The Pathophysiology & Practical

Management of Diabetic Ketoacidosis - 2006

David H. Jelley, M.D.

Pediatric Endocrinologist
Warren Clinic Diabetes Center
Clinical Associate Professor of Pediatrics, OUHSC Tulsa
 O
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2 CH3 -C ~S-CoA (2C)
acetyl CoA
CoA
(6C)
-hydroxy--
Acetoacetyl methylglutaryl CoA
CoA (4C) (HMG CoA)
acetyl CoA CoA
+ H2O

(4C) acetyl CoA

NADH + H+ acetoacetate
acetoacetate
H+
NAD+

(4C) (3C)

-hydroxybutyrate
-hydroxybutyrate CO2
acetone
acetone
 Learning points:

 History of medicine
 Clinical physiology/ pathophysiology
 Treatment
 Complications
Before the discovery of insulin
Diabetes . . . is a melting
down of the flesh and limbs
into urine. The nature of
the disease is chronic, but
the patient is short-lived if
the constitution of the
disease be completely
established, for the melting
is rapid, the death speedy.
Thirst unquenchable; and
one cannot stop them from
either drinking or making
water.
Aretaeus A.D. 81-136
The discovery of insulin
Three months later
 Diabetic ketoacidosis (DKA) -
definition
A state of absolute or  Hyperglycemia
relative insulin  Blood glucose > 200mg%
deficiency resulting in  Acidosis
hyperglycemia and an  pH < 7.30
accumulation of  Bicarb < 15 mmol/L
ketoacids in the blood  Ketosis
with subsequent  Elevated serum or urine
ketones
metabolic acidosis
 Physiology of carbohydrate
metabolism
 Glucose and lipid metabolism are regulated
by the pancreatic hormone insulin, and its
counterregulatory hormones:
 Glucagon
 Catecholamines
 Cortisol
 Growth hormone
 Physiology of carbohydrate
metabolism
 During a fast, blood glucose levels fall and insulin
secretion subsequently decreases to basal levels and
counterregulatory hormone levels increase,
allowing mobilization of stored energy substrates
 Glycogen is broken down to form glucose
(glycogenolysis)
 Protein is catabolized to amino acids which are converted
to glucose (gluconeogenesis)
 Fats are broken down to free fatty acids, which are
converted in the liver to glucose or ketoacids
(ketogenesis)
 To develop DKA there must be both a relative
lack of insulin and a relative overactivity of
the counterregulatory hormones

 Insulin (anabolic)  Counterregulatory

 Glucose used for energy
substrate or stored as
glycogen
 Protein formation
 Fats stored as
triglycerides
hormones (catabolic)
 Glycogenolysis
 Proteolysis-
gluconeogenesis
 Lypolysis-FFA &
ketone bodies
 Physiology of DKA

 Diabetic ketoacidosis is a superfasted state in

which the body’s tissues are robbed of their
normal energy substrate, glucose, and
converts to catabolism of glycogen, protein
and fat
 Physiologic cascade in DKA

decreased insulin
counterregulatory hormones

hyperglycemia ketoacidosis

osmotic diuresis renal function changes CNS function changes cardiovascular changes

dehydration
electrolyte depletion
hyperosmolality
 Causes/Precipitating Factors of DKA

 Initial presentation of type 1 diabetes

mellitus
 In a patient with known type 1 diabetes
 Infusion site problem, tubing problem, or pump
malfunction
 Intercurrent illness/infection
 Missed insulin injections
 Stress: psychosocial, trauma, surgery
 Clinical presentation: History

 Classic triad: polydipsia, polyuria, polyphagia

(+weight loss)
 Vomiting / abdominal pain
 Increased or deep respirations
 Symptoms of infection
 In a patient with known diabetes:
 Timing and dose of last insulin injection
 Missed insulin injections
 Emotional stress
 Clinical presentation: Exam

 Vital signs
 Hydration status
 Fever or focus of infection
 Ketones on breath – ‘fruity or medicine
smell’
 Kussmaul respirations
 Neurologic status / optic discs
 Laboratory studies

 At the bedside  Laboratory

 Glucose  Chemistry
 Sodium
 Urine ketones  Potassium
 Bicarbonate
 Glucose
 Creatinine
 Venous pH
 Serum BOHB (if diagnosis
is in doubt)
 CBC
 Goals of treatment

 Restore perfusion, which will increase glucose use in the

periphery, restore GFR, and reverse the progressive acidosis
 Stop ketogenesis by giving insulin, which will reverse
proteolysis and lipolysis, and stimulate glucose uptake and
processing, normalize blood glucose, and reverse acidosis
 Correct electrolyte losses
 Avoid the complications of treatment insofar as possible,
including intracerebral complications, hypoglycemia, and
hypokalemia
 Treatment – basic rules

 Admit patients only to a unit in which neurologic

status and vital signs can be monitored frequently
and blood glucose measured hourly

 Personally evaluate the patient early on admission

and frequently thereafter

 Keep good records, including rationalization for

decisions, and a flow sheet
Fluids, fluids, fluids!
Fluids, fluids, fluids!
Caution!
 Fluid management - 1

 Initial volume expansion

 20cc/kg (600cc/m2) of isotonic solution:
.9%/normal saline over the first hour
 Use colloid solution, i.e., Hespan if signs of
shock are present
 Fluid management - 2

 24 hour fluid volume

 10ml/kg for every 1% estimated dehydration by
body weight, e.g., 100ml/kg if 10% dehydrated
 Replace the deficit evenly over 24 hours if BG <
1000 mg%
 if BG 1000-1500 mg%, replace the deficit evenly over
48 hours
 if BG > 1500mg%, replace the deficit evenly over 72
hours
 Fluid management - 3

 To maintain optimal serum insulin

concentration, begin to add dextrose to the
IV fluid as the blood glucose level falls
 Start D5+lytes as BG approaches 250-300mg%
 Change to D10+lytes as BG falls to 150mg%
 Insulin therapy: general guidelines

 Wait until the lab glucose and urine ketones are

known before starting the insulin drip
 Insulin binds to the walls of IV tubing, therefore,
flush with 25 ml of the insulin solution before
starting the infusion
 Do not use a filter in the tubing
 Piggyback the insulin drip onto the IV fluid
replacement to insure ‘matched infusion’ of
dextrose and insulin
 Low-dose continuous insulin drip:
general guidelines

 Start insulin drip at .1 units/kg/hr. Mix to run

@ 10ml/hr
(regular insulin equal to wt. in kg x 2.5, mixed in
250ml bag of saline)
example: 12y/o boy ; wt=50kg
[50*2.5=125units in 250ml=.5u/ml*10ml/hr=5u/hr]
 Sodium

 Initial serum sodium may be ‘low’ for several

reasons
 Depletion secondary to urinary losses / vomiting
 Hyperlipidemia displaces sodium in the most frequently
used laboratory assay, factitiously lowering sodium
values
 Osmotic dilution of the extracellular solute because of
hyperglycemia
 For each 100mg% increase of serum glucose above 100mg%,
there is an expected decrease of 1.6mEq/L in measured sodium
 If BG=500, then add [4*1.6, or 6.4] to the measured Na+ level
 Potassium

 K+ is largely an intracellular ion

 Both lack of insulin and acidosis cause a shift of K+
extracellularly
 High urinary losses of K+ occur 2o to this
compartmental shift and an osmotic diuresis
 Serum K+ levels are usually normal, even when
total body K+ is depleted, because:
 The compartmental shift of K+ inside to outside the cell
 Only extracellular K+ is measured
 Potassium therapy

 NEVER give potassium until the serum potassium

level is known to be WNL
 Once serum K+ is known to be low or normal, K+
therapy can be initiated
 As the acidosis is corrected, K+ is driven back into
the cells resulting in a fall in the serum K+ level
 We try to avoid the chloride salt of K+ to reduce the
hyperchloremic metabolic acidosis
 K+ is usually replaced with a combination of K
Acetate and K phosphate
 Phosphorus
 Similar to potassium, serum phosphate concentration in
patients presenting with DKA are usually normal or slightly
elevate, while total body phosphate stores are significantly
depleted
 Theoretical problems secondary to hypophosphatemia
 A left shift of the Hgb*O2 dissociation curve because of lowered red
blood cell 2,3 DPG levels
 Profound hypophosphatemia can cause muscular weakness, CNS
depression, and myocardial dysfunction
 Clinical sequelae 2o to hypophosphatemia in DKA have not
been documented, and no benefit has been shown from
raising levels to the normal range
 Bicarbonate

 Serum bicarbonate is always depressed in patients

with DKA because this extracellular ion is the
body’s first line buffer against metabolic acidosis
 Little or no real base deficit exists, however,
because the ketoacid and lactic acid anions in tissue
and circulation are ultimately metabolized to
bicarbonate during insulin therapy
 Bicarbonate

 Potential benefits of raising the serum pH

level above 7.1
 Improve myocardial performance and the
response to catecholamines
 Improve the ventilatory response to acidosis
 Increase insulin sensitivity
 Bicarbonate: risks!

 Rapid correction of acidosis shifts the Hgb*O2

dissociation curve to the left, resulting in impaired
tissue oxygen delivery
 Rapid correction of the acidosis, with subsequent
movement of potassium intracellularly may result
in hypokalemia
 Providing bicarbonate according to the calculated
base deficit overcorrects and may result in alkalosis
 Correction of acidosis may result in a paradoxical
CNS acidosis
 Parodoxic CNS acidosis resulting
from bicarbonate therapy
 Exogenous NaHCO3- acutely raise serum pH
 Ventilatory response subsequently falls
 Arterial CO2 tension rises
 CO2 crosses the blood brain barrier more
rapidly than NaHCO3- resulting in CNS
acidosis
 Complications of DKA

 Dehydration/shock/  Aspiration pneumonia

hypotension  Sepsis
 Hypokalemia –  Acute tubular necrosis
hyperkalemia  Myocardial infarction
 Hypoglycemia  Stroke
Cerebral edema
 Cerebral edema

 This complication of DKA is almost

exclusively a condition of childhood
 The pathophysiology is not completely
understood
 Usually occurs between 4-12 hours from the
start of treatment, but may be present at onset
of DKA and can occur up to 24 hours later
 Cerebral edema

 Responsible for 50-60% of all diabetes-related

deaths in children
 Occurs in approximately 1% of cases of DKA
 Mortality rate 28%
 13% survived with mild to moderate neurologic
sequelae
 59% survived without sequelae
 Cerebral edema – risk factors

 Age < 5yrs

 New onset diabetes
 Higher BUN concentration
 Lower partial pressure of CO2
 Falling sodium concentration during treatment
 Treatment with bicarbonate
 Cerebral edema

 Clinical signs are variable

 Gradual deterioration and worsening of
conscious level from admission, or
 More commonly a gradual general improvement
followed by sudden neurological deterioration
 Requires a high index of suspicion and low
threshold for treatment measures
 Cerebral Edema - symptoms

 decreased sensorium  change in VS

 sudden and severe  ophthalmoplegia
headache  pupillary changes
 incontinence  papilledema
 persistent vomiting  posturing; seizure
 combativeness;
disorientation;
agitation
 Cerebral edema -treatment

 Urgent recognition and treatment are

essential
 Mannitol .5-1 gm/kg IV over 15 minutes
 Reduce IV fluid rate to 70% maintenance
 Elevate HOB to 45o
 Consider intubation
 *be cautious re: hyperventilation
 keep pCO2>22mmHg
Remember, the ideal treatment for
DKA is prevention!
 Transition to subcutaneous
insulin
 Turn drip and dextrose off 30-60” after sub-q
insulin injection
 Go directly to planned injection regimen
 Think about timing of insulin action to
determine type and dose of insulin