DKA & HHS

INTRODUCTION
Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also
known as hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the
most serious acute complications of diabetes. DKA is characterized by
ketoacidosis and hyperglycemia, while HHS usually has more severe
hyperglycemia but no ketoacidosis. Each represents an extreme in the spectrum
of hyperglycemia.
PRECIPITATING FACTORS
A precipitating event can usually be identified in patients with diabetic
ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS). The most
common events are infection (often pneumonia or urinary tract infection) and
discontinuation of or inadequate insulin therapy. Compromised water intake due
to underlying medical conditions, particularly in older patients, can promote the
development of severe dehydration and HHS.
Other conditions and factors associated with DKA and HHS include:

1
DKA & HHS

CLINICAL PRESENTATION
ONSET: Diabetic ketoacidosis (DKA) usually evolves rapidly, over a 24-hour
period. In contrast, symptoms of hyperosmolar hyperglycemic state (HHS)
develop more insidiously with polyuria, polydipsia, and weight loss, often
persisting for several days before hospital admission.
The earliest symptoms of marked hyperglycemia are polyuria, polydipsia, and
weight loss.

As the degree or duration of hyperglycemia progresses, neurologic symptoms,

including lethargy, focal signs, and obtundation, can develop. This can progress
to coma in later stages. Neurologic symptoms are most common in HHS,
while hyperventilation and abdominal pain are primarily limited to
patients with DKA.
Neurologic symptoms
Neurologic deterioration primarily occurs in patients with an effective plasma
osmolality (Posm) above 320 to 330 mosmol/kg.
Mental obtundation and coma are more frequent in HHS than DKA because of
the usually greater degree of hyperosmolality in HHS. In addition, some
patients with HHS have focal neurologic signs (hemiparesis or hemianopsia)
and/or seizures.
Mental obtundation may occur in patients with DKA, who have lesser degrees
of hyperosmolality, when severe acidosis exists. However, stupor or coma in
diabetic patients with an effective Posm lower than 320 mosmol/kg demands
immediate consideration of other causes of the mental status change.
Abdominal pain in DKA
Patients with diabetic ketoacidosis (DKA) may present with nausea, vomiting,
and abdominal pain; although more common in children, these symptoms can
be seen in adults.
Abdominal pain is unusual in HHS.
Abdominal pain was associated with the severity of the metabolic acidosis
but did not correlate with the severity of hyperglycemia or dehydration.
Possible causes of abdominal pain include delayed gastric emptying and ileus
induced by the metabolic acidosis and associated electrolyte abnormalities.
Other causes for abdominal pain, such as pancreatitis, should be sought when
they occur in the absence of severe metabolic acidosis and when they persist
after the resolution of ketoacidosis.
--------------------------------------------------------------------------------
2
DKA & HHS

Physical examination
Signs of volume depletion are common in both DKA and HHS and include
 decreased skin turgor, dry axillae and oral mucosa,
 low jugular venous pressure, tachycardia,
 and, if severe, hypotension. Neurologic findings, noted above, also may
be seen, particularly in patients with HHS.

Patients with DKA may have a fruity odor and deep respirations reflecting the
compensatory hyperventilation (called Kussmaul respirations).
--------------------------------------------------------------------------
DIAGNOSTIC EVALUATION
Both diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state
(HHS) are medical emergencies that require prompt recognition and
management.
Initial evaluation
The initial evaluation of patients with hyperglycemic crises should include
assessment of cardiorespiratory status, volume status, and mental status.

The initial history and rapid but careful physical examination should focus on:
 Airway, breathing, and circulation (ABC) status
 Mental status
 Possible precipitating events (eg, source of infection, myocardial
infarction)
 Volume status

The initial laboratory evaluation of a patient with suspected DKA or HHS

should include determination of:
 Serum glucose
 Serum electrolytes (with calculation of the anion gap), blood urea
nitrogen (BUN), and plasma creatinine
 Complete blood count (CBC) with differential
 Urinalysis and urine ketones by dipstick
 Plasma osmolality (Posm)
 Serum beta-hydroxybutyrate (if urine ketones are present)
 Arterial blood gas if the serum bicarbonate is substantially reduced or
hypoxia is suspected
 Electrocardiogram

3
DKA & HHS

Additional testing, such as cultures of urine, sputum, and blood, serum lipase
and amylase, and chest radiograph should be performed on a caseby-case basis.
Infection (most commonly pneumonia and urinary tract infection) is a common
precipitating event. Thus, cultures should be obtained if there are suggestive
clinical findings. Recognize that infection may exist in the absence of fever in
these patients.

Measurement of glycated hemoglobin (A1C) may be useful in determining

whether the acute episode is the culmination of an evolutionary process in
previously undiagnosed or poorly controlled diabetes or a truly acute episode in
an otherwise well-controlled patient.
---------------------------------------------------------------------------------
Laboratory findings
Hyperglycemia and hyperosmolality are the two primary laboratory findings in
patients with DKA or HHS; patients with DKA also have a high anion gap
metabolic acidosis.

Serum glucose
Classic presentation – The serum glucose concentration may exceed 1000
mg/dL (56 mmol/L) in HHS, but it is generally less than 800 mg/dL (44
mmol/L) and often in the 350 to 500 mg/dL (19.4 to 27.8 mmol/L) range in
DKA.

Euglycemic DKA – Euglycemic DKA, in which the serum glucose is normal or

near normal, has been described, particularly in
 patients with poor oral intake,
 treatment with insulin prior to arrival in the emergency department,
 pregnant women,
 And with sodium-glucose co-transporter 2 (SGLT2) inhibitors.

When SGLT2 inhibitors block the sodium-glucose co-transporter 2, the

resulting glucosuria can minimize or prevent the development of
hyperglycemia, despite very low insulin levels/activity and development of
ketoacidosis.

Patients with euglycemic diabetic ketoacidosis generally require both insulin

and glucose to reverse the ketoacidosis.

4
DKA & HHS

Serum ketones
Three ketone bodies are produced and accumulate in DKA:
1. acetoacetic acid, which is the only one that is a true keto-acid;
2. betahydroxybutyric acid (a hydroxyacid formed by the reduction of
acetoacetic acid);
3. and acetone, which is derived from the decarboxylation of acetoacetic
acid. Acetone is a true ketone, not an acid.

Testing for serum ketones is generally performed if urine testing is positive.

Urine ketone bodies are detected with nitroprusside tests, while serum ketones
can be detected with either a nitroprusside test or by direct assay of beta-
hydroxybutyrate levels. Direct assay of beta-hydroxybutyrate levels is preferred,
particularly for monitoring response to therapy.

Nitroprusside testing

This chemical develops a purple color in the presence of acetoacetic acid (and to
a much lesser degree, acetone). Urine dipstick testing with nitroprusside tablets
or reagent sticks is widely utilized, and results are available within minutes.
Although semiquantitative serum ketone testing with nitroprusside was the
major methodology used for detecting elevated blood ketoacid and acetone
levels for many years, it has now been replaced by direct measurement of serum
beta-hydroxybutyrate levels.
Direct measurement of serum beta-hydroxybutyrate

The serum nitroprusside test for ketone bodies has been largely replaced by
direct assays for beta-hydroxybutyrate. Direct assays for serum beta-
hydroxybutyrate eliminate the problems associated with nitroprusside testing
(eg, false positives and false negatives).

One limitation of most of these direct assays, however, is that beta-

hydroxybutyrate is not quantitated above a level of 6 mEq/L. An ideal assay for
"ketoacids" would measure the concentrations of both acetoacetate and beta-
hydroxybutyrate.

Point-of-care bedside analyzers to measure capillary blood betahydroxybutyrate

are becoming increasingly available.

Anion gap metabolic acidosis

The serum anion gap is calculated as follows:
Serum anion gap = Serum sodium - (serum chloride + bicarbonate)

5
DKA & HHS

By convention, it is the actual measured plasma sodium concentration and not

the sodium concentration corrected for the simultaneous glucose concentration
that is used for this calculation.

The serum bicarbonate concentration in DKA is usually moderately to markedly

reduced. In contrast, the serum bicarbonate concentration is normal or only
mildly reduced in HHS. Patients with DKA usually present with a serum anion
gap greater than 20 mEq/L (reference range approximately 3 to 10 mEq/L). In
patients with DKA, the elevated anion gap metabolic acidosis is caused by the
accumulation of beta-hydroxybutyric and acetoacetic acids.

However, the increase in anion gap is variable, being determined by several

factors:
 the rate and duration of ketoacid production
 the rate of metabolism of the ketoacids and their loss in the urine
 and the volume of distribution of the ketoacid anions.

Plasma osmolality
Plasma osmolality (Posm) is always elevated in patients with HHS but less so
with DKA. The typical total body deficits of water and electrolytes in DKA and
HHS are compared in this table.

In patients with HHS, the effective Posm is typically >320 mosmol/kg

(reference range approximately 275 to 295 mosmol/kg).

Effective Posm (in mosmol/kg) is the portion of total osmolality that is

generated by sodium salts and glucose (and, if present, mannitol or sucrose).
Effective osmoles do not penetrate most cell membranes and can cause

6
DKA & HHS

movement of water across membranes to achieve osmolal equilibrium. Effective

Posm does not include "ineffective" osmoles, such as urea, because urea is
rapidly permeable across most cell membranes and its accumulation does not
induce major water shifts between the intracellular spaces (including the brain)
and the extracellular water space.

Effective osmolality can be estimated with either of the following equations,

depending upon the units for sodium (Na) and glucose:
Effective Posm = [2 x Na (mEq/L)] + [glucose (mg/dL) ÷ 18]
Effective Posm = [2 x Na (mmol/L)] + glucose (mmol/L)
The Na concentration in these equations is the actual measured plasma Na
concentration and not the corrected Na concentration. The Na is multiplied
by two to account for the osmotic contribution of sodium's accompanying
anions (primarily chloride and bicarbonate).
Eighteen is a factor to convert glucose units from mg/dL into mmol/L.
If the Posm is measured, using a freezing point reduction osmometer, the result
is the total osmolality. Because effective osmolality excludes urea osmoles
(BUN), it can be estimated as:
Effective Posm = Measured Posm - [BUN (mg/dL) ÷ 2.8]
Effective Posm = Measured Posm - BUN (mmol/L)
2.8 is a factor to convert urea concentration from units of mg/dL into
mmol/L.
Serum sodium
Most patients with DKA and HHS are mildly hyponatremic. However, patients
with HHS who have a marked osmotic diuresis may present with a normal or
even elevated serum Na concentration, despite a markedly elevated serum
glucose concentration that can exceed 1000 mg/dL (56 mmol/L). These patients
have a markedly elevated effective Posm and often have neurologic symptoms
that can include seizures and coma.

Inadequate water intake contributes to the hyperosmolality and is a particular

problem in hot weather and in older individuals who may have an impaired
thirst mechanism.

The measured serum Na concentration in uncontrolled diabetes mellitus is

variable because of the interaction of multiple factors, some that lower Na

7
DKA & HHS

concentration and others that raise it. The increase in Posm created by
hyperglycemia pulls water out of the cells, and this reduces the plasma Na
concentration.
Physiologic calculations suggest that, in the absence of urine losses, the serum
Na concentration should fall by approximately 1.6 mEq/L for each 100 mg/100
mL (5.5 mmol/L) increase in glucose concentration
Pseudohyponatremia/pseudohyperchloremia
Some patients with uncontrolled diabetes develop marked hyperlipidemia and
have lactescent serum. This can create electrolyte artifacts when certain
analyzers are utilized. Hyperlipidemia will displace water and thereby reduce
the plasma water phase fraction below its normal 93 percent. If any step in the
analysis requires an exact volume of plasma (or serum), then a reduced amount
of water (and electrolyte) will be analyzed. This can result in
"pseudohyponatremia." This artifact occurs with any flame photometric analysis
and most indirect potentiometric or ion selective electrode methods. However,
direct potentiometry analytical methods are generally not susceptible to this
artifact.
However, hyperlipidemia can also have an opposite artifactual effect on the
chloride concentration when certain chloride analyzers are employed,
generating marked pseudohyperchloremia.
Serum potassium
Patients presenting with DKA or HHS have a potassium deficit that averages
300 to 600 mEq. A number of factors contribute to this deficit, particularly
increased urinary losses due both to the glucose osmotic diuresis and to the
excretion of potassium ketoacid anion salts.
Despite these total body potassium deficits, hypokalemia is observed in only
approximately 5 percent of cases. The serum potassium concentration is usually
normal or, in one-third of patients, elevated on admission. This is due to a shift
of potassium from intracellular fluid to extracellular fluid (ECF) caused by
hyperosmolality and insulin deficiency.
Insulin therapy shifts potassium into cells and lowers the potassium
concentration. This may cause severe hypokalemia, particularly in patients who
present with a normal or low serum potassium concentration.
Careful monitoring and timely administration of potassium supplementation are
essential.

8
DKA & HHS

Serum phosphate
Patients with uncontrolled hyperglycemia are typically in negative phosphate
balance because of decreased phosphate intake, an acidosis-related shift of
phosphate into the ECF when metabolic acidosis exists, and phosphaturia
caused by osmotic diuresis.
Despite phosphate depletion, the serum phosphate concentration at presentation
is usually normal or even high because both insulin deficiency and metabolic
acidosis cause a shift of phosphate out of the cells and as a result of ECF
volume contraction.
This transcellular shift is reversed and the true state of phosphate balance is
unmasked after treatment with insulin and volume expansion.

Serum creatinine
Most patients with uncontrolled hyperglycemia have acute elevations in the
BUN and serum creatinine concentration, which reflect the reduction in
glomerular filtration rate induced by hypovolemia. High acetoacetate levels can
also artifactually increase serum creatinine levels when certain colorimetric
assays are utilized. However, most laboratories now utilize enzymatic assays,
which are not affected by this artifact.

Serum amylase and lipase

Acute pancreatitis may precipitate or complicate DKA. Serum amylase and
lipase are generally used to diagnose acute pancreatitis, but each of these
enzymes is often elevated in patients with DKA who do not have any other
clinical or radiological evidence of pancreatitis. Therefore, the diagnosis of
pancreatitis in patients with DKA should be primarily based upon clinical
findings and imaging.

Leukocytosis
The majority of patients with hyperglycemic emergencies present with
leukocytosis, which is proportional to the degree of ketonemia. Leukocytosis
unrelated to infection may occur as a result of hypercortisolemia and increased
catecholamine secretion. However, a white blood cell count greater than
25,000/microL or more than 10 percent bands increases suspicion for infection
and should be evaluated.

9
DKA & HHS

Lipids
Patients with DKA or HHS may present with marked hyperlipidemia and
lactescent serum.
Triglycerides fell below 150 mg/dL (1.7 mmol/L) in 24 hours with insulin
therapy.
Lipolysis in DKA, and to a lesser extent in HHS, is due to insulin deficiency,
combined with elevated levels of lipolytic hormones (catecholamines, growth
hormone, corticotropin [ACTH], and glucagon). Lipolysis releases glycerol and
free fatty acids into the circulation. High levels of serum fatty acids cause
insulin resistance at both the peripheral and the hepatic level, and they serve as
the substrate for ketoacid generation in hepatocyte mitochondria.
Insulin is the most potent anti-lipolytic hormone.
------------------------------------------------------------------------------
DIAGNOSTIC CRITERIA

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are

distinguished by the absence of ketoacidosis and usually greater degree of
hyperglycemia in HHS. The diagnostic criteria proposed by the American
Diabetes Association (ADA) for mild, moderate, and severe DKA and HHS.

10
 DKA & HHS

DKA is characterized by the triad of In HHS,

hyperglycemia: . The serum glucose  there is little or no ketoacid
concentration is usually less than 800 accumulation
mg/dL (44 mmol/L) and commonly between  the serum glucose concentration may
350 to 500 mg/dL (19.4 to 27.8 mmol/L). exceed 1000 mg/dL (56 mmol/L),
However, serum glucose concentrations  the plasma osmolality (Posm) may
may exceed 900 mg/dL (50 mmol/L) in reach 380 mosmol/kg,
patients with DKA who are comatose. In  And neurologic abnormalities are
certain settings the glucose level may be frequently present (including coma in
mildly elevated or even normal. 25 to 50 percent of cases).
anion gap metabolic acidosis: Metabolic Most patients with HHS have an admission
acidosis is often the major finding pH >7.30, a serum bicarbonate >20 mEq/L, a
and ketonemia. serum glucose >600 mg/dL (33.3 mmol/L),
and test negative for ketones in serum and
urine, although mild ketonemia may be
present.
---------------------------------------------------------------------------------------------
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of hyperglycemic crises includes other causes of
ketosis, acidosis, hyperosmolality, and/or coma.
Anion gap acidosis
Diabetic ketoacidosis (DKA) must be distinguished from other causes of high
anion gap metabolic acidosis.

11
DKA & HHS

Alcoholic and fasting ketoacidosis

Alcoholic ketoacidosis (AKA) and starvation ketosis are other causes of
ketoacidosis. Low-carbohydrate diets can also precipitate ketoacidosis.

Metabolic acidosis can be relatively severe in patients with AKA. However,

when ketoacidosis develops as a result of starvation, it is usually relatively mild.
Ketoacid levels with prolonged fasting rarely exceed 8 to 10 mEq/L, and the
serum bicarbonate concentration is typically greater than 17 mEq/L. More
severe ketoacidosis may develop with prolonged fasting in children and
pregnant women.

Ketoacidosis without hyperglycemia in a patient with chronic alcoholism is

virtually diagnostic of AKA. Modest elevations in serum glucose in patients
with alcoholic ketoacidosis may reflect underlying unrecognized diabetes or a
catecholamine-mediated stress response. Measurement of glycated hemoglobin
(A1C) can confirm chronic hyperglycemia.

Metabolic encephalopathy
Toxic metabolic encephalopathy is usually a consequence of systemic illness,
and its causes are diverse. In patients with diabetes, both severe hypoglycemia
and severe hyperglycemia can result in coma. Measurement of fingerstick
(capillary) or plasma glucose may be diagnostic.

Acute abdomen
----------------------------------------------------------------------------------------

12
 DKA & HHS

TREATMENT
Overview and protocols — The treatment of DKA ( algorithm 1) and HHS (
algorithm 2) is similar, including correction of the fluid and electrolyte
abnormalities that are typically present (hyperosmolality, hypovolemia,
metabolic acidosis [in DKA], and potassium depletion) and the administration
of insulin.
DKA algorithm

HHS algorithm

13
DKA & HHS

Correction of fluid and electrolyte abnormalities – The first step in the

treatment of DKA or HHS is infusion of isotonic saline to
 Expand extracellular volume and stabilize cardiovascular status.
 This also increases insulin responsiveness by lowering the plasma
osmolality (Posm), reducing vasoconstriction and improving perfusion,
and reducing stress hormone levels.

The next step is correction of the potassium deficit (if present). The choice of
fluid replacement should be influenced by the potassium deficit. The osmotic
effect of potassium repletion must be considered since potassium is as
osmotically active as sodium.
Administration of insulin – Low-dose intravenous (IV) insulin should be
administered to all patients with moderate to severe DKA who have a serum
potassium ≥3.3 mEq/L.
N.B. If the serum potassium is less than 3.3 mEq/L, insulin therapy should be
delayed until potassium replacement has begun and the serum potassium
concentration has increased. The delay is necessary because insulin will worsen
the hypokalemia by driving potassium into the cells, and this could trigger
cardiac arrhythmias.
IV regular insulin and rapid-acting insulin analogs are equally effective in
treating DKA.
Fluid replacement
Type of fluid:
In patients with DKA or HHS, we recommend IV electrolyte and fluid
replacement to correct both hypovolemia and hyperosmolality.
Fluid repletion may be initiated with isotonic saline (0.9 percent sodium
chloride [NaCl]) or isotonic buffered crystalloid (eg, Lactated Ringer).

Patients with euglycemic DKA generally require both insulin and glucose to
treat the ketoacidosis and prevent hypoglycemia, respectively, and in such
patients, dextrose is added to IV fluids at the initiation of therapy. For patients
with a more classic presentation of hyperglycemic DKA, we add dextrose to the

14
 DKA & HHS

saline solution when the serum glucose declines to 200 mg/dL (11.1 mmol/L) in
DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS.
Rate of fluid:
In patients with hypovolemic shock, isotonic saline should initially be infused
as quickly as possible.

In hypovolemic patients without shock or heart failure, isotonic saline is infused

at a rate of 15 to 20 mL/kg lean body weight per hour (approximately 1000
mL/hour in an average-sized person) for the first couple of hours, with a
maximum of <50 mL/kg in the first four hours.

In euvolemic patients, isotonic saline is infused at a lower rate, guided by

clinical assessment.

After the second or third hour, optimal fluid replacement depends upon the state
of hydration, serum electrolyte levels, and the urine output. The most
appropriate IV fluid composition is determined by the sodium concentration
"corrected" for the degree of hyperglycemia. The "corrected" sodium
concentration can be approximated by adding 2 mEq/L to the plasma sodium
concentration for each 100 mg/100 mL (5.5 mmol/L) increase above normal in
glucose concentration.

If the "corrected" serum sodium concentration is

Less than 135 mEq/L, isotonic saline should Normal or elevated, the IV fluid is generally
be continued at a rate of approximately 250 switched to one-half
to 500 mL/hour isotonic saline at a rate of 250 to 500
mL/hour in order to provide
electrolyte-free water

N.B. The timing of one-half isotonic saline therapy may also be influenced by the need for
potassium replacement. Potassium salts have an osmotic effect equivalent to sodium salts,
and adding potassium to isotonic fluids generates a hypertonic solution. Thus, significant
potassium replacement may be another indication for the use of one-half isotonic saline.

15
DKA & HHS

Correction of the hyperosmolar state may enhance the response to low-dose

insulin therapy. Adequacy of fluid replacement is judged by frequent
hemodynamic and laboratory monitoring. In patients with abnormal renal or
cardiac function, more frequent monitoring must be performed to avoid
iatrogenic fluid overload. The goal is to correct estimated deficits within the
first 24 hours. However, osmolality should not be reduced too rapidly, because
this may generate cerebral edema.

Potassium replacement
Potassium replacement is initiated immediately if the serum potassium is ≤5.3
mEq/L, provided urine output is adequate (approximately >50 mL/hour).
Almost all patients with DKA or HHS have a substantial potassium deficit,
usually due to urinary losses generated by the glucose osmotic diuresis and
secondary hyperaldosteronism. Despite the total body potassium deficit, the
serum potassium concentration is usually normal or, in approximately one-third
of cases, elevated at presentation. This is largely due to insulin deficiency and
hyperosmolality, each of which cause potassium movement out of the cells:
 If the initial serum potassium is below 3.3 mEq/L, insulin should not be
administered until the potassium has been raised above this threshold. IV
potassium chloride (KCl; 20 to 40 mEq/hour, which usually requires 20
to 40 mEq/L added to saline) should be given.
The choice of replacement fluid (isotonic or one-half isotonic saline) depends
upon
 the state of hydration
 corrected sodium concentration

16
 DKA & HHS

 dose of KCl
 blood pressure
 and a clinical assessment of overall volume status.
Patients with marked hypokalemia require aggressive potassium replacement
(40 mEq/hour, with additional supplementation based upon hourly serum
potassium measurements) to raise the serum potassium concentration above 3.3
mEq/L.

 If the initial serum potassium is 3.3 to 5.3 mEq/L, IV KCl (20 to 30

mEq) is added to each liter of IV replacement fluid. Adjust potassium
replacement to maintain the serum potassium concentration in the range
of 4 to 5 mEq/L.

 If the initial serum potassium concentration is greater than 5.3 mEq/L,

then potassium replacement should be delayed until the serum
concentration has fallen below this level.
N.B. Potassium salts added to IV fluids have the same osmotic effect as sodium salts, and
this should be considered when determining the potential impact of IV fluid infusion on
osmolality. As an example, 40 mEq of KCl added to 1 L of fluid generates 80 mOsmol/L of
electrolyte osmolarity. The addition of 40 mEq of potassium to 1 L of one-half isotonic
saline creates a solution with an osmolarity of 234 mOsmol/L (77 mEq NaCl and 40 mEq
KCl), which is osmotically equal to three-quarters isotonic saline. (The osmolarity of
isotonic saline is 308 mOsmol/L.) If 40 mEq of KCl is added to isotonic saline, the final
osmolarity will be approximately 388 mOsmol/L. However, KCl will not have the same
extracellular fluid (ECF) expansion effect as NaCl, because most of the potassium will shift
into cells very rapidly.

-------------------------------------------------------------------------------------
Insulin
We recommend initiating treatment with low-dose IV insulin in all patients with
moderate to severe DKA or HHS who have a serum potassium ≥3.3 mEq/L.
The only indication for delaying the initiation of insulin therapy is if the serum
potassium is below 3.3 mEq/L since insulin will worsen the hypokalemia by
driving potassium into the cells. Patients with an initial serum potassium below
3.3 mEq/L should receive fluid and potassium replacement prior to treatment
with insulin. Insulin therapy should be delayed until the serum potassium is
≥3.3 mEq/L to avoid complications such as cardiac arrhythmias, cardiac arrest,
and respiratory muscle weakness.

17
 DKA & HHS

TYPE OF INSULIN:
IV regular insulin and rapid-acting insulin analogs are equally effective in
treating DKA. The choice of IV insulin is based upon institutional preferences,
clinician experience, and cost concerns. We generally prefer regular insulin,
rather than rapid-acting insulin analogs, due to its much lower cost.
N.B. For acute management of DKA or HHS, there is no role for longor intermediate-acting
insulin; however, long-acting (glargine, detemir) or intermediate-acting (NPH) insulin is
administered after recovery from ketoacidosis, prior to discontinuation of IV insulin, to
ensure adequate insulin levels after IV insulin is discontinued.

In this setting, we do not use degludec or ultra-long-acting U-300 insulin glargine (given
their long halflife) as it will take at least three to four days to reach steady state.

In patients with mild DKA (particularly in patients with mild DKA due to rationed or
missed doses of basal insulin), intermediate- or long-acting insulin can be administered at
the initiation of treatment, along with rapidacting insulin.

RATE OF insulin administration:

Intravenous regular insulin: In HHS or moderate to severe DKA, treatment
can be initiated with an IV bolus of regular insulin (0.1 units/kg body weight) in
order to raise insulin levels rapidly, followed within five minutes by a
continuous infusion of regular insulin of 0.1 units/kg per hour (equivalent to 7
units/hour in a 70-kg patient). Alternatively, the bolus dose can be omitted if a
higher dose of continuous IV regular insulin (0.14 units/kg per hour, equivalent
to 10 units/hour in a 70-kg patient) is initiated.
These doses of IV regular insulin usually decrease the serum glucose
concentration by approximately 50 to 70 mg/dL (2.8 to 3.9 mmol/L) per hour.
Higher doses do not generally produce a more prominent glucose-lowering
effect, probably because the insulin receptors are fully saturated and activated
by the lower doses.

However, if the serum glucose does not fall by at least 50 to 70 mg/dL (2.8 to
3.9 mmol/L) from the initial value in the first hour, check the IV access to be
certain that the insulin is being delivered and that no IV line filters that may
bind insulin have been inserted into the line. After these possibilities are
eliminated, the insulin infusion rate should be doubled every hour until a steady
decline in serum glucose of this magnitude is achieved.

18
DKA & HHS

The fall in serum glucose is the result of both insulin activity and the beneficial
effects of volume repletion. Volume repletion alone can initially reduce the
serum glucose by 35 to 70 mg/dL (1.9 to 3.9 mmol/L) per hour due to the
combination of ECF expansion; reduction of plasma osmolality; increased
urinary losses resulting from improved renal perfusion and glomerular filtration;
and a reduction in the levels of "stress hormones," which oppose the effects of
insulin. The serum glucose levels often fall more rapidly in patients with HHS
who are typically more volume depleted.
When the serum glucose approaches 200 mg/dL (11.1 mmol/L) in DKA or 250
to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS, switch the IV saline solution to 5
percent dextrose in saline and attempt to decrease the insulin infusion rate to
0.02 to 0.05 units/kg per hour.
Intravenous insulin analogs — there is no advantage of rapid-acting or ultra-
rapid-acting insulin analogs over regular insulin. Intravenous regular insulin and
glulisine insulin are equally effective and equipotent for the treatment of DKA
Subcutaneous insulin regimens — Patients with mild DKA can be safely
treated with subcutaneous, rapid-acting insulin analogs on a general medical
floor or in the emergency department but only when adequate staffing is
available to carefully monitor the patient and check capillary blood glucose with
a reliable glucose meter, typically every hour.
Treatment of DKA with subcutaneous insulin has not been evaluated in severely
ill patients.
Bicarbonate and metabolic acidosis
Although the indications for sodium bicarbonate therapy to help correct
metabolic acidosis are controversial, there are selected patients who may benefit
from cautious alkali therapy. They include:
 Patients with an arterial pH <6.9 in whom decreased cardiac
contractility and vasodilatation can impair tissue perfusion. At an arterial
pH above 7.0, most experts agree that bicarbonate therapy is not
necessary since therapy with insulin and volume expansion will largely
reverse the metabolic acidosis.

For patients with pH <6.9, we give 100 mEq of sodium bicarbonate in

400 mL sterile water administered over two hours. If the serum potassium
is less than 5.3 mEq/L, we add 20 mEq of KCl. When the bicarbonate
concentration increases, the serum potassium may fall and more
aggressive KCl replacement may be required.

19
 DKA & HHS

 Patients with potentially life-threatening hyperkalemia, since

bicarbonate administration in acidemic patients may drive potassium into
cells, thereby lowering the serum potassium concentration. The exact
potassium level that should trigger this intervention has not been defined;
we administer sodium bicarbonate if the potassium level is >6.4 mEq/L.

The venous pH and bicarbonate concentration should be monitored every two

hours, and bicarbonate doses can be repeated until the pH rises above 7.0.

N.B.Bicarbonate administration is also controversial because, in addition to lack of evidence

for benefit, there are several potential harmful effects:
 If bicarbonate infusion successfully increases the blood bicarbonate concentration,
this can reduce the hyperventilatory drive, which will raise the blood partial pressure
of carbon dioxide (pCO). Increased blood carbon dioxide (CO) tension is more
quickly reflected across the blood brain barrier than the increased arterial bicarbonate.
This may cause a paradoxical fall in cerebral pH. Although neurologic deterioration
has been attributed to this mechanism, it remains a very controversial effect and, if it
occurs, is rare.
 The administration of alkali may slow the rate of recovery of the ketosis. In a study of
seven patients, the three patients treated with bicarbonate had a rise in serum ketoacid
anion levels and a six-hour delay in resolution of ketosis. Animal studies indicate that
bicarbonate infusion can accelerate ketogenesis. This is thought to be related to the
fact that acidemia has a "braking effect" on organic acid generation. This brake is
lessened by any maneuver that increases systemic pH.

 Alkali administration can lead to a post-treatment metabolic alkalosis since

metabolism of ketoacid anions with insulin results in the generation of bicarbonate
and spontaneous correction of most of the metabolic acidosis.

Phosphate depletion
Based upon the observations described below, we do not recommend the
routine use of phosphate replacement in the treatment of DKA or HHS.
However, phosphate replacement should be strongly considered if severe
hypophosphatemia occurs (serum phosphate concentration below 1 mg/dL or
0.32 mmol/L), especially if cardiac dysfunction, hemolytic anemia, and/or
respiratory depression develop. When needed, potassium or sodium phosphate
20 to 30 mEq can be added to 1 L of IV fluid.

20
DKA & HHS

MONITORING
General
 The serum glucose should initially be measured every hour until stable.
 While serum electrolytes, blood urea nitrogen (BUN), creatinine, and
venous pH (for DKA) should be measured every two to four hours,
depending upon disease severity and the clinical response. In-patient
serum glucose measurement should be done with hospital-approved
bedside devices or in the chemistry laboratory and not with continuous
glucose monitoring (CGM) devices.
It is strongly suggested that a flow sheet of laboratory values and clinical
parameters be utilized because it allows better visualization and evaluation of
the clinical picture throughout treatment of DKA:

N.B. Monitoring with arterial blood gases is unnecessary during the treatment
of DKA; venous pH, which is approximately 0.03 units lower than arterial pH,
is adequate to assess the response to therapy and avoids the pain and potential
complications associated with repeated arterial punctures.

21
DKA & HHS

Resolution of DKA/HHS
the hyperglycemic crisis is considered to be resolved when the following goals
are reached:
 The ketoacidosis has resolved, as evidenced by normalization of the
serum anion gap (less than 12 mEq/L) and, when available, blood
betahydroxybutyrate levels

 Patients with HHS are mentally alert and the effective plasma osmolality
has fallen below 315 mOsmol/kg

 The patient is able to eat

Converting to subcutaneous insulin — For patients with DKA, we initiate a
multiple-dose (basal-bolus), subcutaneous insulin schedule when the
ketoacidosis has resolved and the patient is able to eat.

If the patient is unable to eat, it is preferable to continue the IV insulin

infusion. For patients with HHS, IV insulin infusion can be tapered and a
multiple-dose (basal-bolus), subcutaneous insulin schedule started when the
serum glucose falls below 250 to 300 mg/dL (13.9 to 16.7 mmol/L).

The most convenient time to transition to subcutaneous insulin is before a meal.

The IV insulin infusion should be continued for two to four hours after initiating
the short- or rapid-acting subcutaneous insulin because abrupt discontinuation
of IV insulin acutely reduces insulin levels and may result in recurrence of
hyperglycemia and/or ketoacidosis. Basal insulin (NPH, U-100 glargine, or
detemir) can be administered either (a) at the same time as the first injection of
rapid-acting insulin, or (b) earlier (for example, the previous evening), along
with a decrease in the rate of IV insulin infusion. We typically do not administer
degludec or U-300 glargine as the basal insulin when transitioning from IV
insulin due to its very long half-life, and subsequently, the time it takes to reach
steady state (two to three days).

For patients with known diabetes who were previously being treated with
insulin, their pre-DKA or pre-HHS insulin regimen may be restarted. For
patients who are treated with continuous subcutaneous insulin infusion (insulin
pump), the previous basal rate can be resumed. However, if the IV insulin
requirements are significantly higher than their usual insulin requirements, it is
reasonable to increase the basal rate temporarily. For those using partially
automated insulin delivery (hybrid closed-loop) systems, it is also reasonable to
stay in "manual mode" for the first 24 to 48 hours while insulin requirements

22
DKA & HHS

return to baseline. If automated insulin delivery is immediately resumed, blood

glucose levels likely will be higher for the first few days.
In patients with new-onset type 1 diabetes who have presented with DKA, an
initial total daily dose (TDD) of 0.5 to 0.8 units/kg units of insulin per day is
reasonable, until an optimal dose is established. Approximately 40 to 50 percent
of the TDD should be given as a basal insulin, either as once- or twice-daily U-
100 glargine or detemir, or as twice-daily intermediate-acting insulin (NPH).
The long-acting insulin can be given either at bedtime or in the morning; the
NPH is usually given as approximately two-thirds of the dose in the morning
and one-third at bedtime. The remainder of the TDD is given as short-acting or
rapid-acting insulin, divided before meals. The premeal dosing is determined by
the pre-meal glucose level, meal size, and content, glucose trends (when
available from CGM), as well as activity and exercise pattern. If NPH is the
basal insulin used, a mid-day (pre-lunch) rapid-acting insulin may not be
necessary. Good clinical judgment and frequent glucose assessment are vital in
initiating a new insulin regimen in insulin-naive patients. Most importantly, the
regimen needs to be adjusted based on empiric results provided by glucose
monitoring and responsive to individual lifestyle patterns including eating and
activity and exercise patterns.
----------------------------------------------------------------------------
COMPLICATIONS
1. Hypoglycemia and hypokalemia
are the most common complications of the treatment of DKA and HHS. These
complications have become much less common since low-dose intravenous (IV)
insulin treatment and careful monitoring of serum potassium have been
implemented.
2. Hyperglycemia
may recur from interruption or discontinuation of IV insulin without adequate
overlap coverage with subcutaneous insulin.

3. Cerebral edema
Cerebral edema in uncontrolled diabetes mellitus (usually DKA, with only
occasional reports in HHS) is primarily a disease of children, and almost all
affected patients are younger than 20 years old. Symptoms typically emerge
within 12 to 24 hours of the initiation of treatment for DKA but may exist prior
to the onset of therapy. Issues related to cerebral edema in DKA, including
pathogenesis, are discussed in detail separately in the pediatric section but will
be briefly reviewed here.

23
DKA & HHS

Headache is the earliest clinical manifestation, followed by lethargy and

decreased arousal. Neurologic deterioration may be rapid. Seizures,
incontinence, pupillary changes, bradycardia, and respiratory arrest can develop.
Symptoms progress if brainstem herniation occurs, and the rate of progression
may be so rapid that clinically recognizable papilledema does not develop.
DKA-associated cerebral edema has a mortality rate of 20 to 40 percent [1].
Thus, careful monitoring for changes in mental or neurologic status that would
permit early identification and therapy of cerebral edema is essential.
The 2009 American Diabetes Association (ADA) guidelines on hyperglycemic
crises in diabetes in adults suggested that the following preventive measures
may reduce the risk of cerebral edema in high-risk patients:
 Gradual replacement of sodium and water deficits in patients who are
hyperosmolar. The usual IV fluid regimen during the first few hours of
treatment is isotonic saline at a rate of 15 to 20 mL/kg lean body weight
per hour (approximately 1000 mL/hour in an average-sized person) with a
maximum of <50 mL/kg in the first two to three hours.
 Dextrose should be added to the saline solution once the serum glucose
levels have fallen to 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300
mg/dL (13.9 to 16.7 mmol/L) in HHS. In patients with HHS, the serum
glucose should be maintained at 250 to 300 mg/dL (13.9 to 16.7 mmol/L)
until the hyperosmolality and mental status improve and the patient is
clinically stable.

Data evaluating the outcome and treatment of cerebral edema in adults are not
available. Recommendations for treatment are based upon clinical judgment in
the absence of scientific evidence. Case reports and small series in children
suggest benefit from prompt administration of mannitol (0.25 to 1 g/kg) and
perhaps from hypertonic (3 percent) saline (5 to 10 mL/kg over 30 min). These
interventions raise the plasma osmolality (Posm) and generate an osmotic
movement of water out of brain cells and a reduction in cerebral edema.

4. Noncardiogenic pulmonary edema

Hypoxemia and rarely noncardiogenic pulmonary edema can complicate the
treatment of DKA. Hypoxemia is attributed to a reduction in colloid osmotic
pressure that results in increased lung water content and decreased lung
compliance [11]. Patients with DKA who are found to have a wide alveolar-
arterial oxygen gradient and/or rales may be at higher risk for the development
of pulmonary edema.

24
DKA & HHS

25