UBC Faculty Research and Publications

An evaluation of the osmole gap as a screening test for toxic alcohol poisoning Lynd, Larry D; Richardson, Kathryn J; Purssell, Roy A; Abu-Laban, Riyad B; Brubacher, Jeffery R; Lepik, Katherine J; Sivilotti, Marco L Apr 28, 2008

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata


52383-12873_2007_Article_56.pdf [ 472.82kB ]
JSON: 52383-1.0223375.json
JSON-LD: 52383-1.0223375-ld.json
RDF/XML (Pretty): 52383-1.0223375-rdf.xml
RDF/JSON: 52383-1.0223375-rdf.json
Turtle: 52383-1.0223375-turtle.txt
N-Triples: 52383-1.0223375-rdf-ntriples.txt
Original Record: 52383-1.0223375-source.json
Full Text

Full Text

ralssBioMed CentBMC Emergency MedicineOpen AcceResearch articleAn evaluation of the osmole gap as a screening test for toxic alcohol poisoningLarry D Lynd*†1,2, Kathryn J Richardson†2, Roy A Purssell†3,4,5, Riyad B Abu-Laban†3,6, Jeffery R Brubacher†3,4,5, Katherine J Lepik†4 and Marco LA Sivilotti†7Address: 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada, 2Centre for Health Evaluation and Outcomes Sciences, Providence Health Care, Vancouver, Canada, 3Department of Emergency Medicine, Vancouver General Hospital, Vancouver, Canada, 4British Columbia Drug and Poison Information Centre, Provincial Health Services Authority of BC, Vancouver, Canada, 5Division of Emergency Medicine, Dept. of Surgery, Faculty of Medicine, University of British Columbia; Vancouver; Canada, 6Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Research Institute, Vancouver, Canada and 7Departments of Emergency Medicine and of Pharmacology & Toxicology, Queen's University, Kingston, Canada; and Ontario Poison Centre, Toronto, CanadaEmail: Larry D Lynd* - llynd@interchange.ubc.ca; Kathryn J Richardson - krichdsn@interchange.ubc.ca; Roy A Purssell - rpurssel@vanhosp.bc.ca; Riyad B Abu-Laban - abulaban@interchange.ubc.ca; Jeffery R Brubacher - jbrubacher@shaw.ca; Katherine J Lepik - klepik@cfenet.ubc.ca; Marco LA Sivilotti - marco.sivilotti@queensu.ca* Corresponding author    †Equal contributorsAbstractBackground: The osmole gap is used routinely as a screening test for the presence of exogenousosmotically active substances, such as the toxic alcohols ethylene glycol and methanol, particularlywhen the ability to measure serum concentrations of the substances is not available. The objectivesof this study were: 1) to measure the diagnostic accuracy of the osmole gap for screening forethylene glycol and methanol exposure, and 2) to identify whether a recently proposedmodification of the ethanol coefficient affects the diagnostic accuracy.Methods: Electronic laboratory records from two tertiary-care hospitals were searched toidentify all patients for whom a serum ethylene glycol and methanol measurement was orderedbetween January 1, 1996 and March 31, 2002. Cases were eligible for analysis if serum sodium,blood urea nitrogen, glucose, ethanol, ethylene glycol, methanol, and osmolality were measuredsimultaneously. Serum molarity was calculated using the Smithline and Gardner equation andethanol coefficients of 1 and 1.25 mOsm/mM. The diagnostic accuracy of the osmole gap wasevaluated for identifying patients with toxic alcohol levels above the recommended threshold forantidotal therapy and hemodialysis using receiver-operator characteristic curves, likelihood ratios,and positive and negative predictive values.Results: One hundred and thirty-one patients were included in the analysis, 20 of whom hadethylene glycol or methanol serum concentrations above the threshold for antidotal therapy. Theuse of an ethanol coefficient of 1.25 mOsm/mM yielded higher specificities and positive predictivevalues, without affecting sensitivity and negative predictive values. Employing an osmole gapthreshold of 10 for the identification of patients requiring antidotal therapy resulted in a sensitivityPublished: 28 April 2008BMC Emergency Medicine 2008, 8:5 doi:10.1186/1471-227X-8-5Received: 12 April 2007Accepted: 28 April 2008This article is available from: http://www.biomedcentral.com/1471-227X/8/5© 2008 Lynd et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 10(page number not for citation purposes)of 0.9 and 0.85, and a specificity of 0.22 and 0. 5, with equations 1 and 2 respectively. The sensitivityincreased to 1 for both equations for the identification of patients requiring dialysis.BMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5Conclusion: In this sample, an osmole gap threshold of 10 has a sensitivity and negative predictivevalue of 1 for identifying patients for whom hemodialysis is recommended, independent of theethanol coefficient applied. In patients potentially requiring antidotal therapy, applying an ethanolcoefficient of 1.25 resulted in a higher specificity and positive predictive value withoutcompromising the sensitivity.BackgroundSerum osmolality can be measured directly (the 'meas-ured osmolality') using osmometry, or estimated basedon the direct measurement of the concentrations of theprinciple osmotically active substances (i.e. sodium, glu-cose, blood urea nitrogen, and ethanol) and then substi-tuting these values into a formula to determine the'calculated molarity'. The difference between the meas-ured osmolality and the calculated molarity is referred toas the osmole gap [1,2]. The osmole gap is routinely usedto screen patients for the presence of other exogenousosmotically active substances such as ethylene glycol andmethanol, particularly when the ability to measure theserum concentrations of these substances is not available.Screening and diagnostic tests are generally used to clas-sify asymptomatic patients with respect to the likelihoodof the presence of a disease [3]. Screening tests are ideallysuited to detect diseases with a latent period betweenonset of disease (or time of exposure) and the develop-ment of overt symptoms, especially when the early diag-nosis and initiation of therapy improves prognosis [4,5].Toxic alcohol exposure meets these criteria given that seri-ous toxicity is preventable with early diagnosis and initia-tion of antidotal therapy. The rapid and accuratediagnosis of toxic alcohol poisoning is therefore crucial toprevent serious adverse outcomes.In a recent review of the medical literature we did notidentify any well-designed studies of the osmole gap as ascreening test for toxic alcohol exposure [1]. Numerousstudies have either proposed a formula or formulae forestimating serum osmolality [6-14], evaluated the rela-tionship between measured osmolality and calculatedmolarity in non-poisoned patient [6,7,10-12,14,15], ortested the ability of the osmole gap to predict serum etha-nol concentrations in patients exposed only to ethanol[13,16-22]. While none of these studies provide evidenceof the diagnostic performance of the osmole gap, theyform the basis for the widespread use of the osmole gap asa screening test for toxic alcohol exposure.To evaluate the osmole gap as a screening test, its perform-ance must be compared to a gold standard diagnostic test(e.g. gas chromatography) in a sufficient number ofthreshold of the osmole gap) [23]. We have not found anystudies published to date that satisfy these criteria. There-fore, the objectives of this study were: 1) to measure thediagnostic accuracy of the osmole gap for screening forethylene glycol and methanol exposure, and 2) to identifywhether a recently proposed modification of the ethanolcoefficient affects this diagnostic accuracy.MethodsSettingWe conducted a retrospective analysis of laboratoryrecords available from two tertiary care hospitals. Elec-tronic laboratory records from both hospitals weresearched to identify all patients with a serum ethylene gly-col and methanol measurement recorded between Janu-ary 1, 1996 and March 31, 2002. This study was approvedby the institutional ethics review boards.Selection of Study SubjectsCases were only eligible for inclusion in the analysis ifserum sodium, blood urea nitrogen, glucose, ethanol, eth-ylene glycol, methanol, and serum osmolality measuredusing freezing point depression were measured on blooddrawn at the same time. Cases were excluded if additionallaboratory results indicated lipemia, ketosis, dysproteine-mia, or hemolysis. Cases with a serum ethylene glycol andmethanol level of 0 mmol/L and an arterial pH below7.30 were deemed to have either a significant delaybetween exposure and clinical assessment, or anothercause for the acidemia, and were also excluded from theanalysis. In the event of multiple hospital visits only thefirst visit was included in the analysis.Methods of MeasurementIn both hospitals, serum electrolytes, BUN, glucose andethanol concentrations were determined using a high vol-ume analyzer (Beckman CX7, Model 7566, BeckmanInstruments, Inc. Fullerton, CA, USA) and serum osmola-lity was measured by freezing point depression (AdvancedMicro Osmometer model 3300, Advanced InstrumentsInc., Norwood, MA, USA). Serum concentrations of ethyl-ene glycol and methanol were determined using gas chro-matography (Hewlett Packard 5890A GasChromatograph, Hewlett Packard, Avondale, PA, USA),predefined as the gold standard for the diagnosis of toxicPage 2 of 10(page number not for citation purposes)patients at all levels of exposure with a specific definitionof what constitutes a positive test (i.e. the diagnosticalcohol exposure.BMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5Data AnalysisThe calculated molarity was obtained using the equationproposed by Smithline and Gardner which was deemed tobe the equation applied most frequently by clinicians[9,24,25]. The contribution of ethanol to the osmolarityof serum was incorporated using two different coeffi-cients: 1 mOsm/mM (equation 1), as has been standardpractice [13], and 1.25 mOsm/mM (equation 2) as pro-posed by Purssell et al. [18,26]. The osmole gap was thencalculated for each patient using both equations at thefirst instance when all required laboratory parameterswere measured simultaneously, provided that thisoccurred within 24 hours of the first recorded laboratorymeasurement.For the purposes of this analysis, a "positive exposure"was defined a priori as any serum ethylene glycol or meth-anol concentration above the recommended treatmentthresholds. Specifically, we evaluated the ability of theosmole gap to identify patients with a serum ethylene gly-col or methanol concentration above which antidotaltherapy (3 mmol/L and 6 mmol/L, respectively) or hemo-dialysis (8 mmol/L and 15 mmol/L, respectively) is rec-ommended [27,28].The diagnostic accuracy of each equation was determinedfor all possible cut-offs of the osmole gap using Receiver-Operator Characteristics (ROC) curves. Because anosmole gap of 10 is the most common clinically appliedcut-off for the diagnosis of potential toxic alcohol poison-ing [27,29], we calculated the sensitivity, specificity, andpositive and negative likelihood ratios of the test at thisthreshold. If the sensitivity was < 1.0, the hospital chart ofevery patient falsely classified as unexposed using this cut-off was reviewed to characterize their clinical course andoutcome. Based on the conclusions of a study byAabakken et al. [15], we also performed a secondaryexploratory analysis of the diagnostic performance of anosmole gap of 20.Receiver-operator characteristics curves were plotted usingboth equations for each treatment threshold. The areaunder the curve (AUC), or diagnostic index, was then cal-culated for each ROC curve. Non-parametric statisticalanalyses were used to determine whether the AUC foreach ROC curve differed significantly from 0.5. In order toidentify the equation with the best diagnostic perform-ance, the difference in the diagnostic index of each equa-tion was compared, using a non-parametric method thataccounts for correlation within individuals [30]. The pos-itive predictive value (PPV) and negative predictive value(NPV) of each equation was also calculated and plottedagainst all possible osmole gap cut-offs. All analyses wereUSA. 2003) and SAS v.8.02 (SAS Institute, Cary, NC, USA.1999).ResultsCharacteristics of Study SubjectsWe identified 235 patients with 240 hospital visits duringwhich serum ethylene glycol and methanol levels weremeasured by gas chromatography within 24 hours of theirfirst laboratory results (Figure 1). Five patients had twoseparate hospital visits with toxic alcohols measurements,so only the first visit was included in the analysis. Onehundred and three patients were excluded because theydid not have all required measurements performed onserum drawn at the same time; 51 had toxic alcohol levelsrequisitioned but not measured suggesting that they weredeemed to not be required (i.e. very low pre-test probabil-ity of exposure) and 37 had undetectable ethylene glycoland methanol concentrations. The remaining 15 patientshad detectable toxic alcohol serum concentrations, nineof which exceeded the threshold for antidotal therapy. Anosmole gap prior to the measurement of the toxic alcoholconcentration could only be calculated for two of thesepatients, both of which exceeded 10 using both equation1 and 2. One additional patient was excluded due to thepresence of acidosis and no detectable toxic alcohol.The final study population therefore included 131patients, 20 of whom were deemed 'exposed' (i.e. hadconcentrations above the threshold for antidotal therapy)to either ethylene glycol (n = 10), methanol (n = 9), orboth (n = 1). The only patient positive for exposure toboth ethylene glycol and methanol had serum concentra-tions of 3 mmol/L and 122 mmol/L, respectively. Seven-teen patients had serum ethylene glycol (n = 7) andmethanol (n = 10) concentrations above the threshold forhemodialysis.All detectable serum ethylene glycol concentrationsexceeded the threshold for treatment (i.e. 3 mmol/L),ranging from 3 to 68.7 mmol/L (median 6, IQR 19.3).Serum methanol concentrations in patients consideredexposed to methanol ranged from 16 to 202 mmol/L(median 56.4, IQR 100.3). Fourteen additional patientshad methanol levels below the threshold for antidotaltherapy, 11 of which had an osmole gap > 10 derivedusing equation 1 (mean OG 19.3, SD 15.4) versus onlyeight using equation 2 (mean OG 13.1, SD 18.1). Thesepatients were therefore considered false-positive expo-sures. Seventy-six patients (58%) had positive serum eth-anol levels (mean 44.2 mmol/L; range 0.3 to 135 mmol/L), seven of which exceeded 100 mmol/L.Main ResultsPage 3 of 10(page number not for citation purposes)performed using SPSS v 12.0. (SPSS Inc., Chicago, IL, The results of the primary analyses of the osmole gap foridentifying patients with toxic alcohol concentrationsBMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5above the threshold for antidotal therapy are illustrated inFigure 2, and the associated diagnostic indices are pre-sented in Table 2. Both equations resulted in an AUC thatdiffered significantly from 0.5 (p < 0.001) suggesting thatthe osmole gap provides at least some discriminatorydiagnostic information. Although equation 2 resulted in ahigher diagnostic index relative to equation 1 (0.785 ver-sus 0.736, respectively), this difference was not statisti-cally significant (two sided p = 0.06).Although the ROC curves and diagnostic indices associ-osmole gap (Figure 2). Applying an osmole gap cut-off of10 for the identification of patients requiring antidotaltherapy resulted in a sensitivity of 0.90 (95% CI, 0.68 –0.99) with a corresponding specificity of only 0.22 (95%CI, 0.14 – 0.30) (87/111 false positive diagnoses) withequation 1. Equation 2 resulted in a slightly lower sensi-tivity of 0.85 (95% CI, 0.62 – 0.97) as a result of 1 addi-tional false-negative case), but a higher specificity of 0.50(95% CI, 0.40 – 0.59). If applied clinically, the higher spe-cificity of equation 2 would have resulted in 31 fewerpatients receiving a false-positive diagnoses, all of whichFlow diagram outlining the derivation of the final study sampleigure 1Flow diagram outlining the derivation of the final study sample. Shaded boxes represent patients considered to be 'exposed' (i.e. ethylene glycol or methanol serum concentrations exceeding the threshold for antidotal therapy). Legend: All concentrations expressed as mmol/l. EG = ethylene glycol ME = methanol                                 Total ED visits n =240 Total Patients n = 235 103 excluded as did not have all required measurements drawn simultaneously within first 24 hours n = 132 Acidotic + ME & EG = 1 n = 1 Sample to analyze n = 131 Both EG and ME > 0 n = 4 ME & EG = 0 n = 97 Only ME >0 n = 22 Only EG > 0 n = 8 ME <6 n = 14 EG >8 n = 5 EG < 3 ME >15 n = 1 EG >8 ME <6 n = 2 ME >15 n = 8 3 d EG d8 n = 3 3 d EG d8ME >15 n = 1Page 4 of 10(page number not for citation purposes)ated with the two equations were similar, there were dif-ferences in their sensitivities and specificities at a givenhad serum ethanol concentrations >0 mmol/L. Equation2 also produced more favourable positive (LR+) and neg-BMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5ative (LR-) likelihood ratios of 1.68 (95% CI, 1.29 – 2.16)and 0.30 (95% CI, 0.10 – 0.72), respectively, versus 1.15(95% CI, 0.96 – 1.36) and 0.46 (95% CI, 0.11 – 1.30)respectively, for equation 1. Exploratory analysis of anosmole gap cut-off of 20 proposed by Aabakken et al. [15]resulted in a lower sensitivity with both equations 1 and 2(0.65; 95% CI 0.41 – 0.85) and correspondingly morefalse-negative diagnoses (n = 7), but a higher specificity(0.60; 95% CI 0.51 – 0.69, and 0.75; 95% CI 0.66 – 0.83with equations 1 and 2, respectively).Consistent with the results for the threshold for antidotaltherapy, equation 2 resulted in a higher diagnostic indexrelative to equation 1 for the identification of patientsrequiring hemodialysis (0.827 versus 0.870, respectively);however, this difference was not statistically significant (por methanol concentrations above the threshold forhemodialysis. A cut-off of 10 resulted in a sensitivity of1.0 (95% CI, 0.80 – 1.00) for both equations, but equa-tion 2 was more specific (0.51; 95% CI, 0.41 – 0.60 versus0.23; 95% CI, 0.15 – 0.32). The positive and negative like-lihood ratios for equation 2 at a cut-off of 10 were 2.04(95% CI, 1.68 – 2.44) and 0, respectively. Applying anosmole gap of 20 resulted in a decrease in sensitivity withboth equations (0.76; 95% CI 0.50 – 0.93) and a slightimprovement in specificity (0.61; 95% CI 0.52 – 0.70, and0.76; 95% CI 0.67 – 0.83 with equation 1 and 2, respec-tively).The PPV and NPV of all osmole gap cut-offs derived usingboth equations are illustrated in Figure 4. At an osmolegap cut-off of 10, the NPV of equations 1 and 2 were 0.92Receiver Operator Characteristics curves for the two equa-tions when used to identify patients with serum concentra-of thylene glycol and methanol that xceed he hre hold at which hemodialysis is recommendFigure 3Receiver Operator Characteristics curves for the two equations when used to identify patients with serum concentrations of ethylene glycol and metha-nol that exceed the threshold at which hemodialysis is recommended- - - - osmole gap derived using equation 1 (ethanol coeffi-cient of 1)----- osmole gap derived using equation 2 (ethanol coefficient of 1.25).The points delineated by   and   indicate an osmole gap cut-off of 10 derived using equations 1 and 2, respectively. The points delineated by   and  indicate an osmole gap cut-off of 20 derived using equations 1 and 2, respectively.Receiver Operator Characteristics curves for the two equa-tions when used to identify patients with serum concentra-of thylene glycol and me hanol that xceed he hre hold at which antidotal ther py is r com ndedFigure 2Receiver Operator Characteristics curves for the two equations when used to identify patients with serum concentrations of ethylene glycol and metha-nol that exceed the threshold at which antidotal therapy is recommended- - - - osmole gap derived using equation 1 (ethanol coeffi-cient of 1)------ osmole gap derived using equation 2 (ethanol coeffi-cient of 1.25).The points delineated by   and   indicate the cut-off of 10 derived using equations 1 and 2, respectively. The points delineated by   and  indicate the cut-off of 20 derived using equations 1 and 2, respectively.Page 5 of 10(page number not for citation purposes)= 0.056) (Table 2). Figure 3 illustrates the ROC curves forthe identification of patients with serum ethylene glycol(95% CI, 0.75 – 0.99) and 0.95 (95% CI, 0.86 – 0.99),respectively, for the identification of patients with levelsBMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5above the threshold for antidotal therapy (Panel a). Forthe identification of patients with levels above the hemo-dialysis threshold (Panel b), both equations had a NPV of1.0. The PPV of equation 2 was also consistently higher,independent of the osmole gap cut-off.Because a false negative diagnosis of toxic alcohol expo-sure may result in potentially life-threatening or long-term sequelae, we reviewed the health records of the threepatients with an osmole gap < 10 derived using eitherequation despite a serum ethylene glycol concentrationabove the threshold for antidotal therapy.Clinical Summary of False-Negative Cases (osmole gap threshold 10)Case 1A 55 year old male was admitted to an emergency depart-ment at least seven hours post-exposure to ethylene gly-col, obtunded and requiring intubation. Initial laboratoryresults revealed an anion gap metabolic acidosis (HCO3- 3mEq/L, anion gap 31.5) and an osmole gap of 143 (meas-Table 1: Equations used to calculate the serum molarity prior to the calculation of the osmole gap. Equation Number Equation1 Osmc = 2 * Na (mEq/L) + BUN (mmol/L) + glucose (mmol/L) + ethanol (mmol/L)2 Osmc = 2 * Na (mEq/L) + BUN (mmol/L) + glucose (mmol/L) + 1.25 * ethanol (mmol/L)Equation 2 in effect inflates the ethanol concentration by 25% prior to calculating the osmole gap, as proposed by Purssell et al.[18]Osmc = calculated molarity; Na = sodium; BUN = blood urea nitrogenTo convert from SI units, use the following corrections: BUN/2.8 mg/dl, glucose/18.1 mg/dl, ethanol/0.217 mg/dlThe Positive Predictive Value and Negative Predictive Value of osmole gap values ranging between -10 and 30 to identify toxic alcohol concentrations exce di g th  ntidotal therapy (Panel a) and hemodialysis (Panel ) hresholdsFigure 4The Positive Predictive Value and Negative Predictive Value of osmole gap values ranging between -10 and 30 to identify toxic alcohol concentrations exceeding the antidotal therapy (Panel a) and hemodialysis (Panel b) thresholdsBlack lines represent the positive predictive value.Grey lines represent the negative predictive value.- - - - osmole gap derived using equation 1 (ethanol coefficient of 1)Page 6 of 10(page number not for citation purposes)----- osmole gap derived using equation 2 (ethanol coefficient of 1.25)BMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5ured osmolality 446 mOsm/kg; calculated molarity 302.1mOsm/L derived using equation 2). The patient wastreated with intravenous ethanol, thiamine and folateprior to transfer to a tertiary care facility without confirm-atory methanol or ethylene glycol concentrations. How-ever, when all required laboratory parameters weremeasured simultaneously, he had an osmole gap of 7.8(derived using equation 2) and an ethylene glycol level of6 mmol/L. The patient underwent 13.5 hours of dialysisand developed acute renal failure with a peak creatinine of1,410 mmol/L nine days post-exposure, and was dis-charged from hospital 19 days post-exposure with a serumcreatinine of 613 mmol/L.Case 2A 51 year old female with a history of alcoholism, hepati-tis C, hypertension, non-insulin dependent diabetes mel-litus, and intravenous drug use was admitted to theemergency department following a near drowning epi-sode. Although she was initially unresponsive and cyan-otic, upon arrival at the emergency department she wasalert but confused. Initial lab results revealed an anion gapmetabolic acidosis (pH 7.1, HCO3- 11 mEq/L, anion gap27) with an osmole gap of 19.2 calculated using equation2. Three and one-half hours after admission (the timepoint used in this analysis), her serum ethylene glycol,methanol, and ethanol concentrations were 5 mmol/L, 0mmol/L, 54 mmol/L, respectively, with a correspondingosmole gap of 1.7 (calculated using equation 2). She didnot receive any further antidotal therapy or hemodialysisand was discharged following two days of hospitalizationwithout any adverse sequelae.Case 3A 50 year old developmentally delayed male with a priorhistory of ethylene glycol ingestion presented to the emer-gency department approximately 7.5 hours after an inten-tional ingestion of approximately 400 ml of ethyleneglycol. Twenty minutes after arrival, laboratory resultsrevealed an anion gap metabolic acidosis (arterial pH7.27, HCO3- 9.4 mEq/L, anion gap 18), an osmole gap ofated within one hour of presentation followed four hourslater by five hours and forty minutes of hemodialysis. Hisserum creatinine peaked five days post-exposure at 459mmol/L, following which he recovered completely.DiscussionThis is the first study to evaluate the osmole gap as ascreening test for toxic alcohol exposure that conforms tothe STARD criteria for reporting studies of diagnostic accu-racy [31]. In this sample, an osmole gap cut-off of 10derived using the Smithline and Gardner equation withethanol coefficients of 1 and 1.25 resulted in a relativelyhigh sensitivity (> 0.85) but a low specificity (< 0.50) andhigh NPVs for the identification of patients for whomantidotal therapy for toxic alcohol poisoning would beindicated. These results therefore indicate that althoughthis is not an ideal screening test, the osmole gap doesprovide additional diagnostic information. Specifically, aNPV of 0.95 for an osmole gap < 10 indicates a very highprobability that if a toxic alcohol has been ingested, theserum level is below the threshold for antidotal therapy.This analysis does not suggest that the osmole gap shouldbe used in isolation to provide the basis for discharging apatient without further clinical investigation or evalua-tion. However, it does indicate that the osmole gap doesprovide some additional diagnostic and prognostic infor-mation in terms of the probability that a patient will needantidotal therapy or hemodialysis. Using other clinicalinformation and laboratory data in conjunction with theosmole gap will increase the accuracy of the diagnosis.Using equation 2 to account for the supramolar contribu-tion of ethanol resulted in an increase in the specificity ofthe osmole gap without a significant reduction in sensitiv-ity. Although a screening test with a sensitivity of 1.0 ismost desirable in this clinical situation, achieving thiswould result in a low specificity and a corresponding highfalse-positive rate which could result in the unnecessaryinitiation of treatment in these patients. Although antido-tal treatment with either intravenous ethanol or fomepiz-ole is relatively benign, the cost-effectiveness of anyTable 2: Area under the curve (diagnostic index) for osmole gap to identify toxic alcohol exposure.Exposure Threshold AUC (95% CI) p value AUC2 - AUC1 (95% CI) p valueANTIDOTAL THERAPYEquation 1 0.736 (0.599, 0.873) < 0.001 0.049 (-0.001, 0.099) 0.057Equation 2 0.785 (0.665, 0.905) < 0.001HEMODIALYSISEquation 1 0.827 (0.715, 0.939) < 0.001 0.043 (-0.001, 0.086) 0.056Equation 2 0.870 (0.784, 0.956) < 0.001AUC = area under the curve; SE = standard error; CI = confidence intervalPage 7 of 10(page number not for citation purposes)9.8, and an ethylene glycol concentration of 5 mmol/L;ethanol was undetectable. An ethanol infusion was initi-screening test must incorporate all costs and potentialrisks of misdiagnosis and inappropriate initiation of treat-BMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5ment which might include unnecessary hospitalization,treatment, or transfer by air or road ambulance.Of the three exposed patients who may have been falselydiagnosed as unexposed using an osmole gap cut-off of10, two had an elevated osmole gap upon presentation tothe emergency department and would likely have beencorrectly diagnosed as exposed. The third patient had acompelling history of significant ethylene glycol inges-tion, an osmole gap of 9.8, and an anion gap metabolicacidosis when they arrived at the emergency room andwould also likely have been correctly diagnosed based onother available information.A survey of studies of diagnostic accuracy published infour major journals concluded that the methodologiesemployed were generally inadequate to answer the ques-tions posed [32]. The results of that survey lead to thedevelopment of the Standards for Reporting DiagnosticAccuracy (STARD) statement which consists of 25 criteriathat should be adhered to when evaluating the diagnosticaccuracy of a test [31,33]. This is the first formal evalua-tion of the diagnostic accuracy of the osmole gap that: i)includes subjects with all levels of exposure to ethyleneglycol or methanol; ii) evaluates the osmole gap com-pared to the gold standard; and iii) conforms to essen-tially all other STARD criteria.One of the necessary components of any screening testevaluation is a clear and valid definition of what consti-tutes a positive test [23]. Although Aabakken et al. pro-posed a threshold of 20 using a different equation tocalculate serum osmolarity, this was based on 177 consec-utive patients admitted to an ED (mean age 65 years)without any exposure to ethylene glycol or methanol [15].Given that the normal range for the osmole gap may behigher in patients older than 60 years of age and that theosmole gap is generally used in conjunction with otherdiagnostic information, we felt that it is unlikely that thisthreshold is applicable to the diagnosis of toxic alcoholpoisoning [34]. In support of this, although applying anosmole gap cut-off of 20 in our sample resulted in higherspecificity relative to an osmole gap of 10, it had a lowersensitivity that corresponded to six additional false-nega-tive diagnoses [15]. This reduction in sensitivity is con-cerning in this clinical scenario, given the potentialserious and fatal ramifications of a false-negative diagno-sis.The diagnostic performance of the osmole gap is related toboth the cut-off of the test and serum level being detected.Because we were unable to find any other empiric evalua-tion of the most appropriate osmole gap cut-off for theically evaluate the clinically accepted osmole gapthreshold of 10. Additionally, there is limited evidencesupporting the current recommended thresholds of ethyl-ene glycol and methanol concentrations for initiatingantidotal therapy and hemodialysis that we used in thisanalysis. If these thresholds are too conservative as hasbeen suggested, more liberal treatment thresholds wouldimprove the diagnostic performance of the osmole gap[35].Because the inclusion criteria applied in this studyrequired that both ethylene glycol and methanol be meas-ured by gas chromatography, some patients may have hada toxic alcohol level above the threshold for antidotaltherapy that was not measured. The diagnostic perform-ance of the osmole gap may therefore be poorer if appliedto all patients with any suspicion of exposure, includingcases where exposure may have been potentially ruledout, albeit erroneously, before specific serum concentra-tion measurements are performed.This highlights the importance of interpreting the result ofthe osmole gap as it relates to other available informationto estimate the likelihood of a toxic alcohol exposure.Information pertaining to the ingestion history, clinicalsigns and symptoms (e.g. visual disturbances) and otherlaboratory data including pH, HCO3-, anion gap and uri-nalysis should all be considered concurrently [36]. How-ever, this study only evaluated the diagnostic accuracy ofthe osmole gap alone measured within 24 hours of thefirst recorded laboratory measurement. Consequently,these results are likely an underestimate of the overallclinical utility of the osmole gap when evaluated in con-junction with other diagnostic information as early aspossible following exposure.This study has three primary limitations. First, it is limitedby the use of retrospective data and the requirement thatall laboratory tests be performed on serum obtainedsimultaneously; this resulted in the exclusion of 103 sub-jects. However, to avoid making clinical assumptionsusing only laboratory data, we pre-specified that allrequired laboratory parameters had to be measuredsimultaneously. Because these measurements were notnecessarily performed on the first blood sample obtainedupon presentation to the emergency room, we restrictedthis analysis to only laboratory data collected within thefirst 24 hours of the first available blood sample. Therationale for this restriction was to mimic admissionresults as closely as possible within the constraints of a ret-rospective study. Realizing the critical importance of thesimultaneous evaluation of all laboratory parametersimmediately upon admission, and the time of the inges-Page 8 of 10(page number not for citation purposes)diagnosis of toxic alcohol poisoning, we elected to evalu-ate all possible cut-offs using ROC curves, and then specif-tion when interpreting the osmole gap, a prospectiveBMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/5study is required to specifically address this methodologi-cal issue.The second limitation of the study is the potential forreferral or ascertainment bias. This sample only includedpatients who had serum ethylene glycol and methanollevels measured, which might suggest a high pre-test prob-ability of exposure. However, ethylene glycol or methanolwas only detectable in 34/131 (26%) patients. This inci-dence of detectable toxic alcohol concentrations suggeststhat the referral bias was not extreme and that the pre-testprobability of exposure in this sample of patients waslikely only moderate.Finally, there is the potential for work-up bias. If anosmole gap above a specific cut-off is used as a prerequi-site to measuring toxic alcohols using gas chromatogra-phy, this would tend to overstate the sensitivity of the test.We cannot exclude this possibility, especially in patientswith toxic alcohol concentrations just above the thresholdfor antidotal therapy. Although it is possible that some ofthe 51 patients who had ethylene glycol and methanolconcentrations requisitioned but not measured may havehad elevated toxic alcohol concentrations despite anosmole gap below 10, we believe that workup bias wasnot significant in this dataset for several reasons. First, gaschromatography was performed in 25 patients despite anosmole gap below 10 calculated using equation 1, themost commonly applied equation in clinical practice. Sec-ond, we are not aware of any patient in either institutionduring the study period with an osmole gap less than 10that subsequently developed significant toxicity. Andfinally, most of the cases with a detectable methanol con-centration below the threshold for antidotal therapy hadan osmole gap > 10.ConclusionToxic alcohol exposure is a clinical emergency requiringrapid evaluation and initiation of treatment to preventserious morbidity and mortality. Unfortunately, making adefinitive diagnosis is often difficult given that the goldstandard test (i.e. gas chromatography) is not available atmost hospitals. As a result, the inexpensive and widelyavailable osmole gap remains part of the diagnostic strat-egy for most emergency room physicians, despite twoimportant limitations [13,37]. First, the osmole gap lacksspecificity, given that it is also elevated in other clinical sit-uations, e.g. diabetic ketoacidosis, circulatory shock, andalcoholic acidosis [1]. Second, its wide normal rangerenders it insensitive to small but potentially toxic con-centrations of ethylene glycol in particular, but also meth-anol [38]. Despite these limitations, until now there hasnot been a rigorous, methodologically sound evaluationThe results of this analysis indicate that the osmole gapdoes provide additional diagnostic information whenapplied as a screening test for toxic alcohol poisoning, andits' diagnostic accuracy improves when the supramolarcontribution of ethanol to serum molarity is taken intoaccount. However, these results do not support the use ofthe osmole gap in isolation, and further support the con-clusions of Krahn and Khajuria who suggest that these cal-culations are only effective if they are validated onappropriate reference populations, and if strict qualitycontrol procedures are followed [39]. Therefore, a multi-centre prospective evaluation of the osmole gap isrequired to evaluate the overall clinical utility of the test,taking into account the time since ingestion, other labora-tory results, all available clinical diagnostic informationcollected immediately upon admission, and institutionaldifferences.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsLDL was involved in the study concept and design, analy-sis and interpretation of the data, drafting and final revi-sions of the manuscript, and oversaw the study. KJRundertook the statistical analysis and participated in thedrafting of the manuscript. RAP, RBAL and JRB all contrib-uted to the study concept and design, data interpretation,and critical revision of the manuscript. RBAL was alsoinvolved in the acquisition of the data. KJL contributed tothe study design and concept, critical evaluation of themanuscript, and data acquisition, and MLAS participatedin the acquisition of the data, analysis and interpretationof the data, and critical revision of the manuscript. Allauthors have read and approved the final manuscript.AcknowledgementsWe would like to thank Drs. Morris Pudek, Ph.D and Christine Collier, PhD for facilitating the acquisition of all laboratory data. We would also like to thank Harris Huang, B.Sc. for his assistance in undertaking the data extraction.References1. Purssell RA, Lynd LD, Koga Y: The osmole gap as a screeningtest for the presence of toxic substances: a review of the lit-erature.  Toxicol Rev 2004, 23(3):189-202.2. Koga Y, Purssell RA, Lynd LD: The irrationality of the presentuse of the osmole gap: applicable physical chemistry princi-ples and recommendations to improve the validity of cur-rent practices.  Toxicol Rev 2004, 23(3):203-211.3. Bailey B, Amre DK: A toxicologist's guide to studying diagnos-tic tests.  Clin Toxicol (Phila) 2005, 43(3):171-179.4. Cole P, Morrison AS: Basic issues for population screening forcancer.  J Natl Cancer Inst 1980, 64:1263-1272.5. Morrison AS: Screening.  In Modern epidemiology 2nd edition. Editedby: Rothman KJ, Greenland S.  Lippincott-Raven; 1998:7-28. 6. Edelman IS, Leibman J, O'Meara MP, Birkenfeld LW: Interrelationsbetween serum sodium concentrations, serum osmolarity,Page 9 of 10(page number not for citation purposes)of diagnostic accuracy of this test for the diagnosis of toxicalcohol exposure.and total exchangeable sodium, total exchangeable potas-sium, and total body water.  J Clin Invest 1958, 37:1236.Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central BMC Emergency Medicine 2008, 8:5 http://www.biomedcentral.com/1471-227X/8/57. Dorwart WV, Chalmers L: Comparison of methods for calculat-ing serum osmolality form chemical concentrations, and theprognostic value of such calculations.  Clin Chem 1975,21(2):190-194.8. Gennari FJ: Current concepts. Serum osmolality. Uses andlimitations.  N Engl J Med 1984, 310(2):102-105.9. Smithline N, Gardner KD Jr.: Gaps--anionic and osmolal.  JAMA1976, 236(14):1594-1597.10. Glasser L, Sternglanz PD, Combie J, Robinson A: Serum osmolalityand its applicability to drug overdose.  Am J Clin Pathol 1973,60(5):695-699.11. Bhagat CI, Garcia-Webb P, Fletcher E, Beilby JP: Calculated vsmeasured plasma osmolalities revisited.  Clin Chem 1984,30(10):1703-1705.12. Worthley LI, Guerin M, Pain RW: For calculating osmolality, thesimplest formula is the best.  Anaesth Intensive Care 1987,15(2):199-202.13. Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR: Osmol gapsrevisited: normal values and limitations.  J Toxicol Clin Toxicol1993, 31(1):81-93.14. Osypiw JC, Watson ID, Gill G: What is the best formula for pre-dicting osmolar gap?  Ann Clin Biochem 1997, 34 ( Pt 5):551-552.15. Aabakken L, Johansen KS, Rydningen EB, Bredesen JE, Ovrebo S,Jacobsen D: Osmolal and anion gaps in patients admitted to anemergency medical department.  Hum Exp Toxicol 1994,13(2):131-134.16. Osterloh JD, Kelly TJ, Khayam-Bashi H, Romeo R: Discrepancies inosmolal gaps and calculated alcohol concentrations.  ArchPathol Lab Med 1996, 120(7):637-641.17. Galvan LA, Watts MT: Generation of an osmolality gap-ethanolnomogram from routine laboratory data.  Ann Emerg Med1992, 21(11):1343-1348.18. Purssell RA, Pudek M, Brubacher J, Abu-Laban RB: Derivation andvalidation of a formula to calculate the contribution of etha-nol to the osmolal gap.  Ann Emerg Med 2001, 38(6):653-659.19. Geller RJ, Spyker DA, Herald DA: Serum osmolal gap and etha-nol concentration: a simple and accurate formula.  Clin Tox1986, 24:77-84.20. Snynder H, Williams D, Zink B: Accuracy of blood ethanol deter-mination using serum osmolality.  J Emerg Med 1992,10:129-133.21. Coakley JC, Tabqui, Dennis PM: Screening for alcohol intoxica-tion by the osmolar gap.  Pathology 1983, 15:321-323.22. Britten JS, Meyers RA, Benner C: Blood ethanol and serumosmolality in the trauma patient.  Am J Surg 1972, 48:451-455.23. Sackett DL: Clinical epidemiology: a basic science for clinicalmedicine.  2nd edition. Boston, Little Brown; 1991:xvii, 441, [2] ofplates. 24. White SR, Kosnik J: Toxic alcohols.  In Rosen's emergency medicine:concepts and clinical practice 5th edition. Edited by: Marx JA, Hock-berger RS, Walls RM, Adams J. St. Louis, Mo., Mosby; 2002. 25. Londner M, Hammer D, Kelen GD: Fluid and electrolyte prob-lems.  In Emergency medicine : a comprehensive study guide 6th edition.Edited by: Tintinalli JE, Kelen GD, Stapczynski JS. New York ,McGraw-Hill Medical Pub. Division; 2004. 26. Sivilotti MLA, Collier CP, Choi SC: Ethanol and the osmole gap.Ann Emerg Med 2002, 40(6):656-657.27. Ellenhorn MJ: Ellenhorn's medical toxicology : diagnosis andtreatment of human poisoning.  2nd edition. Baltimore , Williams& Wilkins; 1997:xvi, 2047 , [8] of plates. 28. Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA: Ameri-can Academy of Clinical Toxicology: Practice guidelines onthe treatment of methanol poisoning.  J Toxicol Clin Toxicol 2002,40(4):415-446.29. Marx JA, Hockberger RS, Walls RM, Adams J, Rosen P: Rosen'semergency medicine : concepts and clinical practice.  5th edi-tion. Philadelphia, Mosby/Elsevier; 2005:2127-22133. 30. DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing theareas under two or more correlated receiver operatingcharacteristic curves: a nonparametric approach.  Biometrics1988, 44(3):837-845.31. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, IrwigLM, Moher D, Rennie D, de Vet HCW, Lijmer JG: The STARDStatement for Reporting Studies of Diagnostic Accuracy:32. Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van derMeulen JHP, Bossuyt PMM: Empirical Evidence of Design-Related Bias in Studies of Diagnostic Tests.  JAMA 1999,282(11):1061-1066.33. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, IrwigLM, Lijmer JG, Moher D, Rennie D, de Vet HC: Towards completeand accurate reporting of studies of diagnostic accuracy: TheSTARD Initiative.  Ann Intern Med 2003, 138(1):40-44.34. Tietz NW: Clinical guide to laboratory tests.  3rd edition. Phila-delphia , W.B. Saunders Co.; 1995:xxxix, 1096 p.. 35. Kostic MA, Dart RC: Rethinking the toxic methanol level.  J Tox-icol Clin Toxicol 2003, 41(6):793-800.36. Mycyk MB, Aks SE: A visual schematic for clarifying the tempo-ral relationship between the anion and osmol gaps in toxicalcohol poisoning.  Am J Emerg Med 2003, 21(4):333-335.37. Glaser DS: Utility of the serum osmol gap in the diagnosis ofmethanol or ethylene glycol ingestion.  Ann Emerg Med 1996,27(3):343-346.38. Dart RC: Medical toxicology.  3rd edition. Philadelphia , LippincottWilliams & Wilkins; 2004:xxix, 1914. 39. Krahn J, Khajuria A: Osmolality gaps: diagnostic accuracy andlong-term variability.  Clin Chem 2006, 52(4):737-739.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-227X/8/5/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 10 of 10(page number not for citation purposes)Explanation and Elaboration.  Ann Intern Med 2003,138(1):1W-12.


Citation Scheme:


Citations by CSL (citeproc-js)

Usage Statistics



Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            async >
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:


Related Items