The Irrationality of the Present Use of the Osmole Gap

The present clinical use of serum osmometry is erroneous in two respects. The first, and the most important, is the incorrect assumption that serum behaves as a dilute ‘ideal’ solution and that the osmotic activity of a substance depends solely on the number of solute particles. The amount of variance from ideal behaviour of serum containing an exogenous substance is expressed by the osmotic coefficient (?). We have calculated the osmotic coefficient for serum containing ethanol (alcohol) and recommend that the osmotic coefficient for serum containing other low molecular weight substances such as methanol (methyl alcohol), isopropyl alcohol and ethylene glycol also be calculated. This is necessary for the accurate calculation of the contribution of these substances to the serum osmolality. Secondly, the practice of subtracting the calculated serum molarity from measured serum osmolality is not valid since it represents a mathematically improper expression. The units of these two terms are different. The ‘osmole gap’ (OG) is typically viewed as the difference between serum osmolality determined by an osmometer and the estimated total molarity of solute in serum by directly measuring the concentration of several substances and then substituting them into a published formula. Some authors call this sum the calculated or estimated osmolarity but, because the concentrations are measured directly and not with an osmometer, the calculated term represents molarity. The units of osmolality are mmol/kg of H₂O and the units of molarity are mmol/L. Therefore, the practice of subtracting calculated serum molarity from measured serum osmolality is not mathematically sound and is an oversimplification for ease of application. This mathematical transgression necessarily adds an error to the incorrectly calculated OG. Despite this, the OG is commonly used in clinical medicine. Serum osmolality can be converted to molarity provided the weight percentage and the density of the solution are known and thus, we recommend that this conversion be done prior to calculation of the gap. We recommend that the gap between measured serum osmolarity and calculated serum molarity be called the ‘osmolar gap’. After having corrected for non-ideality for serum and for inconsistency of units, the standard value and reference range for this gap must be determined in an adequate number of patient populations and in a variety of clinical settings. An example of this determination, using data from a group of ethanol-poisoned patients is given. This correction should be applied before the evaluation of the osmolar gap as a screening test for other low molecular weight substances proceeds.     

The use of the osmole gap as a screening test for the presence of exogenous substances

The rapid and accurate diagnosis of toxic alcohol poisoning due to methanol (methyl alcohol) [MeOH] and ethylene glycol (EG), is paramount in preventing serious adverse outcomes. The quantitative measurement of specific serum levels of these substances using gas chromatography is expensive, time consuming and generally only available at major tertiary-care facilities. Therefore, because these toxic substances are osmotically active and the measurement of serum osmolality is easily performed and more readily available, the presence of an osmole gap (OG) has been adopted as an alternative screening test. By definition, the OG is the difference between the measured serum osmolality determined using the freezing point depression (Osm(m)) and the calculated serum molarity (Mc), which is estimated from the known and readily measurable osmotically active substances in the serum, in particular sodium, urea, glucose, and potassium and ethanol (alcohol). Thus, the OG=Osm(m)-Mc, and an OG above a specific threshold (the threshold of positivity) suggests the presence of unmeasured osmotically active substances, which could be indicative of a toxic exposure. The objectives of this study were to review the principles of evaluating screening tests, the theory behind the OG as a screening test and the literature upon which the adoption of the OG as a screening test has been based.This review revealed that there have been numerous equations derived and proposed for the estimation of the Mc, with the objective of developing empirical evidence of the best equation for the determination of the OG and ultimately the utility of OG as a screening test. However, the methods and statistical analysis employed have generally been inconsistent with recommended guidelines for screening test evaluation and although many equations have been derived, they have not been appropriately validated.Specific evidence of the clinical utility of the OG requires that a threshold of positivity be definitively established, and the sensitivity and specificity of the OG in patients exposed to either EG or MeOH be measured. However, the majority of studies to date have only evaluated the relationship between the Osm(m) (mmol/kg H2O) and the Mc (mmol/L) in patients that have not been exposed to either MeOH or EG. While some studies have evaluated the relationship between the OG and serum ethanol concentration, these findings cannot be extrapolated to the use of the OG to screen for toxic alcohol exposure. This review shows that there has not been an appropriately designed empirical evaluation of the diagnostic utility of the OG and that its clinical utility remains hypothetical, having been theoretically extrapolated from the non-poisoned population.     

吡诺克辛钠滴眼液渗透压测定

目的:探讨渗透压计测定吡诺克辛钠滴眼液渗透压摩尔浓度方法的可行性和准确性。方法:使用渗透压计测定吡诺克辛钠滴眼液的渗透压摩尔浓度,并对其渗透压摩尔浓度进行稳定性考察。结果:不同配方吡诺克辛钠滴眼液的渗透压摩尔浓度符合眼用制剂的要求。经过室温留样渗透压摩尔浓度没有明显变化,表明该制剂质量稳定。结论:该方法简便、快速、实用,可作为吡诺克辛钠滴眼液渗透压检测的方法。     

Osmolality/osmolarity data and calculations.

In view of the increasing interest in the osmolarity of parenteral solutions, an extensive compilation of pertinent numerical data is described. This compilation tabulates values of density, molar concentration, freezing point lowering,real osmolality, and molar concentration of the isotonic sodium chloride solution for 99 compounds, two-thirds of which are of use in pharmacy. A wide range of concentrations is covered for each compound, the values being listed in increments of 0.50, 1.00, or 2.00 percent w/w. Simple equations to convert molar into molal concentrations and to correlate freezing point lowering, osmotic pressure, osmolality and molality are presented. The practical use and theoretical meaning of the osmotic coefficient are discussed. As an example of a solution with several solutes, the real osmolality and osmolarity of Ringer's Solution is computed from the tabulated values of the freezing point depressions of the component salts.     

Serum osmolal gap and ethanol concentration: a simple and accurate formula

The estimation of serum ethanol concentration by measurement of serum osmolality has been re-evaluated. A formula for calculation of serum osmolality was first validated in 193 patients who had not ingested ethanol. The mean difference between measured and calculated osmolality ("osmolal gap") was 1.5 mOsm/Kg +/- 5.3 mOsm/Kg (1 S.D.). In 37 sera from 35 patients who had ingested ethanol, the osmolal gap was highly correlated with measured serum ethanol (r = 0.994). The serum ethanol (mmol/L) was related to osmolal gap (mOsm/Kg) by the formula: Ethanol = 0.83 X osmolal gap. The factor 0.83 indicated that the behavior of ethanol in serum did not conform to that expected from ideal solutions. This equation accurately predicted serum ethanol in 32 additional samples (r = 0.988). We propose that the formula above be used in place of those that have been previously proposed. The previous formulas involved unwarranted assumptions of ideality and had not been experimentally derived from studies of ethanol in serum.     

Compliance with USP osmolarity labeling requirements.

In view of the USP requirement that the label of certain parenteral products contain the osmolarity of the solution, actual and theoretical osmolarity values for six preparations were determined, and the extent of any deviation was noted. Osmolarity values were determined experimentally by osmometry and converted to osmolarity values for six products: Calcium Chloride Injection USP, Dextrose Injection USP, Mannitol Injection USP, Potassium Chloride Injection USP, Sodium Bicarbonate Injection USP, and Sodium Chloride Injection USP. Theoretical values were calculated according to a standard equation based on the mass of the substance per liter of solution. The most substantial deviations between actual and theoretical osmolarity values occurred with the calcium chloride, sodium bicarbonate, potassium chloride and dextrose solutions. It is proposed that the technology for making osmotic measurements which exists in the industrial setting should be used to provide clinical practitioners with accurate and actual values. It is also urged that the USP specify a procedure for measuring osmolality and calculating actual osmolarity.     

Concentration guidelines for parenteral antibiotics in fluid-restricted patients

A guideline for the preparation of peripherally administered antibiotics in fluid-restricted patients was developed. A maximum osmolality of 560 mOsmol/kg was selected since this corresponds to the theoretical osmolality of dextrose 5% in NaCl 0.9%, a solution commonly administered peripherally without significant incidence of phlebitis. Percentage concentrations corresponding to 560 mOsmol/kg of 26 intravenous antibiotics were calculated using sodium chloride equivalents. The antibiotics were reconstituted using sterile water, dextrose 5%, and NaCl 0.9% to provide an osmolality of 560 mOsmol/kg. The resulting solutions were measured for osmolality using a freezing-point depression osmometer. A total of 78 solutions were prepared and measured in triplicate. Of the 78 measured osmolalities, 67 (86 percent) were within 20 percent of the desired 560 mOsmol/kg. Only two osmolalities were more than 10 percent above the projected value. The percentage concentrations of 26 antibiotics in three solutions corresponding to 560 mOsmol/kg are presented. A method is also provided for tailoring concentrations to achieve desired osmolalities other than 560 mOsmol/kg.     

Determination of a lorazepam dose threshold for using the osmol gap to monitor for propylene glycol toxicity

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.     

The use of a thermoelectric osmometer to measure the osmotic coefficients of aqueous solutions of sodium salicylate at 25°

The use of a thermoelectric osmometer to measure osmotic coefficients for the binary system water-sodium salicylate at low concentrations (0·0 to 0·3 molal) is described. The accuracy and reproducibility of the instrument have been enhanced by employing a microscope to measure sample and reference drop sizes. Activity coefficients, calculated from the osmotic coefficients obtained in these experiments, have been combined with density and diffusional measurements to calculate frictional coefficients for the system.     

Osmotic Properties of Sulfobutylether and Hydroxypropyl Cyclodextrins

Purpose. The purpose of this study was to determine the osmolality of sulfobutylether (SBE) and hydroxypropyl (HP) derivatives of cyclodextrins (CDs) via vapor pressure osmometry (VPO) and freezing point depression (FPD). (SBE) and HP-CDs are efficient excipients capable of solubilizing and stabilizing poorly water-soluble drugs in parenteral formulations. (SBE)-CDs have also been used as solubility enhancers and osmotic agents for the sustained release of poorly water-soluble drugs from osmotic pump tablets. The knowledge of the CD's osmolality in solution or inside such tablets would allow one to further characterize the release mechanisms. Methods. Experiments were conducted at 37°C with eight types of HP and (SBE)-CDs. The aqueous solutions ranged from 0.005-0.350 mol l^{– 1}. Methods were developed to allow the measurement of high osmolalities using a vapor pressure osmometer or a differential scanning calorimeter. Results. The osmolality calculations from the VPO and FPD measurements correlated well. The osmolality of (SBE)-CDs was significantly higher than the osmolality of HP-CDs and increased with the total degree of substitution (TDS). All CDs showed deviations from ideality at high concentrations. Conclusions. Empirical correlations of osmolality with concentration and TDS allowed the prediction of osmolality over a wide concentration range. This study also gave some useful insights into the behavior of CD derivatives in solution.     

The Use of Δ Osmolality to Predict Serum Isopropanol and Acetone Concentrations

We investigated whether serum Δ osmolality will predict the total serum concentration of isopropanol and acetone metabolite. Three isopropanol ingestions were monitored by Δ osmolality determinations followed by quantification of serum isopropanol and acetone concentrations. The Δ osmolality was established by routine chemical analysis and standard freezing point depression osmometry. Serum isopropanol and acetone levels were quantified by gas chromatography-head space analysis (GC-HS). Patients were initially suspected of having isopropanol intoxication secondary to an elevated Δ osmolality discrepancy (measured - calculated > 10 mOsm). Serum concentrations versus Δ osmolality were analyzed by linear regression (correlation coefficient r=0.713; p<0.05). The Δ osmolality paralleled and decreased relative to the total low molecular weight of volatile concentration in each case. In emergencies, Δ osmolality may be a screening test to identify rapidly patients at risk for complications associated with isopropanol ingestion when GC-HS is not available.     

冰点下降法测定流感病毒裂解疫苗的渗透压摩尔浓度

目的:考察国内流感病毒裂解疫苗的渗透压摩尔浓度,为提高该品种的国家标准提供依据。方法:按照中国药典2010年版三部附录,采用冰点下降法测定市售6家企业生产的54批流感病毒裂解疫苗的渗透压摩尔浓度。结果:所考察产品的渗透压摩尔浓度范围在261～308 mOsmol.kg-1之间。结论:所考察产品的渗透压摩尔浓度值存在一定差异,因渗透压摩尔浓度是考察流感病毒裂解疫苗安全性的一项重要指标,在流感病毒裂解疫苗成品质量标准中增加渗透压摩尔浓度检查项是必要的。     

宫腔镜电切术中灌洗液吸收对患者血生化指标的影响

目的了解宫腔镜手术中灌洗液的吸收对患者血生化指标的影响。方法选择宫腔镜电切术患者60例,以5%葡萄糖作为膨宫介质,于术前、术毕、术后1、3h分别采静脉血测定血清钠、氯、钾、CO2-CP、尿素氮、肌酐、血浆渗透压、阴离子间隙及血糖等指标,结果应用SPSS10.0统计软件进行分析。结果60例患者除1例液体吸收超过2000ml者出现轻微恶心外,无手术并发症的发生。术后血清钠、钾、血浆渗透压、阴离子间隙、尿素氮均较术前明显下降,血糖较术前明显升高(P<0.05)。其中血清钠、尿素氮、血浆渗透压、阴离子间隙于术后1h最低,而血糖的最高值及血钾最低值均出现在手术结束时,术后3h各项指标逐渐恢复正常。结论宫腔镜电切术中灌洗液的吸收可导致一过性血清钠、钾、尿素氮、血糖、血浆渗透压及阴离子间隙的改变,减少灌洗液的吸收,术中术后严密监测血生化指标的变化是宫腔镜手术成功与安全的关键。     

Osmolality of parenteral solutions.

Osmolality-concentration profiles for individual and mixed solute systems are presented. Linear relationships between osmolality and concentration held true in all systems examined at concentrations below 0.2 molal levels. At higher concentrations, linearity existed only in select systems. Deviations from linearity can be greater or less than extrapolated values. In view of the need to determine an osmolarity conversion factor for each parenteral formulation and the many errors possible in the use of these values, adoption of osmolality values for labeling parenteral products rather than osmolarity, as stipulated in USP XIX-NF XIV third supplement, strongly recommended.     

Propylene Glycol: The Safe Diluent that Continues to Cause Harm

Propylene glycol (PG) is present in many pharmaceutical products, lotions, ointments, and cosmetics. Although considered to be a relatively safe substance, overdoses have been associated with serious adverse effects. Propylene glycol intoxication occurred in a child and caused central nervous system depression and a severe metabolic acidosis. Initial assessment revealed an elevated serum anion gap, a slight increase in measured serum osmolality, and a normal osmolal gap. The child's acidosis was due to increased concentrations of lactate and pyruvate. The possibility of serious PG intoxication should be considered in any patient with an unexplained serious metabolic acidosis.     

Indicators of dehydration and haemoconcentration are associated with the prevalence and severity of coronary artery disease

1. The vascular endothelium is injured by blood flow abnormalities exacerbated by different risk factors, including markers of haemoconcentration. The aim of the present study was to assess the association between markers of haemoconcentration and dehydration and the prevalence and severity of coronary artery disease (CAD). 2. Subjects in the present study (189 men and 126 women) were classified as either CAD cases or controls according to the results of coronary angiography. The severity of CAD was scored on the basis of the number and the extent of lesions on coronary arteries. Serum electrolytes, osmolality and haematological parameters were measured. 3. Compared with control subjects, patient with CAD had increased levels of serum osmolality, calculated osmolality, tonicity, sodium, glucose and blood urea nitrogen (BUN). Significant differences were also observed in the haematocrit and haemoglobin concentration, but not in erythrocyte counts and total serum protein. On multiple logistic regression analysis adjusting for major risk factors, serum osmolality, glucose and BUN exhibited significant associations with CAD, but the correlations were lessened by diabetes. Analysis using anova showed a significant correlation between serum osmolality, sodium, glucose and BUN and the severity of CAD. The area under the receiver operating characteristic curves, as a relative measure of the test's efficiency, was the highest and significant for serum osmolality, BUN and glucose. 4. The results indicate that some of the markers of dehydration and haemoconcentration are associated significantly with the prevalence and severity of CAD, but the independence of these correlations is questioned. These markers may play a role in the pathogenesis of atherosclerosis.     

Effects of dose, pH, and osmolarity on nasal absorption of secretin in rats. II: Histological aspects of the nasal mucosa in relation to the absorption variation due to the effects of pH and osmolarity

Nasal absorption of secretin in rats was enhanced in an acid solution, and the maximum absorption was observed at a sodium chloride solution molarity of 0.462. In order to examine reasons for the variation of absorbability caused by the change of pH and osmolarity in secretin preparations, both a pretreatment study, in which the nasal mucosa was treated with placebo prior to the administration of a secretin preparation, and a histological study were conducted in rats. The nasal absorption of secretin was determined by measuring the increased secretin of pancreatic juice. Similar profiles of nasal absorption, both after intranasal administration of secretin preparations and as a result of pretreatment effects, were obtained in studies of the effects of pH and osmolarity. However, in the pH-effect study, the absorption with the use of active preparations was observed to be significantly larger than that with the pretreatment effect below a pH of 4.79, and significantly smaller than that with the pretreatment effect at a pH of 7 to 8. The results of histological studies revealed structural changes of the epithelial cells of the nasal mucosa at pH 2.94, and shrinkage of epithelial cells was observed at a sodium chloride solution molarity of 0.462.     

Osmolality of small-volume intravenous admixtures

Osmolalities of commonly administered small-volume i.v. admixtures were determined, and use of diluents with lower osmolality to achieve osmolality values less than 400 mOsm/kg was studied. The theoretical osmolality of 218 hypothetical admixtures of various concentrations of 34 injectable drugs in 50- or 100-mL quantities of 5% dextrose injection or 0.9% sodium chloride injection was calculated using sodium chloride equivalents. If the calculated osmolality value was greater than 400 mOsm/kg, an actual admixture was prepared and osmolality and density were measured. To determine how admixtures with osmolality values less than 400 mOsm/kg could be prepared, theoretical osmolality was calculated using 0.45% sodium chloride injection or sterile water for injection as the diluent. The calculated osmolality value was greater than 400 mOsm/kg for 52 (23.9%) of the 218 admixtures tested. Of the 52 measured osmolality values, 47 were within 15% of the calculated value. Calculated osmolality values for all admixtures were less than 400 mOsm/kg when 0.45% sodium chloride injection or sterile water for injection was used as the diluent. Admixture osmolality should be considered when preparing drugs for i.v. injection. For drugs with high osmolalities, 0.45% sodium chloride injection or sterile water for injection may be used as the diluent.     

盐酸洛美沙星注射液中氯化钠含量的讨论

目的：计算调节盐酸洛美沙星注射液渗透压需要的氯化钠量。方法：采用药剂学中的冰点降低数据法、溶质摩尔浓度计算法和渗透浓度计算法。结果：0．22％的本品100ml等渗溶液需氯化钠0．88g。结论：含0．88％(g／m1)的本品渗透压为298mosm／L,与血浆等渗。     

色甘酸钠滴眼液的质量评价研究

目的 从色甘酸钠滴眼液的溶液颜色、渗透压摩尔浓度、色甘酸钠含量和有关物质等方面开展一系列探索性研究,以期为色甘酸钠滴眼液的安全性和有效性作出更加合理的评价。方法 参照《中国药典》2015年版四部通则,对色甘酸钠滴眼液的溶液颜色进行目视法和色差计法检查,并测定其渗透压摩尔浓度;采用高效液相色谱法测定色甘酸钠滴眼液中色甘酸钠的含量,并与现行药典标准的紫外吸收系数法测定结果比较;在含量测定色谱条件下对13批次样品的有关物质相对含量进行测定。结果 色甘酸钠滴眼液的溶液颜色与性状描述的“无色或几乎无色”不符;渗透压摩尔浓度的测定结果显示,13批次样品中有10批次样品达不到等渗要求;含量测定结果表明,HPLC法测得的色甘酸钠含量略低于UV法所测含量;有关物质测定结果显示,色甘酸钠滴眼液的杂质相对含量总体较低,但随着贮藏时间的延长,杂质相对含量会增大。结论 色甘酸钠滴眼液现行质量标准性状描述不准确,缺乏渗透压摩尔浓度检查项,紫外吸收系数法测定色甘酸钠含量专属性差,易受干扰,不能有效地控制产品内在质量,建议修订质量标准。