Furthermore, diabetes mellitus remains an important cause of hospitalization of young children. The prevalence rate of diabetes continues to grow in all Western …
Diabetic Ketoacidosis and Cerebral Edema
Elliot J Krane, MD
Departments of Pediatrics and Anesthesiology
Stanford University Medical Center
Contents
Introduction
Clinical Characteristics of Cerebral Edema Complicating DKA
The Osmotic Abnormalities in DKA
Overhydration and Hyponatremia During DKA
Summary and Conclusions
Introduction
In 1922 Banting and Best introduced insulin into clinical practice A
decade later the first reported case of cerebral edema complicating
diabetic ketoacidosis DKA was reported by Dillon, Riggs and Dyer writing
in the pathology literature While the syndrome of cerebral edema
complicating DKA was either not seen, ignored, or was unrecognized by the
medical community until 3 decades later when the complication was again
reported by Young and Bradley at the Joslin Clinic, there has since been a
flurry of case reports in the 1960s and 1970s and basic and clinical
research from the 1970s to the 1990s leading to our present day
acceptance of this as a known complication of DKA, or of the management of
DKA
In fact, we now recognize that the
cerebral complications of DKA including
much less frequent cerebral arterial infarctions, venous sinus thrombosis,
and central nervous system infections are the most common cause of
diabetic-related death of young diabetic patients 1, accounting for 31
of deaths associated with DKA and 20 of all diabetic deaths, having
surpassed aspiration, electrolyte imbalance, myocardial infarction, etc
Furthermore, diabetes mellitus remains an important cause of
hospitalization of young children The prevalence rate of diabetes
continues to grow in all Western developed nations, nearly doubling every
decade, resulting in 22,000 hospital admissions in children under 15 years
of age for diabetes in the United States in 1994, the majority of which
were due to ketoacidosis With approximately 4 hospital admissions of
children for DKA per 100,000 population per year 2, every PICU located in
a major metropolitan center will continue to see children with DKA at
significant rates in the future, and every pediatric intensivist will see
at least one case of cerebral edema complicating DKA during his/her career
The Clinical Characteristics of Cerebral Edema Complicating DKA
Cerebral edema complicating
DKA is a syndrome unique to pediatrics While
described in a few adults, this complication occurs predominantly in
children, most of whom are experiencing their onset of diabetes mellitus
with the presentation of DKA 3
Cerebral edema complicating DKA is generally an unpredictable phenomenon
that occurs in children who seem to be metabolically returning to normal,
generally 3-12 hours after the initiation of therapy 4-6
This description may seem true for the clinician faced with a case of
cerebral edema But as cases are subjected to post hoc scrutiny, and
hindsight is liberally applied, it often seems to be the case that
neurologic signs, while subtle, sometimes preceded the onset of clinically
obvious cerebral edema and neurologic collapse These symptoms may be
increased lethargy and diminished arousability, incontinence, or complaints
of headache On the other hand, many of these complaints or observations
may not seem remarkable at the time they occur Lethargy and complaints of
headache in the early hours of morning in a child with an acute viral
illness, and who has been vomiting for several days, are truly not unusual,
and may only be judged to be significant with the benefit of
hindsight
While it is true that only a small percent 05-3 of children with DKA
will experience catastrophic cerebral edema, several investigations
demonstrate that subclinical cerebral edema is common if not universal
during treatment of DKA both in adults 7,8 and children 6 These
observations of cerebral edema during treatment were expanded by Hoffman,
et al 9,10 who demonstrated that the radiologic and transcranial Doppler
evidence of cerebral edema is present before the initiation of therapy for
DKA
We therefore recognize that cerebral edema is a common subclinical
complication of DKA in children, and that in a very few unfortunate
children the cerebral edema becomes clinically manifest, usually with
devastating consequences The cause of the underlying cerebral edema in
DKA, and the cause of neurologic deterioration in the minority of children
whose cerebral pathology progresses, have been the source of considerable
debate over the years The theories commonly invoked are several:
1 Osmotic dysequilibrium between brain and plasma
2 Overhydration and hyponatremia
3 Intracerebral acidosis induced by alkali therapy or the correction of
acidosis; accumulation of
intracellular Na due to the action of the Na-H
membrane exchanger, the antiport 11-13
4 Alterations in cerebral blood flow 9,14
This review will discuss the putative role of theories 1 and 2 in the
development of cerebral edema during DKA References pertaining to theories
3 and 4 are provided for those interested in further reading
The Osmotic Abnormalities in DKA
Several profound metabolic abnormalities exist in the child with DKA; among
the most important are disorders in serum glucose and sodium
concentrations, which are the principal determinants of secondary changes
in the osmolality, osmolarity, and tonicity of the plasma Because these
three terms mean different things but are frequently used interchangeably,
it is useful to define them
By convention, many biological measurements of concentration are expressed
as percentages, or as weight in grams per 100 ml of solution For example,
09 saline solution contains 09 gm of NaCl per 100 ml of water, 5
dextrose contains 5 gm of glucose per 100 ml of water, and a blood glucose
measurement of 80 mg- means that there are 80 mg of glucose per 100 ml of
blood The accuracy of this measurement relies on laboratory accounting for
the
solution temperature at the time of measurement
A measurement that is more biologically appropriate is the molal
measurement of concentration, that is, the concentration in moles,
millimoles, etc per 1000 g of solvent, expressed as a lower case m m,
mm, m, etc This measurement is independent of temperature
Alternatively, concentration of solute can be expressed in molar
measurement, the number of moles, millimoles, etc per liter of solution,
expressed as an upper case M M, mM, etc Because solution volume
changes with temperature, molar concentration is temperature dependent
Because biologic membranes are readily permeable to water molecules there
is continual movement or exchange of water between various fluid
compartments The forces governing the movement of water are hydrostatic
and osmotic pressures Most important to this discussion is the latter
Quantitatively, osmotic pressures greatly exceed hydrostatic pressures in
the body; the magnitude can be appreciated when one realizes that an
osmotic pressure difference of only 6 mOsm/L can move as much water as the
entire hydrostatic pressure generated by the heart
Osmotic pressure is a property of solutions that depends on the
number of
osmotically active molecules in solution, not upon the ionic charge of
those molecules, the size of the molecules, or the physical-chemical
properties of the molecules Thus 1 gram-molecular weight 1 mole of a
compound such as glucose is termed 1 osmole osmol, Osm Most biological
concentrations are expressed in milliosmolar mOsm or microOsmolar Osm
concentrations Ionized molecules eg NaCl dissociate in solution, and
each dissociated ion exerts its own osmotic force For example, NaCl is
principally dissociated in the body, therefore 1 mM of NaCl exerts
approximately 2 mOsm of osmotic pressure; 1mM of CaCl2 exerts 3 mOsm of
osmotic pressure, etc Osmolality is the expression of this quantity of
osmotically active particles per 1000 gm of water or solvent, while the
more commonly used osmolarity expresses the number of osmotically active
particles per liter of solvent
There is a small difference between osmolality and osmolarity principally
due to dissolved protein and fat which comprise 6 to 8 of the solutes in
plasma, but the difference is negligible when dealing with small
concentrations of solute In general, the serum osmolarity can be estimated
to within 10 accuracy by
the equation:
Sosm 2 x [Na] [glucose]/18 [BUN]/28
However, this equation will underestimate osmolarity in the presence of
unusual or unmeasured solutes, such as ketoacids, ketone, and amino acids,
all of which may be significantly elevated during DKA
Tonicity is a term that is used to describe the relative osmolality of
solutions; thus a solution is isotonic when it is isosmotic with body
fluids Normal saline and D5W are isotonic with respect to plasma, in that
red blood cells will neither expand nor shrink if suspended in those
solutions Hypertonic fluids 5 NaCl, mannitol, etc have a greater
solute concentration than body fluids, and will cause cellular dehydration
and shrinkage due to egress of water from cells Although the terms
tonicity and osmolarity are often interchanged in clinical usage, an
alteration of one does not necessarily imply an alteration of another
Tonicity, in this way, can be thought of as the effective osmolality
Eosm High concentrations of low molecular weight permeant molecules
urea, ethanol distribute evenly throughout total body water, and
therefore produce no effect on tonicity Uremia is a common example of a
hyperosmolar state but not a hypertonic
state Glucose, however, is not a
permeant molecule, therefore hyperglycemia indeed induces a hypertonic
state The effective osmolality or tonicity, can be best estimated using
only glucose and sodium in the equation above plus other exogenous
impermeant solutes if any, such as mannitol, glycerol, etc:
Eosm 2 x [Na] [glucose]/18
DKA clearly represents a hypertonic state, as glucose is significantly
elevated in concentration in the plasma It was recognized several decades
ago, in studies of hypernatremic dehydration, that over-rapid correction of
hypertonic states could lead to cerebral swelling and death This
phenomenon was attributed to the development or generation of what was then
termed idiogenic osmoles, osmotically active substances formed within the
cells of the brain that served to counter the extra osmolality of plasma
and protect the cells of the brain from shrinkage during episodes of
hypertonicity Experimental animals made hypertonic with exogenously
administered compounds sodium, glucose, mannitol had concomitant
increases in brain osmolality 15 The term idiogenic osmoles was coined
because of the inability of investigators to chemically identify these
new
osmotically active material in the brains of hypertonic experimental
animals 15,16
Animals made hypertonic have an increase in brain osmolality; the left
column represents the osmotically active constituents of a normal rabbit
brain; the right column represents the same in a rabbit made hyperglycemic
glucose 1000 mg/dl The brain osmolality increased both because of a
general increase in electrolyte and glucose concentrations, but also
because of the generation of about 20 mOsm of unknown osmoles, termed
idiogenic osmoles Adapted from Arieff Kleeman, 1974
It was not a very large leap to then postulate that these idiogenic
osmoles, putatively the result of intra-cerebral glucose metabolism and
therefore large molecules, would dissipate slowly leaving the brain
hypertonic relative to plasma during restoration of euglycemia during
treatment of DKA, and rendering it susceptible to swelling as water moved
into the brain along its osmotic gradient Figure 4 Indeed, idiogenic
osmoles are present in experimental animals during experimental
hyperglycemia and during induced DKA The identity of at least some of
these osmoles has been established as myoinositol1 mOsm/kg,
taurine35
mOsm/kg, and urea the last, of course, an osmole but not one
participating in brain tonicity for reasons discussed above 15,17
During hyperglycemia, extracellular glucose concentration rises, leading to
a preferential loss of water from the intracellular compartment Water
molecules travel in the direction of the arrows, and ultimately are lost in
an osmotic diuresis
Later during hyperglycemia, the brain generates idiogenic osmoles
denoted by stars which serve to draw water back into the cerebrum,
ameliorating intracellular dehydration
But what is the evidence that a reduction of hyperglycemia and correction
of hypertonicity causes cerebral edema?
The seminal work in this area was completed by Arieff and colleagues, who
were unable to establish such a link In their rabbit model, brain
osmolality increased with increasing magnitude and duration of
hyperglycemia, by as much as 40 mOsm/kg during 4 hours of hyperglycemia to
levels of about 1000 mg/dl Half of the increase in brain osmolality was
accounted for by increases in intracellular ion and glucose concentration,
and half of which by the generation of idiogenic osmoles However, they
noted when plasma glucose is
lowered below 14 mM, cerebral edema
occurs which is characterized by a significant augmentation in the cerebral
cortex content of Na, K, Cl- and water Idiogenic osmoles are not only
retained in the brain under such circumstances, but the quantity which are
present during hyperglycemia increases still further as the plasma glucose
is lowered towards normal with insulin By contrast, when the plasma
glucose and Osm are lowered by means of peritoneal dialysis and hypotonic
saline infusion, an osmotic gradient between brain and plasma does not
develop In other words, experimental brain swelling occurs with the
correction of hyperglycemia with insulin, but does not occur with rapid
correction of hyperglycemia with dialysis and hypotonic fluids, and without
the use of insulin Arieff, et al were led to speculate on the role of
insulin on membrane ion pumps, and to caution not to correct hyperglycemia
below 250 mg/dl
Strikingly similar results were found by Tornheim, who studied the brains
of diabetic rats treated with insulin or fluid alone to correct DKA 18
She wrote, Treatment with saline alone did not result in central
overhydration The findings of this study suggest that aggressive
therapy
with fluids and insulin, but not fluid alone, results in global
overhydration of the brains of diabetic animals Prolonged fluid and
insulin treatment with a return of blood glucose to normal values causes
further and preferential accumulation of edema fluid in the cerebral
cortex
How may we integrate this knowledge into clinical practice, and how does it
reconcile with clinical experience? On balance, one may safely conclude
that the osmolality of the brain increases during untreated episodes of
hyperglycemia, due to an influx of cations, glucose, and the generation of
larger complex carbohydrates and amines However, these substances
dissipate rapidly and brain edema does not occur if hyperglycemia is
corrected with even massive quantities of isotonic 18 or hypotonic 15
fluids; if however hyperglycemia is treated with a combination of fluids
and insulin, the brain accumulates further cations and other osmotically
active substances, and brain edema occurs Because all children with DKA
are treated with insulin, the data are consistent with the observation that
cerebral edema occurs only after the initiation of therapy with the
exception of a few rare case reports These data
are also consistent with
the observation that cerebral edema is a very rare complication of
nonketotic hyperglycemic coma NKHC, even though NKHC is associated with
hyperglycemia many times more severe than DKA NKHC is generally treated
with fluid resuscitation alone, but not insulin; in fact, insulin therapy
has been associated with cerebral edema in this setting 19 These data
cannot, however, be easily reconciled with the several observations of ICP,
radiographic, and encephalographic evidence of brain edema before the onset
of therapy with fluids or insulin
Overhydration and Hyponatremia During DKA
As clinicians have sought to understand cerebral edema complicating DKA and
identify strategies for preventing it, considerable attention has been
turned towards the possible role of fluid therapy while all but ignoring a
potential role of insulin in the etiology of cerebral edema
The first call to arms against aggressive rehydration of children with DKA
came from Duck, et al in 1976 19, who described 4 cases of cerebral
edema and combined their data with the data of another 5 previously
reported in the literature These authors observed that all of the children
who developed cerebral
edema had received fluid therapy at a rate in excess
of 4 L/m2/day during the first 3-15 hours of therapy Compared to an
unmatched group of 21 children from these authors practice who did not
develop cerebral edema, these 4 children had lower average serum sodium
concentrations measured at the same hour that cerebral edema occurred 124
vs 131 mEq/L Unfortunately, the authors do not describe the fluid therapy
of this cohort group of 21 children
Remember, however, that protocols in practice throughout the 1970s called
for fluid resuscitation of diabetic patients to be proportional to their
degree of dehydration Most protocols called for initial fluid boluses of
10-30 ml/kg followed by replacement of half the fluid deficit over the
first 8 hours of therapy If we calculate what this would mean for a 30 kg
07 m2 child with typical DKA, that is, who is 10-12 dehydrated, we
would prescribe a fluid bolus of 500 ml of isotonic fluid followed by an
infusion of hypotonic fluid at 145 ml/hr for a 8 hour fluid total of 165
L, half his deficit This amounts to 24 L/m2/8 hr, or 7 L/m2/24 hr, well
above the Duck threshold for risk of cerebral edema In other words, it is
hardly surprising that all
of Ducks patients with cerebral edema received
fluid in excess of 4 L/m2/8 hr because virtually all protocols recommended
this for all but the minimally dehydrated child Ducks analysis,
therefore, fails to take into account the severity of DKA and dehydration
as a factor in the causality of cerebral edema, and presents us only with a
true-true-unrelated paradigm
A decade later the same senior author expanded his observations of the rate
of rehydration and the incidence of hyponatremia in the etiology of
cerebral edema 20 reporting 9 new cases and comparing them to 39
previously published reports Without dwelling on the inherent weaknesses
of retrospective series, especially ones in which the majority of data is
gleaned from secondary sources published reports rather than medical
records, their findings viewed objectively may actually weaken their
argument of fluid management as a cause of cerebral edema, and hyponatremia
as a contributing cause or marker In this series, 10 of cases of cerebral
edema occurred following fluid resuscitation at less than Ducks threshold
of 4 L/m2/24 hr, again, not surprising given published protocols for the
management of DKA Two-thirds of his
reported subjects did not have
measured serum sodiums below 130 mEq/L at the time of neurologic collapse,
although many had declining sodium values Once again, Duck did not
distinguish between rapid rehydration as an etiology of cerebral edema,
versus an independent cause of cerebral edema in the more severely
dehydrated children, who received more rapid rehydration by protocol to
manage their greater degree of dehydration
The other author who has written in favor of conservative fluid management
is Harris, et al 21,22 In his earlier paper, Harris retrospectively
studied over 200 episodes of DKA in children and adults, and described his
prospective experience with a slow-rehydration regimen in 58 subsequent
patients In the former retrospective group, he identified 20 neurologic
complications noted as minor headache, n13 and major death or
neurologic collapse, n7, and noted that serum sodium failed to increase
in 54 of uncomplicated cases of DKA, but in 95 of so-defined complicated
cases p001 In discussing his prospective cohort group who were
rehydrated over 48 hrs, he noted that sodium rose in 95 of patients, and
no major complications occurred While the behavior of serum sodium
was
impressive, the absence of complication even if defined as a headache, and
assumed to be 0 in incidence in the slow rehydration group did not reach
statistical significance in comparing the rapid to slow rehydration groups
p04 by chi-square calculated from their data
In the latter Harris paper, the authors describe a 5 year experience of 48
hour hydration in 231 episodes of DKA They stratified their subjects into
mildly and severely dehydrated groups, and observed that there was a
statistically significant difference between the groups in admission
glucose, BUN, and sodium They had no major neurologic complications with
their treatment protocol, concluding that gradual rehydration can protect
against life-threatening increases in intracranial pressure and brain
herniation
The Harris conclusions that slow rehydration is safe, vis a vis resolution
of the abnormalities of DKA, is probably correct, however can one conclude
that slow rehydration protects against cerebral edema? To answer this
question I would refer the reader to an important and simple biostatistics
paper, If Nothing Goes Wrong, Is Everything All Right? 23 in which
Hanley demonstrates that a zero numerator in a
clinical study does not
imply zero risk, even with large denominators, but that the 95 confidence
interval for stating a 0/n rate is 3/n In other words, in the Harris study
one can state that with 48 hour rehydration the risk of cerebral edema is
not larger than 0 3/231, or 12, approximately the same magnitude of
risk already documented in prior studies without control of rehydration
rates One can hardly argue with the call for prudent fluid therapy and
careful monitoring for and management of hyponatremia, but it is premature
to state that this will prevent cases of cerebral edema
The role of hyponatremia is also uncertain Hyponatremia may play a role in
promoting the development of cerebral edema, or it may be a marker for
children who are developing cerebral pathology and are manifesting a degree
of SIADH on their way to a neurologic catastrophe Hyponatremia is far from
a constant occurrence during the development of DKA: The original case
reports of cerebral edema during DKA from the 1960s described children who
were hypernatremic, and the Duck and Harris papers describe hyponatremia
with varying frequency Certainly its difficult to assign a definite
etiologic role to a
phenomenon which often is not seen during the evolution
of cerebral edema
Finally, several other authors have retrospectively sought an association
between fluid therapy, hyponatremia, and cerebral edema, but have failed to
demonstrate such a link 3,24 In fact, cerebral edema has been reported
in children who received only oral rehydration and insulin 25 The
etiologic role of fluid resuscitation is therefore unresolved
Summary and Conclusions
Severe metabolic and osmolal disturbances occur during routine episodes of
DKA, and the latter has been associated with the development of increased
cerebral osmolality that has been assumed to be responsible for the
development of cerebral edema However, it is possible to substantially
correct hyperglycemia by administering massive quantities of fluid without
inducing cerebral edema, and in so doing cerebral idiogenic osmoles
dissipate
Efforts by clinicians to identify a consistent etiology in patients with
DKA who develop cerebral edema have not been successful Neither excessive
fluid therapy nor hyponatremia are constant features of the disease Of
some interest is the rarity of cerebral edema during treatment of the much
more severe
hyperglycemic states during NKHC, while its more frequent
occurrence during the management of DKA
The one common denominator of children who develop cerebral edema
complicating DKA is therapy with insulin, and insulin has been
experimentally shown in more than one study to be associated with the
accumulation of cations and complex carbohydrates in the brain, and the
development of cerebral edema during correction of hyperglycemia in
laboratory animals Insulin may have a direct ion gate effect on glial
cells and neurons, or alternatively may act indirectly by accelerating the
correction of metabolic acidosis associated with DKA, and thus activating a
pH sensitive sodium-proton membrane pump
Finally, the observation of the presence of subclinical cerebral edema
before the initiation of therapy of DKA, and its worsening and persistence
during management, is interesting and difficult to integrate into present
theories regarding the etiology of cerebral edema
The calls for careful management of serum sodium and conservative fluid
management with a deceleration of fluid resuscitation from over 24 hours to
over 48 hours are prudent and cannot be criticized, but it will be several
years
before sufficient clinical data may be accumulated to determine if
such conservative management will reduce the incidence of this frequently
devastating and incompletely understood complication of childhood diabetes
Until we understand more about its prevention, then we must remain vigilant
to its occurrence and treat cerebral edema aggressively with conventional
neuro-intensive care measures to lower ICP and restore cerebral blood flow
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Interpreting zero numerators JAMA 1983; 249:1743-5
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