inadvertently administered at a rate of 2 mg/minute instead of the standard rate of 2 mg/hour. Ten hours later, the administration error was recognized and the infusion stopped. The patient's peak propylene glycol level was 659 mg/dl, pH 6.9, serum bicarbonate level 5 mEq/L, and lactate level 18.6 mmol/L. Fomepizole was started the next day and was continued until hospital day 3. Continuous renal replacement therapy was started and then replaced with continuous venovenous hemofiltration (CVVH) for the remainder of the hospital stay. The patient's acidosis resolved by day 3, when his propylene glycol level had decreased to 45 mg/dl. Fomepizole was discontinued, but the patient's prognosis was poor (anoxic brain injury); thus care was withdrawn and the patient died. Although the patient's outcome was death, his lactic acidosis was treated successfully with fomepizole and CVVH. Clinicians should be aware that an iatrogenic overdose of lorazepam may result in severe propylene glycol toxicity, which may be treated with fomepizole and CVVH.
Assuntos
Acidose Láctica/induzido quimicamente , Doença Iatrogênica , Veículos Farmacêuticos/intoxicação , Propilenoglicol/intoxicação , Overdose de Drogas , Humanos , Infusões Intravenosas , Masculino , Veículos Farmacêuticos/administração & dosagem , Propilenoglicol/administração & dosagem , Propilenoglicol/sangueRESUMO
BACKGROUND: Lorazepam is recommended by the Society of Critical Care Medicine as the preferred agent for sedation of critically ill patients. Intravenous lorazepam contains propylene glycol, which has been associated with toxicity when high doses of lorazepam are administered. OBJECTIVE: To evaluate the accumulation of propylene glycol in critically ill patients receiving lorazepam by continuous infusion and determine factors associated with propylene glycol concentration. METHODS: A 6-month, retrospective, safety assessment was conducted of adults admitted to the medical intensive care unit who were receiving lorazepam by continuous infusion for 12 hours or more. Propylene glycol serum concentrations were obtained 24-48 hours after continuous-infusion lorazepam was initiated and every 3-5 days thereafter. Propylene glycol accumulation was defined as concentrations of 25 mg/dL or more. Groups with and without propylene glycol accumulation were compared and factors associated with propylene glycol concentration were determined using multivariate correlation regression analyses. RESULTS: Forty-eight propylene glycol serum samples were obtained from 33 patients. Fourteen (42%) patients had propylene glycol accumulation, representing 23 (48%) serum samples. Univariate analyses showed the following factors were related to propylene glycol accumulation: baseline renal dysfunction, presence of alcohol withdrawal, sex, age, Acute Physiology and Chronic Health Evaluation (APACHE II) score, rate of lorazepam continuous infusion, and 24-hour lorazepam dose. Multivariate linear regression modeling demonstrated that propylene glycol concentration was strongly associated with the continuous infusion rate and 24-hour dose (adjusted r(2) > or = 0.77; p < 0.001). Independent correlation analyses showed that these 2 variables were so strongly associated with propylene glycol concentration (r(2) > or = 0.71; p < 0.001) that they alone predicted propylene glycol concentration. Seven (21%) patients developed renal dysfunction after continuous-infusion lorazepam was initiated, but associated causes were indeterminable. Other possible propylene glycol-associated adverse effects were not observed. CONCLUSIONS: The continuous infusion rate and cumulative 24-hour lorazepam dose are strongly associated with and independently predict propylene glycol concentrations. Despite the absence of confirmed propylene glycol-associated adverse effects, clinicians should be aware that propylene glycol accumulation may occur with continuous-infusion lorazepam.
Assuntos
Hipnóticos e Sedativos/administração & dosagem , Lorazepam/administração & dosagem , Veículos Farmacêuticos/farmacocinética , Propilenoglicol/sangue , Adulto , Fatores Etários , Idoso , Estado Terminal , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Veículos Farmacêuticos/efeitos adversos , Propilenoglicol/efeitos adversos , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Fatores SexuaisRESUMO
STUDY OBJECTIVE: To determine a threshold dose for parenteral lorazepam when screening for propylene glycol toxicity with the osmol gap, and to characterize which osmol gap values are more predictive of toxic propylene glycol concentrations and resultant clinical toxicity. DESIGN: Prospective, two-phase observational study. SETTING: Thirty-two bed, multidisciplinary intensive care unit. PATIENTS: Thirty-five adult patients receiving any dose of parenteral lorazepam (phase 1), and 14 patients receiving lorazepam in doses of 1 mg/kg/day or higher (phase 2). MEASUREMENTS AND MAIN RESULTS: Serum osmolality was measured every other day during lorazepam therapy, and the osmol gap (measured osmolality minus calculated osmolarity) was determined. A serum propylene glycol concentration was obtained when the osmol gap first exceeded 10. In phase 1, 35 patients were monitored for 186 patient-days. Ten patients (29%) developed an osmol gap greater than 10; only one (10%) of these patients had propylene glycol concentrations greater than 18 mg/dl. In phase 2, 14 patients received lorazepam at a median dose of 631 mg (interquartile range [IQR] 437-972 mg) over a median of 5.5 days (IQR 4-8.75 days). Nine patients (64%) had propylene glycol concentrations greater than 18 mg/dl; six (67%) of these nine developed transient acute kidney injury, metabolic acidosis, or both. The correlation between osmol gap and propylene glycol concentration was 0.44 (p=0.006). An osmol gap of 10 or greater had a likelihood ratio of 4.4 to predict a propylene glycol concentration greater than 18 mg/dl. An osmol gap of 12 or greater had a likelihood ratio of 2.7 to predict the development of possible propylene glycol clinical toxicity. CONCLUSION: Screening for propylene glycol toxicity with the osmol gap may be helpful for patients receiving intravenous lorazepam in doses of 1 mg/kg/day or higher. An osmol gap of 10 or greater was predictive of elevated propylene glycol concentrations, and values of 12 or greater were predictive of clinical changes suggestive of propylene glycol toxicity.
Assuntos
Hipnóticos e Sedativos/administração & dosagem , Lorazepam/administração & dosagem , Propilenoglicol/toxicidade , Equilíbrio Ácido-Base , Adulto , Idoso , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Propilenoglicol/sangue , Estudos Prospectivos , Curva ROCRESUMO
Four lactating Holstein cows fitted with ruminal cannulas and permanent indwelling catheters in the mesenteric artery, mesenteric vein, hepatic portal vein, and hepatic vein were used in a cross-over design to study the metabolism of propylene glycol (PG). Each cow received 2 treatments: control (no infusion) and infusion of 650 g of PG into the rumen at the time of the morning feeding. Propylene glycol was infused on the day of sampling only. Samples of arterial, portal, and hepatic blood as well as ruminal fluid were obtained at 0.5 h before feeding and at 0.5, 1.5, 2.5, 3.5, 5, 7, 9, and 11 h after feeding. Infusion of PG did not affect ruminal pH or the total concentration of ruminal volatile fatty acids, but did decrease the molar proportion of ruminal acetate. The ruminal concentrations of PG, propanol, and propanal as well as the molar proportion of propionate increased with PG infusion. The plasma concentrations of PG, ethanol, propanol, propanal, glucose, L-lactate, propionate, and insulin increased with PG and the plasma concentrations of acetate and beta-hydroxybutyrate decreased. The net portal flux of PG, propanol, and propanal increased with PG. The hepatic uptake of PG was equivalent to 19% of the intraruminal dose. When cows were dosed with PG, the hepatic extraction of PG was between 0 and 10% depending on the plasma concentration of PG, explaining the slow decrease in arterial PG. The increased net hepatic flux of L-lactate with PG could account for the entire hepatic uptake of PG, which suggests that the primary hepatic pathway for PG is oxidation to l-lactate. The hepatic uptake of propanol increased with PG, but no effects of PG on the net hepatic and net splanchnic flux of glucose were observed. Despite no effect of PG on net portal flux and net hepatic flux of propionate, the net splanchnic flux of propionate increased and the data suggest that propionate produced from hepatic metabolism of propanol is partly released to the blood. The data suggest that PG affects metabolism of the cows by 2 modes of action: 1) increased supply of l-lactate and propionate to gluconeogenesis and 2) insulin resistance of peripheral tissues induced by increased concentrations of PG and propanol as well as a decreased ratio of ketogenic to glucogenic metabolites in arterial blood plasma.
Assuntos
Bovinos/metabolismo , Lactação/metabolismo , Propilenoglicol/metabolismo , Rúmen/metabolismo , Aldeídos/metabolismo , Animais , Dióxido de Carbono/metabolismo , Estudos Cross-Over , Ingestão de Alimentos , Feminino , Insulina/sangue , Insulina/metabolismo , Fígado/irrigação sanguínea , Fígado/metabolismo , Artérias Mesentéricas/metabolismo , Oxigênio/metabolismo , Propionatos/metabolismo , Propilenoglicol/sangue , Rúmen/química , Baço/irrigação sanguínea , Baço/metabolismo , Fatores de TempoRESUMO
Propylene glycol is a commonly used solvent for oral, intravenous, and topical pharmaceutical preparations. Although it is considered safe, large intravenous doses given over a short period of time can be toxic. Underlying renal insufficiency and hepatic dysfunction raise risk for toxicity. Toxic effects include hyperosmolality, increased anion gap metabolic acidosis (due to lactic acidosis), acute kidney injury, and sepsis-like syndrome. Treatment of toxicity includes hemodialysis to effectively remove propylene glycol. Prevention is best achieved by limiting the dose of propylene glycol infused.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/terapia , Propilenoglicol/efeitos adversos , Solventes/efeitos adversos , Injúria Renal Aguda/diagnóstico , Meia-Vida , Humanos , Incidência , Rim/metabolismo , Rim/fisiopatologia , Concentração Osmolar , Propilenoglicol/sangue , Diálise Renal , Fatores de RiscoRESUMO
STUDY OBJECTIVES: To correlate serum propylene glycol concentration with osmol gap, serum lactate concentration, and amount of propylene glycol administered to mechanically ventilated patients receiving continuous infusions of lorazepam (80% propylene glycol by weight), and to characterize the prevalence of hyperosmolality and range of serum propylene glycol concentrations in this patient population. DESIGN: Prospective, controlled, observational study. SETTING: Adult surgical and cardiothoracic intensive care units (ICUs) of a 1200-bed, urban, tertiary care, teaching hospital. PATIENTS: Sixty-four consecutively enrolled intensive care patients requiring mechanical ventilation and pharmacologic sedation. INTERVENTION: Thirteen patients received continuous infusions of high-dose lorazepam (> or = 6 mg/hr) for a minimum of 36 hours, and 26 received continuous infusions of low-dose lorazepam (2-5.99 mg/hr) for 36 hours. Twenty-five control patients received sedatives that did not contain propylene glycol. MEASUREMENTS AND MAIN RESULTS: Serum propylene glycol and lactate concentrations, osmolality, and basic metabolic profiles were obtained 72-108 hours after ICU admission. Clinical data, drug administration, and severity of illness scores were recorded. Osmol gap and the amount of propylene glycol administered before serum sampling predicted propylene glycol concentrations (r(2)=0.692, p<0.05). Osmol gap alone also predicted serum propylene glycol concentrations (r(2)=0.532, p<0.05). Serum lactate concentrations did not correlate with serum propylene glycol concentrations. Unlike the low-dose and control patients, eight (62%) of 13 high-dose patients had osmol gaps above 10. All 13 high-dose patients had serum propylene glycol concentrations previously associated with toxicity. CONCLUSION: Osmol gap can be used as a surrogate marker for serum propylene glycol concentration. In critically ill patients receiving lorazepam for sedation, an osmol gap above 10 was associated with concentrations previously reported to cause toxicity.
Assuntos
Hipnóticos e Sedativos/farmacocinética , Ácido Láctico/sangue , Lorazepam/farmacocinética , Soluções Farmacêuticas/química , Propilenoglicol/sangue , Adolescente , Adulto , Idoso , Cuidados Críticos , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hipnóticos e Sedativos/administração & dosagem , Infusões Intravenosas , Modelos Lineares , Lorazepam/administração & dosagem , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Respiração Artificial , SolventesRESUMO
Propylene glycol (PG), a widely used solvent and lubricant, is thought to have low toxicity when ingested. Three cases were identified where PG, either alone or in combination with other chemical agents, contributed to death. The decedent in whom PG was the sole agent was a 32-year-old schizophrenic man with cardiomegaly and renal impairment. The blood PG concentration was 4410 mg/L at least 9.5 h following ingestion.