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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.

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.

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.

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.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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.

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., (© The Author(s) 2013.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Objectives: The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol concentrations. Secondary objectives were a) to document the occurrence of propylene glycol accumulation associated with continuous high-dose lorazepam infusion; b) to assess the relationship between lorazepam dose, serum propylene glycol concentrations, and propylene glycol accumulation; and c) to assess the relationship between the osmol gap and serum propylene glycol concentrations., Design: Prospective, observational study., Setting: Tertiary care, medical intensive care unit., Patients: Nine critically ill adults receiving high-dose lorazepam (> or =10 mg/hr) infusion., Interventions: Cumulative lorazepam dose (mg/kg) and the rate of infusion (mg.kg(-1).hr(-1)) were monitored from initiation of lorazepam infusion until 24 hrs after discontinuation of the high-dose lorazepam infusion. Serum osmolarity was collected at 48 hrs into the high-dose lorazepam infusion and daily thereafter. Serum propylene glycol concentrations were drawn at 48 hrs into the high-dose lorazepam infusion, and the presence of propylene glycol accumulation, as evidenced by a high anion gap (> or =15 mmol/L) metabolic acidosis with elevated osmol gap (> or =10 mOsm/L), was assessed at that time., Measurements and Main Results: The mean cumulative high-dose lorazepam received and mean high-dose lorazepam infusion rate were 8.1 mg/kg (range, 5.1-11.7) and 0.16 mg.kg(-1).hr (-1)(range, 0.11-0.22), respectively. A significant correlation between high-dose lorazepam infusion rate and serum propylene glycol concentrations was observed (r =.557, p =.021). Osmol gap was the strongest predictor of serum propylene glycol concentrations (r =.804, p =.001). Propylene glycol accumulation was observed in six of nine patients at 48 hrs. No significant correlation between duration of lorazepam infusion and serum propylene glycol concentrations was observed (p =.637)., Conclusion: Propylene glycol accumulation, as reflected by a hyperosmolar anion gap metabolic acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam infusion for > or =48 hrs. Study findings suggest that in critically ill adults with normal renal function, serum propylene glycol concentrations may be predicted by the high-dose lorazepam infusion rate and osmol gap.

Objectives: Using data from patients who developed elevations in serum creatinine concentrations while receiving continuous-infusion lorazepam, we sought to determine the correlations between the magnitude of serum creatinine concentration rise and each of the following variables: serum propylene glycol level, cumulative lorazepam dose, and duration of lorazepam administration. An additional objective was to identify clinical markers for propylene glycol toxicity., Design: Retrospective chart review., Setting: Medical-surgical intensive care unit and burn unit at a university hospital., Patients: Eight patients who developed elevations in serum creatinine concentrations while receiving continuous-infusion lorazepam (range 2-28 mg/hr)., Measurements and Main Results: The mean cumulative dose of lorazepam was 4305 mg (range 1200-10,920 mg), and the mean propylene glycol level determined at the time of peak serum creatinine concentration was 1103 microg/ml (range 186-3450 microg/ml). Serum creatinine concentrations increased in all eight patients during lorazepam infusion and decreased in seven within 3 days after stopping infusion. A weak-to-moderate correlation existed between the magnitude of the rise in serum creatinine concentration and propylene glycol level (r=0.53). A weak-to-moderate correlation also was identified between cumulative lorazepam dose and magnitude of serum creatinine concentration rise (r=0.43), and a strong-to-moderate correlation was found between duration of lorazepam infusion and magnitude of serum creatinine concentration rise (r=0.60). Propylene glycol levels were strongly correlated with both serum osmolality and osmol gap., Conclusion: The patients' increased serum creatinine concentrations are likely to have resulted from exposure to propylene glycol as a result of lorazepam infusion. Serum osmolality and osmol gap may be useful markers for propylene glycol toxicity.

The case of a 49-year-old alcoholic man with obtundation is presented. The patient was presumptively diagnosed with methanol intoxication due to the presence of metabolic acidosis with high anion and osmolar gaps. Laboratory testing revealed toxic levels of propylene glycol instead. An exercise in estimating the concentration of toxic alcohols and glycols is given, and the literature on poisoning with this unusual but commonly encountered intoxicant is briefly reviewed.

Objective: To determine if propylene glycol accumulates in children receiving continuous lorazepam infusion and, if accumulation occurs, to determine if it is associated with significant laboratory abnormalities., Design: Prospective study., Setting: A tertiary care pediatric intensive care unit., Patients: Eleven intubated pediatric intensive care patients receiving continuous lorazepam infusion for sedation., Interventions: Propylene glycol accumulation was determined by comparing concentrations at baseline, after 48 hrs, and at end of therapy. Laboratory abnormalities were determined by comparing serum lactate and osmolar gap at baseline, after 48 hrs, and at end of therapy. Correlation between the cumulative dose of lorazepam received and the propylene glycol concentration measured at the end of therapy was determined., Measurements and Main Results: Patients aged 1-15 months were studied. Lorazepam infusion rates ranged from 0.1 to 0.33 mg.kg.hr and lasted 3-14 days. Propylene glycol accumulated significantly in patients receiving continuous infusion of lorazepam. The propylene glycol concentration increased during the study from 86 +/- 93 microg/mL at baseline to 763 +/- 660 microg/mL at the end of the study ( p=.038). A statistically significant correlation between the cumulative dose of lorazepam received and propylene glycol concentration at the end of therapy was demonstrated ( r(2)=.65, p<.005). However, the propylene glycol accumulation was not associated with significant laboratory abnormalities. Neither serum lactate concentrations nor osmolar gap were significantly elevated over baseline., Conclusion: Propylene glycol accumulated significantly in pediatric intensive care patients receiving continuous lorazepam infusion, and propylene glycol concentration correlated with the cumulative lorazepam dose the patient received. However, significant laboratory abnormalities due to propylene glycol accumulation were not observed.

Implications: We report a case of toxicity from the drug solvent propylene glycol resulting from prolonged, large-dose lorazepam infusion. The case is unusual in that toxicity developed during continuous veno-venous hemofiltration with dialysis, a renal replacement therapy that should been have been effective at eliminating the chemical and its metabolites.

Background: We describe a case of acute propylene glycol toxicity following ingestion of ethanol and propylene glycol-containing antifreeze in which blood lactate, serum propylene glycol, ethanol, and CO2 concentrations were serially measured., Case Report: A 61-year-old man was hospitalized after acute ingestion of ethanol and automotive antifreeze. His clinical presentation and course were essentially unremarkable. Initial lab tests revealed serum ethanol concentration, 167 mg/dL, normal serum electrolytes and osmol gap, 120 mOsm/kg. Intravenous 10% ethanol infusion was begun for suspected ethylene glycol toxicity and discontinued at approximately 17 hours post-ingestion. Toxicological analysis of urine was positive for ethanol and propylene glycol, and negative for ethylene glycol, methanol, and isopropanol. Blood lactate was mildly elevated and serum CO2 concentration was normal. Gas chromatographic analysis of serial serum specimens for propylene glycol concentration revealed a maximum value of 470 mg/dL at 7 hours and a nonlinear decline to below detection limit (3 mg/dL) at 57 hours after antifreeze ingestion. The patient was discharged on hospital day 2., Conclusion: The propylene glycol elimination pattern, absence of significant acid-base disturbance, and minimal lactate elevation in this case are consistent with ethanol-related inhibition of propylene glycol metabolism. The effect of ethanol on clinical outcome after acute propylene glycol intoxication remains uncertain.

Epidemiological studies suggest that alcohol consumption is an independent risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM). Alcoholism is known to be associated with increased plasma levels of two novel diols, 2,3-butanediol and 1,2-propanediol, metabolites known to impair insulin action in isolated adipocytes. This study examines whether 2,3-butanediol and 1,2-propanediol have the capacity to impair insulin action acutely in vivo in the rat. Using the euglycemic-hyperinsulinemic clamp, it is shown that the two diols reduce whole-body glucose utilization (by approximately 30%), with the onset of insulin resistance in vivo occurring at plasma concentrations of 2,3-butanediol (33 micromol/L) at least one order of magnitude (P < .001) lower than 1,2-propanediol (432 micromol/L). Tracer methodologies using [U-14C]glucose and 2-deoxy[1-(3)H]glucose indicate that the reduction in whole-body glucose utilization is accompanied by a reduction in glucose uptake and glycogen synthesis in the skeletal muscle and heart. The association between elevated plasma diol levels and insulin resistance demonstrated in this report raises the question of whether there is a link between the high plasma diol levels in alcohol abusers and their increased susceptibility to NIDDM.