EXPERIENCE
`
`AND REASON-Briefly
`
`Recorded
`
`.
`
`and reason
`to experience
`but
`theorizing
`to plausible
`not
`pay attention
`one must
`‘ ‘In Medicine
`on facts,
`and
`it
`is based
`that
`provided
`is to be approved,
`. I agree
`that
`theorizing
`together.
`.
`drawn
`from unaided
`. But conclusions
`from what
`is observed.
`makes
`its deductions
`systematically
`.
`.
`from observed fact.’
`Precepts.
`can hardly
`‘ Hippocrates:
`only
`those
`drawn
`be serviceable;
`reason
`(Short communications
`of
`factual material
`are published
`here. Comments
`and criticisms
`appear as
`Letters
`to the Editor.)
`
`in Small
`Hyperosmolality
`Infants
`Due to Propylene
`Glycol
`
`Propylene
`drug
`many
`is
`regarded
`and
`humans
`renal,
`CNS,
`absorption
`The
`wounds
`burn
`of
`serum
`cause
`Investigation
`perosmolality
`several
`ing
`that
`osmolar
`due
`a multivitamin
`in
`nutrition.
`This
`relatively
`large
`be
`received
`by
`receiving
`multiple
`
`to
`
`in
`
`glycol
`preparations.
`as
`having
`animals
`hematologic,
`of
`propylene
`recently
`has
`hyperosmolality.6’7
`of
`the
`cause
`a premature
`infants
`in
`administration
`preparation
`fi(cid:1)iding
`raises
`dose
`propylene
`very
`infants,
`
`CO,,
`and
`
`glycol
`
`urea
`Serum
`24 mmol/L.
`total
`L;
`concentration
`serum
`glucose
`mg/dL
`48
`stopped
`for
`nutrition
`was
`Parenteral
`serum
`osmolality
`decreased
`The
`sumed.
`remained
`at
`this
`approximate
`and
`mosm/kg
`The
`lactate
`level
`was
`normal.
`blood
`weeks;
`large
`a
`was
`identified
`when
`hyperosmolality
`urine
`was
`detected
`in
`the
`propylene
`A review
`spectrometry.
`matography-mass
`the main
`source
`of
`propylene
`revealed
`that
`MVI-12,
`a multivitamin
`preparation
`(USV
`that
`tical)
`contains
`30% propylene
`glycol.
`received
`had
`10 mL
`(3
`g of
`propylene
`preparation
`daily
`in
`her
`parenteral
`initially
`When
`measured,
`her
`serum
`level was
`930 mg/dL.
`
`41
`
`was
`
`was
`nitrogen
`was
`148 mg/dL.
`hours,
`then
`re-
`to
`about
`350
`level
`for
`two
`cause
`of
`the
`amount
`of
`gas
`chro-
`by
`of medications
`glycol
`Pharmaceu-
`The
`patient
`glycol)
`of
`this
`nutrition
`solution.
`propylene
`glycol
`
`par-
`from
`removed
`immediately
`was
`MVI-12
`Just
`nursery.
`used
`in the
`solutions
`nutrition
`enteral
`ob-
`was
`a
`blood
`sample
`discontinuation,
`to
`prior
`for meas-
`receiving
`MVI-12
`from
`all
`infants
`tamed
`potassium,
`chloride,
`total
`of
`serum
`sodium,
`urement
`osmolality,
`and
`propylene
`Serum
`glu-
`glycol.
`CO2,
`and
`urea
`were
`not
`measured
`simultaneously;
`cose
`recent
`however,
`none
`of
`the
`infants
`studied
`had
`had
`meas-
`abnormalities
`in these
`metabolites.
`The
`same
`infants,
`urements
`obtained
`from eight
`control
`veni-
`not
`receiving
`parenteral
`nutrition,
`who
`re-
`punctures
`other
`reasons.
`tests
`had
`peated
`later,
`on
`infants
`those
`36
`cal-
`gap
`been
`MVI-12.
`The
`osmolal
`receiving
`times
`minus
`culated
`as
`the measured
`osmolality
`liter.
`the
`serum
`sodium
`measured
`in millimoles
`chro-
`Propylene
`glycol
`was
`measured
`by
`gas-liquid
`con-
`matography.
`Serum
`was
`diluted
`1:1 with
`water
`An
`taming
`glycol
`as
`an
`internal
`standard.
`ethylene
`(inner
`aliquot
`injected
`into
`a
`3
`ft
`2 mm
`was
`THEED
`diameter)
`glass
`column,
`packed
`with
`0.8%
`(tetrahydroxyethylenediamine)
`on
`Carbopack
`Injector,
`oven,
`and
`temperatures
`
`all
`
`had
`were
`who
`was
`two
`per
`
`The
`
`x
`
`detector
`
`C.
`were
`
`PEDIATRICS
`
`Vol. 72 No. 3 September
`
`1983
`
`353
`
`(1,2-propanediol)
`Although
`low
`toxicity
`there
`have
`and
`
`is
`propylene
`in
`
`used
`glycol
`
`in
`
`in
`of
`
`a
`
`adults,
`reports
`been
`toxicity.’5
`cardiac
`through
`large
`glycol
`been
`documented
`as
`
`unexplained
`of
`led
`to
`infant
`were
`nursery
`of
`propylene
`used
`in
`concern
`glycol
`especially
`
`hy-
`find-
`hyper-
`glycol
`parenteral
`about
`that
`
`the
`may
`those
`
`our
`
`of
`small
`medications.
`
`the
`
`METHODS
`
`CASE REPORT
`
`index
`The
`following
`g,
`890
`the
`begun
`on
`was
`support
`respiratory
`received
`and
`she
`ninth
`On
`the
`was
`started
`ventricular
`12th
`On the
`Serum
`failure.
`124 mmol/L;
`
`weighing
`born
`was
`infant,
`a female
`patient,
`nutrition
`Parenteral
`a 27-week
`gestation.
`She
`required
`some
`third
`day
`after
`birth.
`distress
`syndrome,
`respiratory
`for
`hyperbilirubinemia.
`for
`phototherapy
`of aminophylline
`therapy
`a regimen
`day,
`episodes
`of apnea,
`and
`a grade
`III
`intra-
`for
`hemorrhage
`was
`documented
`by
`ultrasound.
`day,
`she
`developed
`unexplained
`acute
`renal
`osmolality
`was
`407 mosm/kg,
`sodium
`was
`potassium,
`5.9 mmol/L;
`chloride,
`88 mmol/
`
`Hospital
`Children’s
`to (A.M.G.)
`requests
`Reprint
`Aye, NW, Washington,
`ical Center,
`111 Michigan
`Copyright
`PEDIATRICS
`(ISSN
`0031
`4005).
`American
`Academy
`of Pediatrics.
`
`Med-
`National
`DC 20010.
`by
`1983
`
`the
`
`©
`
`were
`
`for
`hours
`
`MYLAN INST. EXHIBIT 1085 PAGE 1
`
`MYLAN INST. EXHIBIT 1085 PAGE 1
`
`

`

`170#{176}C,respectively.
`150#{176}C,120#{176}C,and
`a flow
`rate
`of 30 mL/min
`was
`used
`gas.
`Detection
`was
`by
`flame
`ionization.
`
`Nitrogen
`the
`
`as
`
`carrier
`
`at
`
`1)
`
`RESULTS
`
`*
`
`1
`
`C)
`E
`-a
`
`0C
`
`.)
`>.
`-a
`(9
`Lu
`
`zL
`
`u
`-a
`>-
`a.
`
`0 a
`
`.
`
`Lu
`Cl)
`
`0
`
`10
`
`20
`
`TIME
`
`30
`(hrs)
`
`40
`
`50
`
`infants
`Ten
`least
`at
`these
`
`five
`
`had
`days
`infants,
`
`The
`
`a
`
`of MVI-12
`to sampling.
`osmolality
`were
`
`10 mL
`prior
`serum
`osmolalities
`1).
`
`in
`
`received
`each
`immediately
`for
`four
`had
`ten
`Of
`highest
`mosmol/kg.
`>300
`(Fig
`babies
`in
`the
`smallest
`found
`control
`six
`detectable
`not
`was
`Propylene
`glycol
`nutrition.
`parenteral
`receiving
`not
`infants
`who
`were
`infants
`Two
`other
`control
`of
`propyl-
`70 mg/dL
`to
`attributed
`was
`serum,
`ene
`glycol
`in
`their
`infant
`and My-
`therapy
`with
`phenobarbital
`other.
`the
`rash
`costatin
`cream
`for
`diaper
`the
`between
`There
`was
`a direct
`relationship
`concentra-
`glycol
`molal
`and
`serum
`propylene
`gap
`= 47.5
`+
`osmol
`gap
`times
`tion
`(propylene
`glycol
`r = .96).
`less
`somewhat
`The
`osmolal
`gap was
`9.2;
`serum
`than
`the
`expected
`osmolality
`of
`the measured
`propylene
`propylene
`glycol.
`The
`decrease
`in
`serum
`hours)
`50
`glycol
`over
`36
`hours
`(in
`one
`case,
`level
`19.3
`hours,
`shown
`2. The
`mean
`half-life
`was
`in Fig
`with
`of
`10.8
`to
`30.5
`hours
`(excluding
`one
`a range
`patient
`an
`unexplained
`slow
`decrease
`pro-
`in
`with
`must
`pylene
`level).
`This
`be
`viewed
`a rough
`glycol
`estimate
`of half-life,
`as only
`two
`sample
`were
`available
`for
`all
`but
`one
`patient.
`
`had
`which
`in one
`in
`
`os-
`
`is
`
`as
`points
`
`after
`levels
`patients
`line
`
`in-
`
`glycol
`indicates
`dashed
`half-life.
`
`serum
`in
`
`a
`
`Fig 2.
`Change
`discontinuation
`who
`continued
`dicates
`patient
`
`propylene
`serum
`in
`Asterisk
`of MVI-12.
`phenobarbital;
`to
`receive
`with
`unexplained
`long
`
`DISCUSSION
`
`found,
`
`a
`
`1000
`
`900
`
`BOO
`
`(cid:1),7OO
`E
`
`600
`
`500
`
`400
`
`C,
`U)
`
`z (cid:1)
`
`infants,
`small
`in
`have
`We
`propylene
`by
`caused
`hyperosmolality
`preparation.
`multivitamin
`parenteral
`indicates
`other
`centers
`tion
`with
`this
`multivitamin
`preparation
`package
`that
`generally
`The
`used.
`for
`patients
`that
`MVI-12
`intended
`chosen
`because
`age
`and
`older;
`yet
`it was
`only
`parenteral-use
`preparation
`containing
`
`may
`
`is
`
`that
`be
`insert
`
`marked
`glycol
`Communica-
`the
`dose
`higher
`than
`indicates
`of
`years
`the
`it
`is
`Biotin.
`
`of
`
`11
`
`chosen
`was
`relative
`may
`
`provide
`to
`estimated
`occur
`
`to
`not
`
`adequate
`requirements.
`with
`lower
`
`amounts
`
`Hy-
`of
`
`doses
`
`dose
`This
`of vitamins
`perosmolality
`this
`preparation.
`the
`other
`glycol.
`in
`the
`
`On
`propylene
`monly
`
`used
`.
`
`hand,
`Many
`nursery:
`.
`
`many
`of
`
`other
`these
`Digoxin
`
`drugs
`drugs
`Bactrim
`
`are
`
`contain
`com-
`phe-
`
`.
`diazepam,
`cream.
`to
`receive
`
`.
`vitamin
`It
`is
`not
`multiple
`
`hy-
`D,
`uncom-
`drugs
`
`nobarbital,
`dralazine,
`mon
`for
`
`phenytoin,
`and Mycostatin
`small
`sick
`infants
`
`S
`
`S
`
`S
`
`1000
`
`2000
`BODY WEIGHT
`
`3d00
`gm)
`
`S
`
`4000
`
`50’OO
`
`300
`
`200
`
`100
`
`0 S
`
`.
`
`‘U
`U)
`
`Fig 1.
`Propylene
`had
`received
`tients
`Circles
`indicate
`days.
`propylene
`glycol;
`taimng
`ing
`phenobarbital;
`triangle
`Digoxin
`Bactrim
`phenobarbital
`taming
`2.64 mL of propylene
`12.
`
`and
`levels
`glycol
`of MVI
`10 mL
`patients
`not
`squaresindicate
`indicates
`and
`
`All
`weight.
`body
`least
`for
`at
`daily
`receiving
`drugs
`patients
`patient
`hydralazine
`in addition
`
`pa-
`five
`con-
`receiv-
`receiving
`(con-
`to MVI-
`
`glycol)
`
`354
`
`PEDIATRICS
`
`Vol.
`
`72
`
`No.
`
`3
`
`September
`
`1983
`
`MYLAN INST. EXHIBIT 1085 PAGE 2
`
`MYLAN INST. EXHIBIT 1085 PAGE 2
`
`(cid:1)
`(cid:1)
`(cid:1)
`

`

`likely
`is
`It
`multivitamins.
`sufficient
`receive
`would
`levels
`being
`substantial
`infants
`all
`As
`(10 mL)
`dose
`a greater
`limited
`serum
`
`data
`propylene
`
`in
`of
`dose
`do
`
`related
`
`to
`glycol
`It
`
`has
`basis
`as
`
`age.
`
`with
`that
`
`CNS
`on
`
`a
`
`one
`to
`
`to
`susceptible
`may
`cause
`possible
`
`renal
`
`in
`pro-
`pro-
`Fi-
`and
`hepatic
`
`these
`any
`to
`
`parenteral
`to
`addition
`in
`these
`infants
`of
`some
`that
`in
`glycol
`result
`to
`propylene
`concentrations.
`serum
`in
`shown
`daily
`received
`the
`same
`study
`this
`received
`the
`smaller
`infants
`MVI-12,
`Our
`per
`kilogram
`of
`body
`weight.
`of
`not
`suggest
`that
`the
`half-life
`glycol
`is
`size
`or
`gestational
`Propylene
`has
`been
`associated
`depression.4’5
`been
`estimated
`is
`approximately
`it
`weight-for-weight
`due
`third
`as
`intoxicating
`ethanol.’
`Depression
`function
`this
`intoxication
`impair
`respiratory
`could
`of propylene
`in infants.
`Rapid
`intravenous
`injection
`glycol
`has been
`associated
`collapse
`circulatory
`with
`injection
`and
`arrhythmia
`in
`calves.2
`Intravenous
`As
`sheep
`produces
`intravascular
`hemolysis.3
`it may
`pylene
`glycol
`is metabolized
`lactate,
`duce
`lactic
`acidosis
`in
`individuals.8
`nally,
`propylene
`glycol
`a
`diuresis,
`there
`is
`concern
`about
`and
`toxicity.’
`patients
`of our
`Some
`However,
`problems.
`problems
`clinical
`glycol.
`propylene
`body
`water
`into
`all
`be
`expected
`have
`to
`perosmolality
`due
`as sodium
`glucose.
`to
`seen
`prudent
`be
`cautious
`taming
`propylene
`glycol,
`amount
`of
`propylene
`glycol
`small
`infants.
`
`of
`some
`demonstrated
`ascribe
`yet
`as
`cannot
`we
`hyperosmolality
`than
`other
`glycol
`is
`As
`propylene
`the
`hyperosmolality
`the
`same
`consequences
`nondiffusible
`substances
`For
`present,
`using
`try
`to
`administered
`
`to
`
`and
`
`the
`when
`and
`
`to
`
`as
`
`diffusible
`would
`
`not
`hy-
`such
`it would
`drugs
`con-
`limit
`the
`to
`very
`
`ACKNOWLEDGMENTS
`
`assistance
`The
`Laboratories
`
`of Hugh
`(Fairfax,
`VA)
`
`Granger
`is gratefully
`
`Medical
`of American
`acknowledged.
`
`MD
`PHD
`MD
`
`ALLEN
`ROGER
`MARILEA
`
`MHAIRI
`FRCP(E),
`GILBERT
`
`M. GLASGOW,
`L. BOECKX,
`K. MILLER,
`G. MACDONALD,
`DCH
`P. AUGUST,
`
`MBCHB,
`
`MD
`
`Departments
`Clinical
`lism,
`Neonatology
`Children’s
`111 Michigan
`Washington,
`
`Hospital
`Aye,
`DC
`
`of Endocrinology
`Laboratories,
`
`and Metabo-
`and
`
`National
`NW
`
`Medical
`
`Center
`
`Department
`George
`School
`Washington,
`
`of Child
`Washington
`of Medicine
`DC
`
`and
`
`Health
`University
`and
`Health
`
`Development
`
`Sciences
`
`STEPHEN
`Department
`University
`Denver
`
`I. GOODMAN,
`of Pediatrics
`of Colorado
`
`MD
`
`School
`
`of Medicine
`
`REFERENCES
`
`3.
`
`1. Seidenfeld
`and
`toxicity
`2. Gross
`DR,
`of
`intravenous
`oxytetracycline
`1979;40:783
`Potter
`BJ:
`Br
`sheep.
`4_ Arulanantham
`associated
`1978;93:515
`5_ Martin
`vehicle
`6. Bekeris
`of
`cause
`1979;72:633
`7. Kulick
`burn
`the
`Trauma
`8. Cate
`JC,
`acidosis.
`
`MA, Hanzlik
`of propylene
`Kitzman
`JV,
`administration
`in
`propylene
`
`PJ: The
`glycol.
`Adams
`
`actions
`properties,
`general
`1932;44:109
`J Pharmacol
`HR:
`Cardiovascular
`effects
`of
`of
`propylene
`and
`glycol
`Am J Vet Res
`glycol
`in
`calves.
`
`Hemoglobinuria
`J Pharmacol
`K, Genel
`ingestion
`
`with
`
`by
`
`caused
`1958;13:38S
`nervous
`M: Central
`of
`propylene
`
`propylene
`
`glycol
`
`in
`
`system
`glycol.
`
`J
`
`toxicity
`Pediatr
`
`Finberg
`G,
`liquid
`in
`L, Baker
`an
`elevated
`
`L:
`dosage
`C,
`
`Propylene
`form.
`Fenton
`serum
`
`glycol:
`J Pediatr
`J,
`et
`al:
`osmolality.
`
`A potentially
`1970;77:877
`Propylene
`Am
`
`glycol
`J Clin
`
`toxic
`
`a
`
`as
`Pathol
`
`MI,
`
`Lewis
`patient:
`1980;20:223
`Hedrick
`N Engi
`
`Bansal
`NS,
`Analysis
`
`et
`
`V,
`an
`
`al: Hyperosmolality
`osmolal
`discrepancy.
`
`of
`
`in
`J
`
`glycol
`R: Propylene
`J Med
`1980;303:1237
`
`intoxication
`
`and
`
`lactic
`
`EXPERIENCE
`
`AND
`
`REASON
`
`355
`
`MYLAN INST. EXHIBIT 1085 PAGE 3
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`MYLAN INST. EXHIBIT 1085 PAGE 3
`
`

`

`Hyperosmolality in Small Infants Due to Propylene Glycol
`ALLEN M. GLASGOW, ROGER L. BOECKX, MARILEA K. MILLER, MHAIRI G.
`MACDONALD, GILBERT P. AUGUST and STEPHEN I. GOODMAN
`1983;72;353
`Pediatrics 
`
`Updated Information &
`Services
`
`including high resolution figures, can be found at:
`http://pediatrics.aappublications.org/content/72/3/353
`
`Permissions & Licensing
`
`Information about reproducing this article in parts (figures, tables) or in its
`entirety can be found online at:
`http://www.aappublications.org/site/misc/Permissions.xhtml
`
`Reprints
`
`Information about ordering reprints can be found online:
`http://www.aappublications.org/site/misc/reprints.xhtml
`
`MYLAN INST. EXHIBIT 1085 PAGE 4
`
`MYLAN INST. EXHIBIT 1085 PAGE 4
`
`

`

`Hyperosmolality in Small Infants Due to Propylene Glycol
`ALLEN M. GLASGOW, ROGER L. BOECKX, MARILEA K. MILLER, MHAIRI G.
`MACDONALD, GILBERT P. AUGUST and STEPHEN I. GOODMAN
`1983;72;353
`Pediatrics 
`
`The online version of this article, along with updated information and services, is located on
`the World Wide Web at:
`http://pediatrics.aappublications.org/content/72/3/353
`
`
`
`Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
`been published continuously since 1948. Pediatrics is owned, published, and trademarked by the
`American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1983 by the
`American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
`
`MYLAN INST. EXHIBIT 1085 PAGE 5
`
`MYLAN INST. EXHIBIT 1085 PAGE 5
`
`