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23 Cystic Fibrosis
353
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Use PubMed Clinical Queries to nd the most recent evidence. Use this search
strategy: (“Cystic Fibrosis”[Majr] OR “cystic brosis[tiab]”)
Chapter 24
Diabetic Ketoacidosis
ChristopherJ.Rees, RichardM.Cantor, CharlesV.Pollack,Jr.,
andJaimeFrielBlanck
Name andSynonyms
Diabetic Ketoacidosis; DKA
Incidence/Epidemiology
• Diabetic ketoacidosis (DKA) is classically thought to occur only with type 1
diabetes mellitus, but it can also occur with type 2 diabetes in the setting of
severe physiologic stress (infection, trauma, acute MI, or acute CVA).
• It can also occur as a presenting syndrome of type 2 DM, especially in patients
of Hispanic or African American origin.
• It is more common in children and young adults than in adults.
• The annual incidence ranges from 4–8 cases per 1,000 patients with
diabetes.
C. J. Rees
Emergency Department, Pennsylvania Hospital, Philadelphia, PA, USA
R. M. Cantor
Department of Emergency Medicine and Pediatrics, State University of NewYork Upstate
Medical University, Syracuse, NY, USA
C. V. Pollack,
Department of Emergency Medicine, Thomas Jefferson University,
Philadelphia, PA, USA
J. F. Blanck
Welch Medical Library, Johns Hopkins University, Baltimore, MD, USA
C. V. Pollack, Jr. (ed.), Differential Diagnosis of Cardiopulmonary Disease,
https://doi.org/10.1007/978-3-319-63895-9_24
Jr. ()
355© Springer Nature Switzerland AG 2019
356
C. J. Rees et al.
• Hospital admissions for DKA have been increasing. There were about 80,000
discharge diagnoses of DKA in 1989, in 2009 there were 140,000 discharge
diagnoses of DKA, an increase of 50 %.
• Hospital length of stay for DKA has fallen in the same period from about 6
days to 3.5 days.
• Overall mortality has been declining for the last 20 years and now averages
less than 5 % for all patients. This is likely due to improved recognition and
care.
• Mortality is still much higher for the extremes of age and illness. Mortality is
greater than 20 % in the elderly.
Differential Diagnosis
• The differential diagnosis of DKA includes all the causes of an elevated anion
gap metabolic acidosis. The classic mnemonic for the causes of an elevated
anion gap acidosis is MUD PILES:
• Methanol
• Uremia (renal failure)
• DKA, alcoholic ketoacidosis, and starvation acidosis
• Paraldehyde/phenformin ingestion (medications that are no longer
available)
• Iron/INH overdose
• Lactic acidosis (from multiple causes such as sepsis, metformin
overdose)
• Ethylene glycol ingestion
• Salicylate overdose
• Paraldehyde and phenformin are medications that are no longer
marketed.
• Other ingestions/exposures that should be included in this list are: carbon
monoxide, cyanide, and toluene.
• Other diagnoses to consider in the setting of hyperglycemia include: hyperglycemic, hyperosmolar, and nonketotic (HHNK) coma (also referred to
as hyperosmolar hyperglycemic state [HHS] or diabetic hyperosmolar
state[DHS]). In this disorder the hyperglycemia tends to be more severe
(>600 mg/dl), with little or no elevation in the anion gap. It tends to occur
in older patients, have a more prolonged onset and course, and is usually
associated with more pronounced mental status changes than DKA.The
mortality in HHNK is also higher than in DKA.
24 Diabetic Ketoacidosis
357
Diagnostic criteria in DKA and HHS [Shah SJ.Diabetic Ketoacidosis in the Urgent
Anesthesia Setting. In: Benumof JL, editor. Clinical Anesthesiology [Internet].
NewYork, NY: Springer NewYork; 2014 [cited 2015 Nov 5]. p.407–14. Available
from: http://link.springer.com/10.1007/978-1-4614-8696-1_49] Caption from
original
• The differential diagnosis prior to the identication of the metabolic abnormalities is much broader and based upon the presenting symptoms. These
may include: sepsis/shock/hypovolemic syndromes, abdominal pain associated with nausea and vomiting, change in mental status, and tachypnea.
Pathophysiology andEtiology
• The primary pathophysiologic mechanism behind the development of DKA is
an insulin deciency, especially a lack of an appropriate insulin release to
hyperglycemia.
• Cells require insulin to utilize glucose as a fuel source. In the absence of insulin, the body will seek alternative fuel sources. Catabolic (counterregulatory)
hormones will be released that help break down and utilize protein and fat
stores as fuel.
• The primary counterregulatory hormone is glucagon, but other involved
counterregulatory hormones include catecholamines, cortisone, and growth
hormone.
• The effect of these catabolic hormones is to increase gluconeogenesis and
glycogenolysis, which in turn increases production of glucose and worsens
hyperglycemia. Increasing both these processes also raises the production of
byproducts and precursors such as free fatty acids and glycerol.
358
C. J. Rees et al.
• Theses catabolic hormones also increase proteolysis. This boosts the amount
of free glucogenic amino acids, which can be used with glycerol to produce
glucose and worsen hyperglycemia.
• The free fatty acids that are produced during gluconeogenesis bind to albumin, and then are taken up by the liver, where they are converted to ketone
bodies (beta-hydroxybutyrate [βHB], acetoacetic acid [AcAc], and acetone).
• Some body tissues can utilize ketone bodies for energy, but inefciently. A
low insulin level reduces the ability of brain, cardiac, and skeletal muscle to
utilize ketones as an energy source, which increases the ketonemia.
• These ketone bodies are responsible for the metabolic acidosis of DKA.
• Under normal physiologic conditions, βHB and AcAc exist in a 1:1 equilib-
rium. During the increased lipolysis and ketogenesis of DKA, this ratio will
approach 10:1. It is important to remember, however, that during insulin therapy, βHB will be metabolized at a faster rate than AcAc. This has important
implications for monitoring therapy that will be discussed under the treatment
section.
• Hyperglycemia causes an osmotic diuresis, resulting in profound uid losses
and volume depletion, which exacerbates hyperglycemia and ketonemia.
• The volume decits can be profound and can lead to hypotension and shock.
• The osmotic diuresis also results in profound electrolyte losses (K, Na, Cl,
PO2, Ca, Mg, and N).
• The acidosis causes a shift in potassium from intracellular to extracellular
exacerbating total body potassium losses.
• In the setting of marked ketonemia, the kidney will exchange chloride for
ketones, allowing the ketones to be excreted. The excretion of ketones leads
to a decrease in potential bicarbonate, which leads in turn to less buffering
capacity and then to worsening of the acidosis, which can lead to a hyperchloremic metabolic acidosis, in addition to the ketoacidosis.
• The breakdown of adipose tissue leads to an inammatory response with the
release of prostaglandins I2 and E2. These cause a peripheral vasodilation that
can worsen hypotension and shock.
• Multiple factors and conditions are known to precipitate DKA.Many acute
illnesses, as well as physiologic stress, can lead to hyperglycemia, and in the
setting of insulin deciency this leads to DKA.
• It is important to attempt to identify cause when a patient presents with DKA.
• In a signicant minority of patients, no precipitating cause can be identied.
• The following list contains some of the common causes of DKA, but any
acute illness and/or period of physiologic stress can initiate DKA, so this list
is not exhaustive.
• Reduction of or lack of daily insulin injections
• Malfunction of insulin pump
• Any acute infectious process
• Acute MI
• Stroke
• Acute GI bleed
24 Diabetic Ketoacidosis
• Pregnancy
• Medications (especially steroids)
• Substance abuse (multifactorial, e.g., cocaine can cause hyperglycemia
directly and then these patients forget or have no insulin available)
• Severe, acute illness or trauma
359
DKA pathophysiology. DKA is shown as unchecked lipolysis occurring alongside
progressive water and electrolyte loss. Osmotic diuresis, progressive hypovolemia,
and further reductions in glucose and ketone clearance in the absence of insulin creates a feed-forward loop that increases concentrations of antagonistic hormones and
perpetuates the cycle [Steenkamp DW, Alexanian SM, McDonnell ME. Adult
Hyperglycemic Crisis: A Review and Perspective. Current Diabetes Reports. 2013
Feb;13(1):130–7.] Caption from original
Presentation
Typical/“Classic”
• DKA develops acutely over a period of 24–48 hours.
• The early symptoms are often related directly to hyperglycemia with resultant
osmotic diuresis and worsening volume loss (polydipsia/polyuria).
• As the metabolic abnormalities worsen and acidosis develops, tachypnea
occurs as physiologic compensation to try and decrease the pCO2 to reduce
the acidosis. Kussmaul respirations (a profound increase in the rate and depth
of breathing) may develop.
360
• Diffuse, nonspecic abdominal pain associated with nausea and vomiting are
common symptoms at presentation (especially in children). They are often
related directly to DKA (prostaglandin release is felt to play a role) but can
also indicate an underlying cause for the DKA.
• Vomiting contributes to the development of metabolic abnormalities, electrolyte losses, and the development of volume depletion and dehydration.
• As volume depletion worsens, the patient may develop clinical signs of shock
with tachycardia, hypotension, and signs of poor perfusion (poor skin turgor,
dry mucous membranes, peripheral cyanosis).
• Profound ketonemia (especially acetone) can cause a fruity odor on the breath.
• A change in mental status may occur, but is more common in HHNK.
It is felt to be multifactorial and related to volume depletion, metabolic acidosis, hyperosmolarity, and hemodynamic abnormalities.
C. J. Rees et al.
Atypical
• DKA is associated with multi-organ dysfunction. As such, it is associated
with multiple, varying symptoms and presentations as above.
• Fever may be present due to an underlying infection, but it is important to
remember that the absence of fever does not exclude underlying infection as
a cause for DKA.
• DKA may present with the symptoms of the underlying causative disorder.
• Hypothermia may be present due to peripheral vasodilation from prostaglandin release.
• Abdominal pain with nausea and vomiting are frequent presenting symptoms
of DKA as discussed in Typical/“Classic”, above. However, abdominal pain
and other abdominal symptoms may be due to the underlying cause. Acute
pancreatitis can be both a cause and an effect of DKA.Lipase may be elevated
in both situations, so it is often difcult to make the distinction.
• An alteration of decrease in the level of consciousness may occur, but is more
commonly seen in HHNK. An altered level of consciousness seems to be
more associated hyperosmolarity than with acidosis.
Primary Differential Considerations
• DFKA is a rather distinctive clinical entity. It is most likely to be confused
with hyperosmolar nonketoic coma and alcoholic ketoacidosis. Other initial
differential considerations might include:
• Lactic academia
• Septic shock
• Acute pancreatitis
• Salicylate toxicity
24 Diabetic Ketoacidosis
History andPhysical Exam
Findings That Conrm Diagnosis
• There are no historical or physical examination ndings that are conrmatory
for DKA.
• The diagnosis of DKA requires laboratory conrmation.
Factors That Suggest Diagnosis
• A history of reduced or no insulin use should suggest the diagnosis.
• Any patient with diabetes who presents with an acute illness or severe injury
should have the diagnosis of DKA considered.
• Patients being treated for other acute illnesses need to have their metabolic
status monitored and controlled to avoid precipitating DKA.
Factors That Exclude Diagnosis
361
• There are no historical or physical exam ndings that can reliably exclude the
diagnosis of DKA.
• DKA is only excluded by laboratory analysis documenting the lack of
ketonemia.
• It is important to remember that while most patients with DKA will have
marked hyperglycemia (400–800 mg/dL), it is possible to have DKA with
only modest elevations in glucose (250–500 mg/dL).
Ancillary Studies
Laboratory
• The diagnosis of DKA requires laboratory conrmation.
• Patients with suspected or conrmed DKA need to have a complete laboratory analysis of electrolytes and acid-base status. This includes measurement
of glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphate,
magnesium, renal function, liver function, arterial or venous pH, calculation
of the anion gap, and determination of ketonemia. A urine dipstick should
also be performed for ketonuria and glucosuria, and for evidence of urinary
infection.
362
C. J. Rees et al.
• These patients may also need further laboratory evaluation for a precipitating
cause for DKA.This may require evaluation of cardiac biomarkers, pancreatic enzymes, and thyroid function.
• The diagnosis is generally conrmed by the presence of all the following
ndings:
• a blood glucose >250 mg/dL
• an anion gap >11 (usually greater than 20)
• a bicarbonate <15 mEq/L, an arterial or venous pH<7.3
• at least moderate ketonemia
• All diabetic patients should have a ngerstick glucose determination performed when being evaluated for any acute illness.
• The glucose in DKA is usually between 400 and 800 mg/dL.Higher levels,
especially those above 1,000 mg/dL are more common in HHNK.Lower levels (250–500 mg/dL) may be seen, especially in the presence of starvation/
inadequate food intake due to nausea or vomiting, alcohol abuse, and other
intercurrent illnesses. It may also be lower in the presence of pregnancy, liver
disease, and if insulin was given within several hours prior to evaluation.
• In DKA, the anion gap increases due to the presence of the unmeasured
anions, beta-hydroxybutyrate (βHB) and acetoacetate (AcAc). When calcu-
lating the anion gap, use the measured serum sodium, not the corrected
sodium (see sodium below).
• Venous blood gases can be used to assess the serum pH.There is a high degree
of correlation between venous and arterial pH in DKA.The venous pH is
about 0.03 lower than the arterial pH.Arterial blood gases are painful, and can
cause severe complications such as arterial injury and thrombosis, so venous
blood gases are currently recommended.
• The degree of acidosis can be assessed by both the serum pH and bicarbonate
is consistent with the metabolic acidosis. Patients with protracted, severe
vomiting may also develop a metabolic alkalosis and have normal or slightly
elevated bicarbonate levels. In this setting, an elevated anion gap may be the
only indication that an underlying acidosis exists.
• Historically, serum and urine ketones were assessed by the use of the nitroprusside reagent. This is mostly a qualitative assay, but the strength of reaction (color change) may give an indication of the amount of ketone present.
This reagent only reacts with AcAc, it does not detect βHB.In DKA, βHB is
the predominant ketone body. βHB and AcAc exist in an equilibrium that
favors βHB in acidic environments. So early in the course, if using the nitroprusside reagent, the level of ketonemia or ketonuria may seem lower than it
actually is. As the patient is appropriately treated, and the acidosis improves,
the equilibrium will favor the conversion of βHB to AcAc (prior to clearance
of the ketone bodies). When using the nitroprusside reagent, there may seem
to be a paradoxical increase in ketonemia or ketonuria as the patient improves.