Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation

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.     

Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review

A 34-year-old woman with a history of renal insufficiency induced by long-term cocaine use was admitted with acute shortness of breath remarkable for submandibular and anterior throat swelling. She required intubation, mechanical ventilation, and sedation. Sedation was administered with daily infusions of intravenous lorazepam 65, 313, and 305 mg for 3 days, respectively. Forty-eight hours into the infusion the patient experienced anion gap metabolic acidosis with hyperlactatemia, hyperosmolality, and increased osmolal gap. Propylene glycol (PG), a component of lorazepam intravenous formulation, was considered the potential source of the metabolic abnormality. The patient received greater than 40 times the acceptable recommended amount of PG over 72 hours. Cessation of lorazepam produced major improvements in lactic acid, serum osmolality, and anion and osmolal gaps. The large PG exposure associated with long-term cocaine-induced renal insufficiency produced a toxic metabolic state. Agents containing PG should be avoided in patients with compromised renal function (creatinine clearance < or = 30 ml/min) induced by cocaine use.     

New toxicity data for the propylene glycol ethers - a commitment to public health and safety

Propylene glycol ethers are a class of solvents used in a wide array of industrial, commercial and consumer applications, such as in paints, cleaners and inks. A robust toxicity database exists for the propylene glycol ethers that provide strong product safety support. Standard toxicity studies conducted under good laboratory practices indicate a lack of genotoxic, developmental and reproductive hazards. Recent testing efforts have primarily focused in two areas: (1) examination of the chronic toxicity/oncogenicity potential of propylene glycol monomethyl ether (PGME) in rats and mice and (2) expansion of the developmental toxicity database to higher molecular weight P-series glycol ether derivatives (i.e. propylene glycol n-propyl ether (PGPE), propylene glycol n-butyl ether (PGBE) and dipropylene glycol n-butyl ether (DPGBE)). In PGME chronic toxicity/oncogenicity studies no treatment-related increases in the incidence of tumors occurred in either species. Like other previously tested P-series derivatives, PGPE, PGBE and DPGBE were negative in rodent and rabbit developmental toxicity studies. Collectively, the toxicity database for P-series glycol ether products continues to support the lack of significant health effects with proper use of the commercial products.     

A review of the comparative mammalian toxicity of ethylene glycol and propylene glycol.

The purpose of this article is to review and interpret the scientific literature on the mammalian toxicity of ethylene glycol (EG) and propylene glycol (PG), with the goal of comparing the toxicity of the two chemicals. This type of review may serve as the basis for risk management decision-making. Because EG is not a GRAS (generally recognized as safe) chemical, its uses are restricted when compared with PG; thus, certain routes of exposure are not relevant here for toxicological comparison (e.g., subcutaneous, intramuscular, and intravenous). Therefore, this review is focused on the oral, inhalation, and dermal routes of exposure. However, where toxicological data derived from an alternative route of exposure serve to eludicate mechanisms of toxicity, data from these routes are considered. Based on the review provided herein, the following conclusions can be drawn. From the standpoint of lethality, acute effects, and reproductive, developmental, and kidney toxicity, the toxicity of EG exceeds that of PG. Further, localized dermal effects from EG and PG are both mild, with data suggesting that PG may have a skin contact sensitization potential. Finally, PG exposure in laboratory animals has been associated with reversible hematological changes; no data were located for EG from which to draw a toxicological comparison.     

Derivation of inhalation toxicity reference values for propylene oxide using mode of action analysis: Example of a threshold carcinogen

Propylene oxide (PO) is an important industrial chemical used primarily in the synthesis of other compounds. Inhalation carcinogenesis studies in rodents, with no-observed-adverse-effect levels (NOAELs) of 100 and 200?ppm, have revealed that chronic, high exposure to PO can induce tumors at the site of contact. Despite these characteristics, there is no evidence that typical environmental or occupational exposures to PO constitute a health risk for humans. The nongenotoxic effects of PO (glutathione depletion and cell proliferation) that augment its DNA-reactive and non-DNA-reactive genotoxicity are expected to be similar in humans and rodents. Available evidence on mode-of-action suggests that cancer induction by PO at the site of contact in rodents is characterized by a practical threshold. Human toxicity reference values for potential carcinogenic effects of PO were derived based on nasal tumors identified in rodent studies and specified uncertainty factors. The 95% lower confidence limit on the dose producing a 10% increase in additional tumor risk (LED10) was calculated using the rat and mouse data sets. The human reference values derived from the rat and mouse LED10 values were 0.7 and 0.5?ppm PO, respectively. A similar noncancer reference value, 0.4?ppm, was derived on the basis of non-neoplastic nasal effects in rats.     

Acute tubular necrosis associated with propylene glycol from concomitant administration of intravenous lorazepam and trimethoprim-sulfamethoxazole

A 46-year-old morbidly obese man was admitted to the medical intensive care unit with respiratory failure. He required pressure-control ventilation and high levels of sedation with continuous-infusion lorazepam. He developed Stenotrophomonas maltophilia pneumonia; treatment included scheduled intravenous trimethoprim-sulfamethoxazole. Each of these drugs contain several hundred milligrams/milliliter of propylene glycol. On day 17 of his hospital course, 3 days after starting the trimethoprim-sulfamethoxazole, the patient developed acute renal failure consistent with acute tubular necrosis. Propylene glycol toxicity was suspected; therefore, all drugs containing propylene glycol were discontinued, and laboratory data were collected. A marked osmol gap, metabolic acidosis, and renal toxicity were attributed to both continuous and large intermittent doses of intravenous propylene glycol. Particular attention should be paid to the total amount of propylene glycol provided to patients from administered drugs. Patients in the intensive care setting who require high doses of intravenous lorazepam for sedation, as well as antimicrobial therapy with trimethoprim-sulfamethoxazole for treatment of either Stenotrophomonas maltophilia or Pneumocystis carinii pneumonia, may be at increased risk for propylene glycol toxicity and should be monitored closely.     

Comparative short-term inhalation toxicity of ethylene glycol monomethyl ether and propylene glycol monomethyl ether in rats and mice

Male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 100, 300, or 1000 ppm ethylene glycol monomethyl ether (EGME) or to 0, 300, 1000, or 3000 ppm propylene glycol monomethyl ether (PGME) 6 hr/day for a total of 9 days during an 11-day interval. Although structurally similar, the biological activities of the two materials were dramatically different. The high concentration of EGME (1000 ppm) had pronounced adverse effects on body weight gain, peripheral blood counts, bone marrow, testes, and lymphoid tissues. Similar but less pronounced changes also occurred in some animals in the 300 ppm EGME group. Exposure to 3000 ppm PGME resulted in increased liver weights in male rats as well as central nervous system depression and decreases in specific gravity of urine of both male and female rats. However, there were no gross or histopathologic changes in either rats or mice which could be attributed to exposure to PGME. Hence the treatment-related changes which occurred in rats and mice exposed to PGME vapors, even at the highest concentration (3000 ppm), would constitute, at most, a minimal effect. Although PGME and EGME have comparable vapor pressures, the potential hazard of exposure to PGME vapors appears to be distinctly less than to EGME vapors.     

Effect of energy on propylene glycol aerosols using the capillary aerosol generator

The CAG is being developed for pulmonary drug delivery. Liquids are pumped, heated and vaporized by the CAG, whence they nucleate and condense to form aerosols. This study characterized the effect of energy on the aerosolization process. With increasing energy, the CAG produced an increasing fine particle fraction (FPF) until "optimal aerosolization" was achieved between 40 and 45 J; this energy range agreed with that theoretically required to vaporize the dose of PG. Further increases in energy above this optimal range did not improve PG's aerosolization efficiency. Based on the energy, FPF and temperature profiles, it was possible to deduce the nature of the liquid flow-boiling during aerosol generation. The aerosol particle size went through a minimum, as energy was increased through the "optimal range." In the "energy excess" region, where additional energy increased PG vapor temperature and velocity, droplet sizes were increased primarily due to changes in the nucleation rates and supersaturation ratios affecting the nucleation and condensation processes occurring within the vapor jet. The in vitro MMAD of the PG aerosol changed as a function of the applied energy, suggesting that for any pharmaceutical application, the choice of applied energy is critical to deposition profile of the aerosol.     

Pharmacokinetics of propylene glycol in the rabbit

Propylene glycol (PG) is widely used as a drug solvent in the pharmaceutical industry. However, it has produced central nervous system toxicity during chronic administration. The current study was undertaken to describe the pharmacokinetics of propylene glycol during acute and constant-rate intravenous dosing, using the rabbit as an animal model. In the acute dosing experiment, metabolism of PG was the dominant disposition pathway, characterized by concentration-dependent metabolic clearance. Renal excretion of PG accounted for only 2.4 to 14.2% of the total dose following acute administration due to significant reabsorption in the rabbit kidney. An ascending-convex relationship exists between renal clearance and urine flow. During constant-rate intravenous infusion studies, there was a disproportionate relationship between infusion rate and steady-state concentration, providing further evidence for capacity-limited disposition kinetics. The ascending-convex relationship between renal clearance and urine flow was also apparent in the long-term infusion studies.     

Pharmacokinetics of propylene glycol in the rabbit

Propylene glycol (PG) is widely used as a drug solvent in the pharmaceutical industry. However, it has produced central nervous system toxicity during chronic administration. The current study was undertaken to describe the pharmacokinetics of propylene glycol during acute and constant-rate intravenous dosing, using the rabbit as an animal model. In the acute dosing experiment, metabolism of PG was the dominant disposition pathway, characterized by concentration-dependent metabolic clearance. Renal excretion of PG accounted for only 2.4 to 14.2% of the total dose following acute administration due to significant reabsorption in the rabbit kidney. An ascending-convex relationship exists between renal clearance and urine flow. During constant-rate intravenous infusion studies, there was a disproportionate relationship between infusion rate and steady-state concentration, providing further evidence for capacity-limited disposition kinetics. The ascending-convex relationship between renal clearance and urine flow was also apparent in the long-term infusion studies.     

顶空气相色谱法测定藻酸双酯钠丙二醇酯基取代程度

目的 建立藻酸双酯钠丙二醇酯基取代程度的气相测定方法。方法 利用强碱碱解藻酸双酯钠丙二醇酯基为1,2-丙二醇,按顶空气相色谱法进样分析。气相色谱柱为DB-WAX毛细管色谱柱（30 m×0.32 mm,0.5 μm）,载气为氮气,顶空平衡温度120℃,程序升温,氢火焰离子化检测器（FID）。结果 1,2-丙二醇质量浓度在0.1~3.0 mg·mL-1范围内线性关系良好（r=0.9995）,精密度RSD小于3%。 结论 该方法灵敏度高、准确性好,有助于完善藻酸双酯钠质量标准研究,减少不良反应的发生。     

Development of a microbial toxicity monitor

In context of the current state of microbial toxicity monitoring systems, a need was recognized for further work on dissolved oxygen (DO) monitoring technique to establish the concept's validity and to improve upon both sensitivity and design using the experience of existing variations covered in the literature. Higher flow velocity, no moving parts, removal of the DO probe from direct contact with the aeration chamber, and a packed bed biofilter were the design features incorporated into the microbial toxicity monitor (MTM) described herein. Results obtained from testing five heavy metals, four organics and pH indicated that there was a direct relationship between concentration of contaminants and MTM response. The MTM can be useful as a primary tier monitoring system because of its continuous flow operation, automation, low cost, and ease of maintenance.     

An attempt to clarify the influence of glycerol, propylene glycol, isopropyl myristate and a combination of propylene glycol and isopropyl myristate on human stratum corneum

The present study is a comparison of the influences of glycerol, propylene glycol (PG), isopropyl myristate (IPM) and a combination of PG and IPM (1/1; w/w) on human stratum corneum (SC) by means of differential scanning calorimetry (DSC) and wide and small angle X-ray-diffraction (WAXD and SAXD). The effects of glycerol and PG on SC structure can be attributed to their functional groups. In DSC transition temperatures of lipid fractions are decreased whereas SAXD long distances of lamellar phases reveal an additional interference due to an integration into hydrophilic regions of hexagonally packed lipids (PG) or orthorhombically packed lipids (glycerol). The increased repeat distance is attributed to the polar character of both molecules. However, with IPM the long distance remains unaffected. IPM is integrated into the lipophilic regions of SC lipid matrix as concluded from an increase of WAXD reflections of orthorhombical lipids and a decrease of WAXD reflections of hexagonal lipids. The combination of PG/IPM affects SC microstructure in a specific manner. DSC shows a decrease in transition temperatures of the lipid fractions, although not as much as expected from the single substances. Additionally, the combination of IPM/PG affects the short distances of orthorhombically and hexagonally packed lipids in WAXD measurements similar as PG alone, whereas the long distance seems to remain unaffected as in the case of IPM pretreatment. Adjuvants with penetration enhancing potential reveal different effects on SC lipid microstructure, which have to be kept in mind in terms of formulating systems for transdermal administration.     

Development of a simple spectrophotometric method for propylene glycol detection in tablets

A simple spectrophotometric procedure was developed and validated to indirectly assess the quantities of propylene glycol (PG) remaining in compressed liquid/powder admixtures. Such simplified quantitation may facilitate several testing procedures related to various aspects of formulation development and material testing of pharmaceutical powder excipients using various nonvolatile liquids as the diluents. In the present study, this new and simple approach for PG quantitation was developed as an integral part of a new method termed the liquisolid compressibility (LSC) test, used to characterize the compaction behavior of powder excipients. According to LSC testing, several admixtures of a nonvolatile liquid (in this case PG) and a powder, differing in their PG/powder weight ratio, are compressed in order to assess their compactabilities. The PG content of such compacts may then be directly quantitated by the USP gas chromatographic method or, indirectly, by this new simple spectrophotometric procedure. The new approach involves the addition of a dye marker to the PG prior to its incorporation into the powder. After compression, the PG amount remaining in the compacts may be determined by simply extracting the dye from the tablets and analyzing the extracts spectrophotometrically. In this manner, the dye content thus obtained may be extrapolated to the respective net amount of PG originally added as a dye/PG solution to the powder. Statistical comparison of the results obtained from both methods revealed almost absolute correlation.     

紫外分光光度法测定1，2-丙二醇中醛类物质含量的研究

目的建立UV法测定1,2-丙二醇中的醛类物质。方法以醛类物质与盐酸甲基苯并噻唑酮反应后再加三氯化铁显色为原理,以甲醛为对照品,在655nm处测吸光度来计算1,2-丙二醇中醛类物质的含量。结果醛类物质在655nm处有吸收,醛类浓度在0．00909～0．2273μg·mL^-1线性关系良好,回归方程为Y=2．418X＋0．009,（r=1．0000）,平均回收率99．5％（n=6）,RSD为1．6％。结论本方法快速、准确,重现性好,可用于测定1,2-丙二醇中醛类物质的含量。     

Impaired performance and sedation after a single dose of lorazepam

In a double-blind cross-over study using normal student volunteers, the effects of 1 and 2.5 mg lorazepam on self-rated mood and bodily symptoms, as well as performance in a number of tests were assessed. Both doses significantly increased self ratings of physical and mental sedation, the effects being more marked 4 h after drug administration than after 1 h. Lorazepam impaired simple reaction time, verbal learning, number cancellation, symbol copying and performance in the digit-symbol substitution test. The impairments were greater with the 2.5 mg dose and were more marked 4 h after drug administration than after 1 h.