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JCE & M • 2000
Vol 85 • No 2
THERAPEUTIC CONTROVERSY
References
1. Scibila J, Finegold D, Dorman J, Becker D, Drash A. 1986 Why do children
with diabetes die? Acta Endocrinol Suppl. 279:326 –333.
2. Rosenbloom AL. 1990 Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care. 13:22–33.
3. Pappius HM. 1974 Fundamental aspects of brain edema. In: Vinkin PJ, Bruyn
GW, eds. Handbook of clinical neurology, vol. 16, part 1: Tumors of the brain
and skull. Amsterdam: North Holland Publishing Co.; 167–185.
4. Clements Jr RS, Blumenthal SA, Morrison AD, Winegrad AI. 1971 Increased
cerebrospinal fluid pressure during treatment of diabetic ketosis. Lancet.
2:657– 661.
5. Fein IA, Rackow EC, Sprung CL, Grodman R. 1982 Relation of colloid osmotic
pressure to arterial hypoxia and cerebral edema during crystalloid volume
loading of patients with diabetic ketoacidosis. Ann Intern Med. 96:570 –574.
6. Carroll P, Matz R. 1983 Uncontrolled diabetes mellitus in adults: experience
intriguing diabetic ketoacidosis and hyperosmolar nonketotic coma with low
dose insulin and a uniform treatment regimen. Diabetes Care. 6:579 –585.
Appropriate Therapy Can Prevent Cerebral Swelling
in Diabetic Ketoacidosis
Laurence Finberg
University of California–San Francisco
San Francisco, California 94111
and
Stanford University
Stanford, California
Appropriate therapy can prevent cerebral swelling in
diabetic ketoacidosis (DKA)
In considering the issue posed by the title, there are two
aspects of fluid movement in the brain that should be emphasized before we consider the pathophysiology of DKA
and its treatment.
The first is a generalized response to induced hyperosmolality in the extracellular space (ECF). What are now
known as osmolytes, previously called “idiogenic osmols,”
small organic molecules that accumulate in cells. In mammals taurine and myoinositol are the principal (only?) osmolytes. These molecules diffuse out or metabolize very
slowly when a return to normal osmolality has occurred.
Because the brain is in a rigid box, such cell swelling will lead
to increased intracranial pressure when there is continuing
hyperosmolality without loss of ECF volume.
The second aspect of fluid movement in and out of the
brain relevant here is the nature of the capillaries through
which water and solute diffuse. The brain capillaries, unlike
most capillaries elsewhere in the body, have tight junctions
between the cells. This anatomic feature produces “the blood
brain barrier.” Solutes not actively transported across the
membrane, which includes sodium and chloride ions, diffuse
at a much slower rate than these ions diffuse across other
capillaries where movement is nearly instantaneous. In the
brain, equilibrium for sodium takes 6 h (1). On the other
hand, diffusion of water is virtually instantaneous in the
brain as elsewhere.
Consider, then, what happens when an osmotic gradient
between the plasma and brain fluid is created. Water moves
instantly to equalize the osmotic concentrations while the
dominant solutes (Na⫹ and Cl⫺) move slowly. If the dilution
gradient is from plasma to brain ECF, there will be an increase in brain volume. While the water is in the brain, ECF
that is edema. If, however, the brain cells have been exposed
to a hyperosmotic state and cells already possess osmolytes,
then the water will be picked up by the cells producing brain
swelling with or without “edema.”
Now let us apply this knowledge to DKA. Before DKA
occurs, there is a period of hyperglycemia. In a new diabetic
this may have had a fairly long duration before diagnosis is
appreciated; some going on to DKA. The prolonged hyperglycemia will have caused osmolyte concentration in cells,
causing them to swell moderately. This has been verified by
brain imaging (2). The swelling may be severe enough to
cause symptoms, but usually at this stage there is enough
reduction in ECF volume to modulate pressure changes.
If the patient has treatment begun at this point, with fluid
having an osmotic concentration below plasma, water will
flow disproportionately into the brain and intracranial pressure will rise. A large iv bolus of insulin metabolizes glucose
to water that further aggravates the process. The excess water
will be pulled to cells by the osmolytes and as the cycle
continues, intracranial pressure progresses to cause headache, coma, and possibly death.
How should the clinician deal with this situation? It is
more common in children than adults, probably because of
their more rapid metabolism and water turnover. It is more
common in first episodes of DKA, possibly because of a more
prolonged hyperglycemic state before DKA.
Inappropriate therapy clearly will worsen the condition
and in the past has done so. Five issues are important:
1. DKA dehydration is a hyperosmotic state that calls for
slow repair, optimally over 48 h as with any hyperosmotic dehydration.
2. Use a fluid that has sodium and chloride or sodium,
chloride, and bicarbonate in physiologic amounts (i.e.
isotonic with normal ECF). Later in therapy, the NaCl
concentration may be lowered.
3. If the patients’ circulation is stable, administer the fluid
at a rate that covers ongoing insensible losses, physiologic urine loss (the excess urine loss is offset by water
of metabolism), and 1⁄48 of the estimated deficit per
hour. In other words, add the physiologic requirements
for 48 h to the estimated deficit and deliver 1⁄48 per hour.
If the circulation is not stable, give isotonic sodium salt
fluid rapidly until stability is restored, then immediately slow down.
4. In estimating the patients’ deficit, do not assume a 10 –
15% body weight loss unless shock is present. The
losses, especially in older children, are usually close to
5–7% of weight.
5. Give insulin by slow drip; do not give a bolus dose.
Hyperglycemia should be reduced gradually.
Having started the therapy, these children require
close monitoring of their symptoms and of their electrolytes and glucose levels. Perhaps the most useful
determination is the “corrected ” sodium concentration,
which is calculated as:
Corrected Na⫽ ⫽ Serum Na⫹
⫹
Serum glucose (mmol/l) ⫺ 5.5
2
THERAPEUTIC CONTROVERSY
This number is a surrogate for a more physiologic concentration level in serum water, but it is in the units ordinarily used by clinicians and varies in identical fashion. This
adjusts for the “osmotic space” filled by the excess glucose.
If the corrected number is outside the physiologic range for
sodium concentration (i.e. ⬎149 meq/L), the patient is hypernatremic, and less sodium than usual will be needed.
Conversely, if the corrected sodium is less than 132 meq/L,
more is needed.
If the patient either before or after the start of therapy has
a headache or any other evidence of new neurological impairment, administer hypertonic mannitol to reduce intracranial pressure. Do not wait for fixed dilated pupils; it will
already be too late.
Applying these principles, Harris and Fiordilese (Ref. 3
and personal communication regarding the current number
in the series and the lack of mortality and sequelae) have
treated over 400 episodes of DKA without a fatality or sequelae. Twelve of their patients exhibited either headache or
other neurological manifestations, which led to the use of
hypertonic mannitol infusion, sometimes advised and given
at a referring hospital before arrival at their institution. All
of these patients recovered neurologically and are otherwise
intact; a remarkable record.
Errors of the past aggravated the already abnormal distribution of water in the brain. In particular, the administration of too much fluid (usually diluted below isotonic for
sodium chloride) caused water influx into the brain, causing
an increase in intracerebral pressure and the administration
of an iv bolus of insulin, which increased ECF water from
glucose metabolism. These events may cause hemorrhage,
thrombosis, or cerebral herniation.
Thus, there is a pathophysiologic explanation for cerebral
“edema” during ill-advised management of DKA, and there
are a set of principles which when carefully followed have
permitted successful correction of the disturbance.
References
1. Finberg L, Luttrell C, Redd H. 1959 Pathogenesis of lesions in the nervous
system in hypernatremic states. II. Experimental studies of gross anatomic
changes and alterations of chemical composition of the tissues. Pediatrics.
23:46 –51.
2. Krane EJ, Rockoff MA, Wallman JK, et al. 1985 Subclinical brain swelling in
children during management of diabetic ketoacidosis. N Engl J Med.
312:1147–1151.
3. Harris GD, Fiordelisi I. 1994 Physiologic management of diabetic ketoacidemia: a five year prospective pediatric experience in 231 episodes. Arch
Pediatr Adolesc Med. 148:1046 –1052.
Cerebral Edema in Diabetic Ketoacidosis: A Look
Beyond Rehydration
Andrew Muir
Department of Pediatrics
University of Florida
Gainesville, Florida 32610
I
NJUDICIOUS fluid resuscitation is frequently suggested
as the cause of the cerebral edema that is the most common cause of mortality among pediatric patients with diabetic ketoacidosis (DKA) (1). The evidence, however, supports the hypothesis that neurological demise in DKA is a
509
multifactorial process that cannot be reliably prevented by
cautious rehydration protocols. Mortality and severe morbidity can, however, be reduced when healthcare providers
watch vigilantly for and respond rapidly to the sentinel neurological signs and symptoms that precede, often by hours,
the dramatic collapse that is typically described in these
patients.
Children being treated for DKA develop clinically important neurological compromise about 0.2–1.0% of the time (2).
Subclinical neurological pathology, causing raised intracranial pressure, likely precedes the initiation of therapy in
almost all cases of DKA (3–5). Intracranial hypertension has
been considered to be aggravated by therapy of the DKA (4,
6, 7), but in keeping with the physicians’ perplexity about the
problem, even this widely held tenet has recently been challenged (8).
The pathogenic mechanism for this terrifying complication remains unknown. Hypothetical causes of cerebral
edema in children with DKA must account for: 1) its occurrence (with rare exceptions; Refs. 9 and 10) after the
onset of therapy; 2) the preponderance of children over
adults being affected, and as will be discussed later; 3)
profound neurological dysfunction in the presence of minimal or no radiologically visible cerebral edema; and 4)
initial pathological changes in the basal regions of the
brain. Ideally, hypotheses would also explain the existence
of edema in most cases of DKA and of neuropathology
arising before treatment. These last two features, however,
could occur independently of the disease process that
causes “brain liquefaction” in children. A summary of the
discussion that follows is presented in Table 1.
Why not fluid management?
Despite a number of independent efforts, no clinical or
biochemical correlates with neurological decline have been
consistently identified. Fein et al. (6) reported subclinical
cerebral edema, low plasma colloid oncotic pressure, and
reductions of the partial pressure of oxygen in arterial blood
as patients progressed through treatment of DKA. A relationship between iv replacement with crystalloid and subclinical pulmonary and cerebral edema was suggested. UsTABLE 1. The case for a multifactorial cause of cerebral edema
in DKA
Mild edema and other histopathology exists before treatment
Rare reports of symptomatic cerebral edema presenting before any
possible influence of therapy on the brain
Inconsistent correlations of cerebral edema with serum
Osmolality
Sodium concentration
Acid base status
Glucose concentration
Inconsistent correlation of cerebral edema with therapeutic fluid
replacement volume
Inability to experimentally confirm idiogenic osmole effect in brain
in vivo
Clinical deterioration and radiologic abnormalities in brain do not
arise synchronously
Requirement of insulin to induce edema in some animal models
(possible effects of insulin on ion pumps, energy metabolism?)
Other plausible, though untested, models of disease pathogenesis
(e.g. ischemia, neurotoxic amino acids)