Harmonization of Osmolal Gap – Can We Use Common Equation

Can We Now Recommend a Common
Calculation for Osmolar Gap?
Oral Presentation
AACB 4th Harmonisation Workshop, Sydney, May 2015
Dr James Doery
INTRODUCTION
What is the osmolal gap?
Why measure? Clinical application.
What formula? Can we KISS??
Can we make a decision?
Osmolality
Measure of solute concentration, defined as the
number of osmoles of solute per kilogram of
solvent.
It may be thought of as a count of the number of
dissolved particles (ions) in a solvent (water).
Osmolality is one of the 4 colligative properties of a
solution.
Colligative properties are properties of solutions that all depend
upon the ratio of the number of solute particles to the number
of solvent molecules in a solution, and not on the type of chemical
species present.
Colligative properties include:
•Osmotic pressure
•Depression of freezing point*
•Lowering of vapour pressure*
•Elevation of boiling point
As the concentration of solute particles changes all 4 colligative
properties change together and proportionately. So if we know one
we can derive the other 3.
If we can ‘measure’ (derive) osmolality by a
simple method such as freezing point
depression or vapour pressure why would we
want to calculate osmolality ?
Answer
Because the calculated osmolality will
sometimes be wrong!!!
That is, it may be significantly out of kilter
with the real (measured) osmolality.
… because there is some unmeasured
analyte ‘hiding’ in the plasma!!
This error we refer to as the osmolal gap
Osmolar gap can be clinically useful to detect
possible toxic concentrations of analytes which
cannot be measured easily, rapidly, or at all, in
most laboratories.
The most important are the toxic alcohols
•Methanol
•Ethylene glycol (antifreeze)
•Isopropyl alcohol
Also increased by
•ethanol, mannitol, glycerol, sorbitol,
•fructose, ketones, etc if present in significant
amounts
For over 60 years biochemists have
tinkered as to the best formula to
calculate osmolality and thus the
osmolar gap!
QUESTIONS
•How do we determine the “best” formula to calculate
osmolality & therefore osmolal gap
Logically, the one closest to zero and the lowest SD in
normal sera?
The secondary question is how will we convert the
osmolal gap into a clinical decision point?
1975
After reviewing 13 equations proposed by
various authors since 1958 Dorwart &
Chalmers derived a relatively simple
calculated osmo equation based on 715
hospital patient sera.
1.86 Na + glucose + urea + 9
Dorwart equation
Clin Chem 1975; 21: 190-194
1976
Smithline & Gardner:
“ ’Gaps’ is a bedside diagnostic game. It is
played in two versions by nephrologists. The
more popular version, Anion Gaps, shows the
presence of undetermined anions and alerts
the physician to the possibilities of laboratory
error, severe derangements in serum protein
metabolism, or the ingestion of certain ionic
compounds that directly or indirectly alter
the concentration of routinely undetermined
anions. “
JAMA 1976; 236: 1594
“A second version, Osmolal Gaps,
shows the presence of unmeasured
osmoles or of increased plasma solids
and can be used to direct attention
to laboratory, error,
hyperproteinemia, hyperlipidemia, or
the presence of unmeasured osmoles
in the serum.”
Smithline & Gardner went on to
propose a very simple formula to
calculate the osmolality.
2 Na + glucose + urea
Smithline equation
JAMA 1976; 236: 1594-1597
1984
100 plasma samples from hospitalized patients
1 & 2: Modified Dorwart and Chalmers – added K Bhagat equations
3. Dorwart and Chalmers (1975)
1987
100 normal, 100 general hospital & 100 ICU patients.
Compared 5 formulae (incl Smithline & Bhagat)
Closest to measured osmo was Smithline & Gardner 1976
2 Na + urea + glucose
Smithline
Mean gap -2 mosm
This was also the simplest equation!
Over the years at least another
35 formulae have been
proposed some including K,
other anions or cations and
correction factors and
constants.
2005
Using 37 healthy subjects & ED patient data,
they evaluated and proposed:
CO = 1.86 x (Na + K) + Urea + 1.15 Gluc + 14
Mean gap: -0.75 mosm (SD 3.7) (RI -8.0 to 6.5)
(Also provided a correction for ethanol if measured.)
2013
Fazekas et al, 2013
36 equations ?
But are all equations feasible ?
Equation 5: involved iCa and Mg++
Equation 35: involved lactate and HCO3-
34 equations have one or more of Na, K, Urea, Gluc
Examples:
•2 Na
•1.89 Na + 1.38 K + 1.08 glucose + 1.03 urea + 7.47
•(Na + K + Cl + lactate + glucose + HCO3 + urea + 6.5) x 0.985
Conclusion:
Only 4/36 were fit for purpose ie mean gap of <1.
Study sponsored by Roche
2014
27 years later! (Harmonised measurement of Na, glucose & urea!)
Choy et al AACB Talk at AACB ASM
Tested 34 equations on the mean values for LSC 1 & 2
2013
•6 equations gave gap +/- 2 of the measured osmo
•3 equations were in common use;
•Bhagat 63%: 1.86 (Na + K) + glucose + urea + 9
•Smithline 32%:
2 Na + glucose + urea
•Dorwart:
1.86 Na + glucose + urea + 9
Worked across all instrument groups
Gap
-1,-2
0,0
MonashPathology
MonashHealth
Harmonised calculation of osmolal gap using the KISS principle
2015
RCPA
Update
Kay Weng Choy1, Nilika Wijeratne1,2,3, Zhong X Lu1,2, Jill Tate4, Graham RD Jones5,6, James CG Doery1,2
1Monash
Pathology, 2Department of Medicine, Monash University, Clayton, VIC, 3Dorevitch Pathology, Heidelberg, VIC 3084;
Pathology, Royal Brisbane & Women’s Hospital, QLD 4029, 5RCPAQAP Chemical Pathology, Adelaide, SA 5000;
6SydPath, St Vincent’s Hospital, Darlinghurst, NSW 2000, Australia.
4Chemical
kay.choy@monashhealth.org
INTRODUCTION
The osmolal gap (OG, measured osmolality – calculated
osmolality) is useful to estimate the presence of unmeasured
osmotically active compounds in serum. At least 34 formulae
for calculated osmolality (CO) have been published1 (Table 1).
We have proposed2 that the Smithline3 formula (osmolality =
2 Na + glucose + urea) be used routinely. This is not only one
of the simplest and most popular but that it has the best clinical
utility4. The RCPAQAP Chemical Pathology Calculated Results
Program survey 2014 showed that 26 labs (63%) used the
Bhagat5 formula (osmolality = 1.86 (Na + K) + glucose + urea
+ 10) and 13 labs (32%) used the Smithline formula. These
two formulae were assessed using data from the RCPAQAP
Liquid Serum Chemistry (LSC) Program.
RESULTS
DISCUSSION
Using the Smithline formula, the mean CO for different
instrument groups for the two healthy serum pools ranged
from 283-289 for Serum 1 and 285-290 for Serum 2
(Table 2).
Using the Bhagat formula, the mean CO for different
instruments ranged from 281-287 for Serum 1 and 283-288
for Serum 2.
When the mean CO was compared to the mean measured
osmolality the Smithline formula gives OG close to zero. The
Bhagat formula gives OG of 1-3 mOsm/kg.
As well as being simple, CO in healthy individuals should
be as close to measured osmolality as possible, i.e. OG
should be close to zero. Although another potential way of
dealing with the OG bias is by an OG reference interval
this seems like an unnecessary complication especially
with the Bhagat formula where a constant is added to give
the positive results.
The Smithline formula is simple and one of the most
commonly used. The literature4 has demonstrated that the
formula is fit for purpose across different groups of
patients. It is now demonstrated in this study that the
formula is also adequately robust across different
laboratory instruments.
Instrument
METHODS
Data were obtained from the LSC Program 2014 involving
serum pools from two healthy individuals. CO was
determined across different instrument groups and also for
all instruments combined using the two most widely used
formulae.
Using the mean measured osmolality as the gold standard
the OG was compared for each formula.
Serum 1
Measured
Osmolality
Mean 286
Serum 2
Measured
Osmolality
Mean 289
n
Smithline3
Bhagat4
Beckman
Roche
Integra
Abbott
2
Mean
CO
283
1.1
Mean
CO
281
1.0
24
284
2.0
282
2.6
37
285
2.4
283
2.3
SD
SD
Vitros
27
287
2.9
285
2.8
Siemens
Advia &
Dimension
30
289
2.4
287
2.1
Hitachi
Cobas &
modular
25
289
2.4
287
2.4
All
145
286
3.2
285
3.1
Beckman
Roche
Integra
Abbott
2
287
4.0
285
3.9
24
285
2.0
283
1.9
37
286
2.1
284
2.1
Vitros
27
290
2.5
288
2.4
Siemens
Advia &
Dimension
30
290
2.4
288
2.3
Hitachi
Cobas &
modular
25
289
2.4
287
2.2
All
145
288
3.1
286
3.0
Table 2. Calculated osmolality across different instrument groups
using data from RCPAQAP Liquid Serum Chemistry (LSC)
Program 2014 (serum pools from two healthy individuals).
Table 1. Formulae for calculated osmolality available in the
literature1.
The uncertainty of the OG will be determined by the sum
of the errors in the CO (i.e. errors in sodium, glucose and
urea), error in measured osmolality and variability in
unmeasured analytes.
Not withstanding this limitation it is surprising that
laboratories have been slow to adopt a routine automatic
calculation of OG whenever the osmolality is requested
and the components for calculation available at the same
time.
CONCLUSION
• We recommend the use of the Smithline formula
which would produce OG close to zero with an SD
of around 3.
• We also propose that the OG could be reported
automatically whenever a serum osmolality is
requested thereby maximising clinical information
in all situations where osmolality is under scrutiny.
• If all laboratories adopt this approach we can
indeed KISS - Keep It Straight and Simple !
REFERENCES
1. Fazekas AS, Funck GC, Klobassa DS, Ruther H, Ziegler I, Zander R,
Semmelrock HJ. Evaluation of 36 formulas for calculating plasma
osmolality. Intensive Care Medicine 2013; 39:302-308.
2. Choy KW, Wijeratne NG, Lu ZX, Jones GRD, Doery JCG. Harmonisation of
osmolal gap. Can we use common equation and reference intervals? Clin
Biochem Rev 2014; 35 Suppl: S21.
3. Smithline N, Garder KD. Gaps - anionic and osmolal. JAMA 1976; 236: 15941597.
4. Worthley LIG, Guerin M, Pain RW. For calculating osmolality, the simplest
formula is the best. Anaesth Intens Care 1987; 15: 199-202.
5. Bhagat CI, Garcia-Webb P, Fletcher E, Beilby JP. Calculated vs measured
plasma osmolalities revisited. Clin Chem 1984; 30: 1703-1705.
RCPAQAP data used with permission.
RCPA Update 2015
2015
So what is the best formula?
CO in healthy individuals should be as close to measured
osmolality as possible i.e. OG should be close to zero.
The Smithline formula is simple and one of the most
commonly used.
The literature has demonstrated that the formula is fit for
purpose across different groups of patients.
LSC Study has demonstrated that the formula is also
adequately robust (gap SD 3) on all major analysers in
laboratories across Australasia.
We recommended the use of the
Smithline formula which would
produce OG close to zero with an
SD of around 3.
We also proposed that the OG could
be reported automatically whenever
a serum osmolality is requested
thereby maximising clinical
information in all situations where
osmolality is under scrutiny.
Application to toxic alcohol ingestion
Ethanol  acetaldehyde  acetate
Methanol  formaldehyde  formate
Ethylene glycol  glyco-aldehyde  glycolate Glyoxalate  oxalate
An ethanol co-efficient of 1.25 mOsm/mM maximises sensitivity,
specificity and positive predictive value in identification of patients
requiring dialysis.
1983
Use of OG in alcohol intoxication
1985
Bhagat, Beilby & Garcia-Webb
Letter to Clin Chem observing an “error” in the
estimation of ethanol from osmolal gap. Their data
demonstrates the “ethanol coefficient” of 1.25
2008
An evaluation of the osmole gap as a screening
test for toxic alcohol poisoning. (Smithline formula)
•20/131 patients had ethylene glycol or methanol levels above the
threshold for antidotal therapy.
•Used an ethanol co-efficient of 1.25 to subtract the contribution of
ethanol.
•An osmolal gap threshold of 10 produced a sensitivity of 90% and
specificity of 22% for antidotal therapy and sensitivity of 100% for
patients needing dialysis
Lynd LD, Richardson KJ, Purssell RA, Abu-Laban RB, Brubacher JR, Lepik KJ, Sivilotti MLA An evaluation
of osmole gap as a screening test for toxic alcohol poisoning. BMC Emergency Medicine 2008; 8:5-10
Road testing …..
What if we apply this same simple formula
in a broad population on whom osmo was
clinically requested?
•Melbourne Pathology
•MMC
Melbourne Pathology
Monash Health
Monash Health - No Alcohol
Monash Health Intoxicated patients
Can we estimate alcohol from the gap?
Gap/1.25 = alcohol Smithline & Gardner
2015
Summary
•The Smithline & Gardner formula is simple and one of the
most commonly used.
•The literature has demonstrated that the formula is fit for
purpose across different groups of patients.
•Our recent data based on LSC 2013 & 2014 has
demonstrated in this study that the formula is also robust
across different laboratory instruments.
•“Live” data ie. Patients on whom an osmolality was clinically
desired has demonstrated the excellent performance
Hospital Practice.
•Using a conversion factor of 1.25 we can accurately estimate
alcohol concentrations.
Are you ready to vote?
Q1. Can we harmonise on Smithline and Gardner
formula?
2 Na + glucose + urea
•Yes
•No
Q2. Should we routinely report the calculated
osmo and the gap when osmolality is requested?
•Yes
•No
Q3. Should we routinely report the ethanol
coefficient of 1.25 as a text comment whenever
ethanol is measured?
•Yes
•No
Acknowledgements
RCPAQAP
Dr Kay Weng Choy
Dr Nilika Wijeratne
Dr Zhong Lu
Dr Ken Sikaris
A/Prof Graham Jones
1975