DKA & HYPERGLYCEMIC HYPEROSMOLAR STATE (HHS)

D. Franzon, MD

Pathogenesis: Physiology
Diabetic ketoacidosis (DKA) is probably the most commonly encountered
metabolic disorder in the PICU. The incidence of DKA is 4.6-8.0 per 1000
person-years among patients with diabetes and it is a significant cause of
morbidity and mortality with a mortality rate between 4 and 10% although in
pediatrics, the mortality rate is 1-2%.

Essential Pathophysiology of DKA:
Absolute or relative deficiency of insulin
Resultant excess of counter-regulatory hormones
Increased hepatic glucose production and diminished glucose uptake by
peripheral tissues cause the hyperglycemia in DKA leading to glycosuria,
osmotic diuresis and dehydration

Insulin
Insulin has both stimulatory and inhibitory effects.
o Stimulatory effects (+): anabolism glycogen storage; protein and
fat storage in muscle, liver, and adipose tissue; enhances cellular
uptake of ketone bodies.
o Inhibitory effect (-): prevent catabolism glycogenolysis,
gluconeogenesis, proteolysis, lipolysis, and ketogenesis.
Insulin deficiency states, such as diabetes, effect end organ metabolic
responses, which in turn increases serum glucose levels.
o Liver: uninhibited hepatic ketogenesis and gluconeogenesis and
glycogenolysis occur.
o Muscle: anabolic functions are impaired and glucose fails to enter
cells, glycogen is depleted, and catabolism takes place.
o Fat tissue: lipolysis continues while fat absorption and triglyceride
synthesis are blocked.

Counter-Regulatory Hormones are elevated when insulin is deficient
Glucagon stimulates beta-oxidation of fatty acids leading to the production
of ketoacids: acetoacetate, and beta-hydroxybutyrate. This ketogenesis is
a hallmark of DKA.
Growth hormone, cortisol and catecholamines all enhance
gluconeogenesis, block glucose uptake by muscle and promote lipolysis.

Acidosis
Overproduction of ketoacids, beta-hydroxybutyric acid, acetoacetic acid

DKA & HHS

2 ketoacids dissociated at physiologic pH excess hydrogen ions bind

bicarbonate decreased serum bicarbonate levels circulating ketone
bodies in anion form lead to the anion gap acidosis of DKA
Anion gap = [Na+ (Cl- + HCO3-); normal anion gap = 12
Acetoacetate is converted to acetone by a spontaneous nonenzymatic
process in direct proportion to its serum concentration; this is an
important pathway by which excess acid is discarded by the body. The
lungs or the kidneys in turn can excrete acetone.
In normal circumstances, the ratio of B-hydroxybutyrate / acetoacetate is
2-3:1, but in DKA it may be as high as 15:1.
Commonly used tests measure acetoacetate levels well but measure
acetone poorly and dont measure beta-hydroxybutyrate at all, which may
underestimate the degree of ketosis.

Dehydration
Hyperglycemia induces osmotic diuresis leading to total body water deficit
often to 10-15% of body weight. The kidney can re-absorb glucose with
serum levels up to 180mg/dL above which glucose is wasted and water
follows.
Electrolytes follow free water and are therefore also lost in the urine.
Deficits of electrolytes, in general are as follows:
o Na+: 5-13 mmol/kg
o Cl-: 3-7 mmol/kg
o K+: 3-15 mmol/kg
o PO4/Mg/Ca++: 1-2mmol/kg of each

NaCl
With the osmotic diuresis, the water loss exceeds the NaCl loss.
Because of the osmotic shift of water in both the extra- and intra-cellular
space, plasma [Na+] is usually low or normal in DKA i.e. intra-cellular
water shifts to the extra-cellular matrix due to increased serum osmolality.
In HHS however, the plasma [Na+] can be increased.
The measured [Na+] can be corrected by adding 1.6 meq/L of [Na+] for
every 100mg/dL above 100mg/dL elevation in glucose. Keep in mind that
the measured sodium level is the actual [Na] in the blood and that the
corrected Na is a theoretical calculation that is a useful guideline for
hydration. Extreme lipemia can also decrease the measured Na value and
is an artifact.

K+
There is profound total body [K+] depletion in DKA and HHS. Urinary
losses with osmotic diuresis, inadequate oral intake, and emesis, which
are typical in DKA, lead to total body [K+] depletion.

DKA & HHS

At the time of presentation, however, plasma [K+] is normal or elevated

because of the shift that occurs from intracellular to extracellular space.
Etiologies for this [K+] shift include hyperglycemia / low insulin levels,
acidosis, and proteolysis. (Recall that one of the treatments for
hyperkalemia is glucose / insulin; the Na-K-ATPase pump is triggered by
insulin driving [K+] into the cells.)
Once insulin therapy is initiated, hypokalemia is unmasked; therefore
repletion should be initiated early in treatment.

PO4/Mg/Ca++
Profound hypophosphatemia often occurs in DKA resulting in depressed
levels of erythrocyte 2,3-DPG which decreases the P50 of oxyhemoglobin
(shifts the oxyHb curve leftward increasing O2 affinity). Initially, acidosis
counterbalances this by increasing the P50. Although replacement of PO4
is of theoretical benefit and it is standard of care in most institutions,
studies have shown no clear benefit.
PO4++ replacement can result in decreased levels of Mg/Ca++; therefore
these levels must also be closely monitored.
In maintaince fluids, K+ PO4++ rather than K+ Cl- can be used to avoid the
hyperchloremic acidosis sometimes seen during therapy.
Diagnosis:

Clinical Presentation
History: polyuria, polydipsia, polyphagia, and weight loss over the
preceding weeks
Precipitating factor: often infections, but often unidentifiable
Presenting signs: abdominal pain, vomiting and altered sensorium
Physical exam: lethargy, dehydration, hyperpnea and acetone (bitter
almonds) detected on their breath and often acutely ill
PICU admission: patients with profound shock, altered level of
consciousness, respiratory failure, arrhythmias, or severe acidosis

Differentiating DKA and HHS
DKA typically develops in younger, lean patients with type 1 diabetes.
HHS is more likely in older, obese, type 2 diabetes patients and symptoms
may develop more slowly.
Physical exam clues that help differentiate DKA from HHS:
o Acanthosis in axilla or neck area typical in Type 2 DM
o Assess thyroid palpable thyroid maybe consistent with autoimmune mediated endocrinopathy type I DM
o Kussmaul respirations deep respirations seen with type I DM
o Acetone on breath c/w type I DM
o Body habituslean or large

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Laboratory Findings
DKA:
Serum glucose >300 mg/dl
Blood pH < 7.3
Ketonuria, glucosuria
[HCO3-] < 15 mEq/L
Elevated betahydroxybutyrate in blood.

HHS:

Hyperglycemia is more severe

Blood pH may be > 7.30
Absent/trace ketones in urine
[HCO3-] may not be low
Serum osmolality >320
mmol/kg
Osm = [glu/18] +[BUN/2.8]
+[2(Na + K)]

Other laboratory values that can be abnormal in DKA patients but may not
represent significant comorbid disease are as follows:
Elevated WBC: usually due to stress & dehydration
Elevated amylase: usually nonpancreatic source, i.e. parotid, lipase must
be checked since pancreatitis is associated with HHS
Prolonged PT, PTT: etiology unclear

Admission labs / studies for DKA patient:
Comprehensive chemistry
panel
ABG / VBG
CBC w/diff
Serum osmoles
Urine ketones
Serum beta-hydroxybutyrate
Serum lactate
Insulin, C-peptide

Hemoglobin A-1C
T4, TSH
Anti-Islet cell Ab, anti-insulin
Ab (for new onset)
U/A
+/- Blood, urine culture
+/- CXR and EKG
Head CT if comatose

Management of DKA in the PICU

Fluids
DKA patients usually present with severe dehydration of 10-15% deficit.
Initial fluid therapy should be aimed at resuscitation and reversal of shock.
Begin with 10-20ml/kg bolus of isotonic crystalloid (NS) and repeat if
shock persists (i.e. tachycardia, poor perfusion, borderline or low BP).
For patients in DKA, fluids must be administered to correct shock but over
aggressive rapid hydration should be avoided. There is concern of rapid
hydration inciting cerebral edema and no clear data exists to date
supporting or refuting this theory.

3 components to fluid management in DKA:
Deficit

DKA & HHS

o The fluid deficit is typically replaced over the first 24 hours once
the shock state is treated.
Ongoing losses (urine, emesis)
o Some patients will continue to have a significant ongoing osmotic
diuresis throughout the early part of therapy. These losses should
be accounted for and replaced to prevent persistent shock.
Maintenance
o Isotonic maintenance fluids are started as 0.9%NaCl (NS). Typically
isotonic fluids (NS) are preferable in order to keep the serum Na+
from dropping during rehydration and to help prevent cerebral
edema. However, if with therapy the corrected serum Na+ is
becoming quite high (i.e. Na+ > 155) the maintenance fluids can be
changed to 1/2 or 3/4NS.
o In the absence of hyperkalemia (K+ <5.0 mEq/L) and in the
presence of adequate renal function, 40 mEq/L of K+ can be added
to the fluids (generally half as K+Cl- and half as K+PO4- as
discussed previously).
Example of a 20kg child:
o Deficit: patient presents 15% dehydrated the calculated deficit is
3 Liters. She receives 30ml/kg of NS in the ED 600ml. The
remainder of the fluid deficit should be replaced over 24 hrs: 3000
600 = 2400 or 100ml/hr of IVF.
o On going losses: Suppose the same 20kg child is voiding 200 ml/hr,
the losses can be replaced with either intermittent fluid blouses or
with a urine output replacement cc per cc or cc per cc every 24hrs. Either NS or NS can be used for replacement depending on
the corrected serum Na. Once the urine output has normalized,
<5cc/kg/hr, the replacement can be stopped.
o Maintaince: = 60 ml/hr (per the 4/2/1 rule)
Total hourly fluid rate = deficit + maint + ongoing losses =
100ml/hr + 60ml/hr + urine replacement (i.e. 200 cc of NS
x2hrs)

Adding Dextrose
Change IVF when
o Blood sugar < 300mg/dL, D5 NS
o Blood sugar < 200mg/dL, start D10 NS
2 bag system: one bag containing D5 fluids and a second bag with NS
along with each bag having 20 meq K+Cl- + 20 meq K+PO4- are titrated to
maintain a blood glucose of 150-250 mg/dL.
o For example: if the blood glucose is 230mg/dL with IVF at 160
ml/hr, start D5%NS bag at 80 ml/hr and decrease NS bag to 80
ml/hr = total fluids 160 ml/hr at D2.5%.

DKA & HHS

o Suppose next glucose is 180mg/dL increase the D5% bag to

100 ml/hr and decrease the NS bag to 60 ml/hr.
By appropriately titrating the glucose intake, rapid blood sugar decrease
to hypoglycemic levels can be prevented. 2-4 grams of glucose per unit
of insulin is required to maintain a stable blood glucose level.

Insulin therapy
A continuous infusion of regular insulin at 0.1 U/kg/hr.
o If the blood glucose levels are decreasing too quickly, dextrose
should be added to the IVF but the insulin infusion should
continue at the same rate since it is the primary treatment to
correct the acidosis.
o Its easily adjustable and safe.
o Hypoglycemia is generally avoided with a predictable,
consistent drop in glucose
o Potentially, less hypokalemia and more inhibition of lipolysis
occurs with a consistent dose of insulin
There is no established need for an initial IV bolus of 0.1 U/kg and no
data to support subcutaneous insulin administration for DKA. This rate
should produce a gradual decrease in glucose levels of about 50-100
mg/dl per hour.
In HHS patients, the insulin drip may require titration to achieve the
desired rate of fall of glucose and to improve the hyperosmolar state.
Patients with HHS are typically type-2 diabetics and are insulin resistant
rather than deficient and therefore may require more insulin to correct the
hyperosmolar state.
*Note: Insulin attaches to IV tubing and glass. Therefore, the insulin
infusion should be run through the tubing for 5-30 minutes prior to being
attached to the patient to provide a consistent dose of drug delivery.
Hyperglycemia corrects prior to the acidosis. The insulin infusion is
continued until the following conditions are met:
o HCO3- > 18
o Blood pH > 7.3
o Anion gap < 12
o Improved level of consciousness (GCS 15)
o Able to tolerate oral intake
Transitioning from continuous infusion to SQ insulin: order of events
o Check glucose, let the patient eat/drink, administer SQ dose per
sliding scale, and then stop the insulin drip. Heplock the dextrose
containing IVF only after confirming adequate oral intake without
emesis in order to avoid hypoglycemia.
o AT this point, the endocrinologist can initiate recommendations
regarding a regular and long acting insulin regimen.

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10 key elements to managing DKA in the ICU: Attention to detail is

important. (These are meant to be basic guidelines.)
1) Ensure 2 large bore IVs are present. A line for lab draws should be
established: a large bore PIV or an arterial line. A central venous catheter
would not be a first choice due to risk of thrombosis unless the patient
presents in shock.
2) All patients should be placed on a cardiac monitor. Serum glucose should
be monitored hourly and a chem.-10 with Na, K, Ca, Mg, PO4 along with a
blood gas should be done every 4 hours.
3) A Foley to monitor urine output is critical to assess ongoing losses and to
direct fluid therapy.
4) Obtain hourly neuro assessments including a GCS.
5) With ongoing therapy and rehydration the serum sodium should rise. A
decreasing sodium level can be a risk factor for cerebral edema.
6) A K+ level less than 3.0mEq/L should be corrected aggressively. Fatal
arrhythmias can occur at values <2.0
7) NaHCO3 should not be administered to DKA patients despite the severity
of acidosis. The risk of mortality and CNS complication are increased by
bicarbonate administration.
8) The insulin drip should not be titrated; the acidosis will only correct with
appropriate insulin administration.
9) Mannitol (0.25 gm/kg) should be at the bedside for acute cerebral edema
(i.e. pupillary changes, acute change in LOC)
10) Order several bags of IV fluids with and without dextrose at the time of
admission to seamlessly transition the patient to dextrose containing fluids
as the blood sugars decrease to 300 mg/dL. The IV fluids can be Y
together to achieve the desired dextrose concentration to maintain blood
glucose levels between 200-300 mg/dl.

DKA & HHS

Complications

Cerebral Edema: This is the most serious complication of DKA.
The pathophysiology is unclear. The potential etiologies include:
o Vasogenic edema: leaking of fluid across the blood-brain-barrier
o Cytotoxic edema: neuronal swelling due to cellular injury or
rapid extracellular osmolar changes
Risk factors for cerebral edema include:
o Children < 5 years of age
o High BUN suggesting greater dehydration
o Severity of acidosis
o Bicarbonate administration
o New diagnosis of diabetes
o Sodium levels dont rise as expected with insulin treatment (i.e.
fall in serum osmolality)
Assure serum Na+ level is rising with rehydration
Hourly neuro checks should be done for 12 hours after treatment
initiation. Any changes in neurologic status necessitate a stat head CT.
Patients with a GCS <8 necessitate intubation.
o For intubation induction, use the appropriate medications to blunt a
spike in the ICP.
o Once intubated, assure the mechanical ventilation matches the
patients CO2 level prior to intubation; i.e. if the patient is
hyperventilating to a CO2 level of 11, match it to prevent worsening
ICP elevation.
Mannitol should be administered, 0.5 gm/kg IV slow push, for acute
mental status changes. Assure a foley is placed for the ensuing diuresis.
If the serum Na+ is dropping with therapy, consider hypertonic saline
3%NS in a small bolus of 3-5cc/kg.
If head CT reveals cerebral edema or the patient has deteriorating
neurologic status, consult neurosurgery for potential need of ICP
monitoring.
Persistent dehydration can also present with mental status changes.
Therefore the patients hydration status should be closely monitored and
fluids aggressively replaced.
Hypoglycemia can also present with mental status changes and must be
ruled out while evaluating a patient with sudden drop in GCS.

Hyperchloremic metabolic acidosis
May occur as part of normal rehydration therapy and has no has no
significant clinical consequences.
However, if acidosis persists after the first 24 hours, urine ketones should
be followed to assure the DKA is resolving. The length of insulin therapy
is not prolonged due to hyperchloremic metabolic acidosis.

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ARDS
Occasionally, DKA patients present in shock and may have low albumin at
the time of presentation due to poor nutrition. Rapid fluid shifts during
resuscitation and rehydration may lead to capillary leak and interstitial
pulmonary edema and ARDS. It is a rare complication in the pediatric
population.

Thrombosis
Because of severe dehydration and a general low flow state, a risk of
thrombosis is present with central line placement. Thrombii have
particularly been noted with femoral lines.
Consider subclavian or IJ lines for patients in shock that require CVP
monitoring or in whom access is difficult. Consider low dose heparin drip
(10 U/kg/hr) to help prevent clot formation.

Hypoglycemia
Assure the IVF and insulin therapy is appropriately managed to prevent
low blood sugar levels.

Hypokalemia
Can be avoided with frequent monitoring and meticulous attention to fluid
management.
Hypokalemia can cause fatal arrhythmias. Saline boluses, or calcium can
amplify the decrease in potassium levels. Therefore, every effort should
be made to maintain a level of 4.0 mEq/L.

DKA & HHS