Hyperglycemic CrisisDiabetic Ketoacidosis and Hyperosmotic Hyperglycemic Nonketotic State
Daniel J Hellrung DO PhD
May 13, 2015
Hyperglycemic Crisis
Case Study
Definition of DKA and HHS
Epidemiology
Pathophysiology
Normal Glucose Control
Dysregulation of Glucose in DKA and HHS
Clinical Features
Evaluation and Diagnosis
Treatment Algorithms
Summary
Case Study
35 y.o. male with PMH of type I diabetes mellitus and GERD presents with 2 days of nausea, vomiting, abdominal pain, shortness of breath, cough and fever.
Meds:
20U glargine qHS with 3U Novolog TID AC and Corrective
20mg omeprazole
Allergies: none
FH: Mother - hypothyroid, Father – hyperlipidemia
Soc: non smoker, occ EtOH
Exam: Temp 38C, BP 132/76, HR 103, RR 32, SpO2 98%, Wt 70Kg, Ht 175cm BMI 22.9
Gen: Appears ill, sleepy and confused
HEENT: dry mucus membranes, sunken eyes
Lungs: right upper lobe crackles, tachypneic, Kussmaul pattern
Heart: tachycardic, regular rhythm, normal S1,S2 w/o murmurs. No LE edema. JVP is normal
Abdomen: BS present, mildly tender to palpation diffusely, percussion w/o localizing pain, no organomegaly
Skin: clammy, no jaundice, no abnormal lesions
Neurologic: confused, sleepy, CN II-XII grossly intact, no focal motor or sensory deficits
Case Study
What are your thoughts about this patient
Are there enough clues to give you an idea of what’s happening?
Are you leaning toward DKA or HHS?
What do you think is the underlying etiology of his symptoms?
Stay tuned for the “rest of the story”…
Definitions
DKA – 4 main points
Hyperglycemia usually 350-500 mg/dl (usually <800 mg/dl)
If patient is comatose BG can rise >900 mg/dl
Ketoacidosis (Anion Gap Metabolic Acidosis)
Dehydration (hypovolemia)
Electrolyte disturbances
Occurs rapidly
HHS
Hyperglycemia usually >1000 mg/dl
Dehydration (hypovolemia)
Plasma osmolality may reach 380 mosmol/kg (normal 275-295)
Typically no metabolic acidosis (if present it is usually mild)
Electrolyte disturbances
Occurs over days to weeks
Overlap does occur in about 1/3 of patients
Definitions
Image courtesy of ebmedicine.net
Differential Diagnosis
Image courtesy of Annals of Internal Medicine, annals.org
Epidemiology
DKA
Usually associated with DM type I
May occur in DM type II in conditions of
Extreme stress (severe sepsis, septic shock, AMI, trauma)
Ketosis-prone DM type II (e.g. “burned out” DM type II)
Age is usually < 65 years
CDC estimated 140,000 hospital discharges for DKA in 2009 as compared to 80,000 in 1988.
Mortality has declined.
Mortality is usually due to the underlying cause of hyperglycemic crisis
Prognosis is poor for the very young and old. Also when presenting with coma and hypotension
HHS
Associated with DM type II, not seen in DM type I
Age is usually > 65 years
Population data is not available for HHS (per CDC)
Epidemiology
Overall Mortality due to
Hyperglycemic Crisis Number of deaths were stable in
the 1980s
Decreased in the 1990s.
In 2009 (last reported stats by the
CDC)
2,417 deaths
19.8% lower than the 3,012
deaths in 1980.
Image courtesy of cdc.gov
Epidemiology
Image courtesy of cdc.gov
Mortality Rate of
Hyperglycemic Crisis Declines in the crude and age-
adjusted rates were similar.
The age-adjusted rate decreased
64% from 48.4 per 100,000 diabetic
population in 1980 to 17.3 per
100,000 diabetic population in
2009.
Epidemiology
Image courtesy of cdc.gov
Mortality Rate by Gender
and Race Black males were
disproportionately affected.
Lowest among white females
In 2009, mortality rate was
42.6 per 100,000 diabetic
population among black
males
19.5 among white males
16.0 among black females
11.7 among white females
Epidemiology – Precipitating factors for DKA
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients
with diabetes. Diabetes Care 2001; 24:131-53
Pathophysiology
Normal Glucose Regulation
Extracellular glucose is regulated primarily by insulin and glucagon
Blood glucose rises after a meal
Glucose enters the pancreatic beta cell
Beta cells (islet cells) produce insulin which down regulates glucagon from the
alpha cells
Insulin causes the liver to shut down production of glucose by reducing
Glycogenolysis
Gluconeogenesis
Insulin also increases glucose uptake in skeletal muscle cells and adipose tissue
Pathophysiology
DKA
Type I Diabetics: insulin dependent due to autoimmune destruction of
beta cells
Recall the 4 main features of DKA
Hyperglycemia
Ketoacidosis (Anion Gap Metabolic Acidosis)
Dehydration (hypovolemia)
Electrolyte disturbances
Let’s go through each one…
Pathophysiology
Pathophysiology
Hyperglycemia
Lack of insulin is akin to lifting the brake from glucagon allowing it
to run amuck.
Glucagon is released from the alpha cells unopposed by
insulin
Glucagon enters the liver cells and stimulates:
Glycogenolysis
Gluconeogenesis
Blood glucose rises fairly precipitously
Pathophysiology
Hyperglycemia Imbalance between insulin and
glucagon
Increase in counter regulatory
hormones including cortisol,
epinephrine, growth hormone
Increase in glycogenolysis and
gluconeogenesis
Blood glucose increases
Common BG
DKA 350-500 mg/dl
HHS >800 mg/dl
Why lower BG in DKA?
Image courtesy dtc.ucsf.edu
PathophysiologyGlycogen
Stored in the liver and muscle
Short term energy supply
Liberated from storage form by
Glycogenolysis
Glucose is produced through
Gluconeogenesis
Image courtesy of bio1151.nicerweb.comImage courtesy of static1.squarespace.com
Pathophysiology
Ketogenesis FFA are liberated from adipose
tissue
Undergo b-oxidation in the liver
Result is 2 ketones and acetone
Acetoacetate
b-Hydroxybutyrate
Acetone is neutral and accounts
for the “fruity” breath.
Ketogenesis results in AGMA
In HHS, No or little acidosis
DMII is insulin resistance
With insulin present,
glucagon is controlled
No FFA for b-oxidation
No acetoacetyl CoA excess
No ketone formation
Image courtesy of pharmqd.com
Pathophysiology
Image courtesy of washington.edu
* Data from Ennis et al (1994) and Kreisberg (1978)
Dehydration (Hypovolemia) Blood Glucose is filtered in the
glomerulus
Reabsorption takes place in the
proximal tubule
SGLT2 transporter carries Na+Glu
into the cell
Glucosuria appears at a blood
glucose level of 200 mg/dl (Tmax
usually 300mg/dl)
Glucosuria causes osmotic
diuresis in distal tubule resulting in
polyuria
Typical free water deficit *
DKA - 6L
HHS - 9L
Why?
Pathophysiology – Osmotic Diuresis
Image courtesy of washington.edu
Water
Water
Pathophysiology
Hyperosmolality High blood glucose (BG)
Increase in ECF by shifting fluid from ICF
Decreases [Na+] by dilutional effects
Osmotic diuresis results in free water loss (with some Na+ and
K+).
Decreased oral intake and losses through emesis
Excretion of ketone anions also contributes to osmotic diuresis
Obligatory losses of urinary cations
Sodium, potassium, and ammonium salts
Hyperosmolality is most prominent in HHS
Higher BG seen in HHS over DKA
Greater degree of osmotic diuresis
The major factor causing mental status changes
Image courtesy of endotext.org
Pathophysiology
Normal is 275-295 mOsm/kg
Pathophysiology
Electrolytes
Disturbances Glucosuria results not
only in water loss but
also electrolytes
In both DKA and HHS
there is a total body
depletion of electrolytes
Most importantly
Na+ and K+
Beware: Patient Labs
may appear to show
normal/high K+… it most
certainly isn’t!
Data from Ennis et al (1994) and Kreisberg (1978)
Pathophysiology
How does the K appear normal then? Remember there is a state of total body K+ depletion and
hyperosmolality
Solvent drag: with hyperosmolality water moves from the ICF to the
ECF and a parallel movement of K+ occurs.
With movement of water out of the cell, the ICF undergoes a
contraction thereby raising IC [K+].
The cell “thinks” the IC [K+] is too high and K+ passively exits the
cell to the ECF
Very minor role in DKA comes from a shift of H+ ions into the cell in
exchange for K+ in an effort to normalize ECF pH
The result can appear to show normal or even elevated K+ on labs
Image modified from courses.lumenlearning.net
Water
Glu
Glu
Glu
Glu
Glu
Glu
Glu
Glu
Glu
Glu
GluGlu
GluGlu
Glu
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients
with diabetes. Diabetes Care 2001; 24:131-53
Summary of Differences
Image courtesy of ebmedicine.net
Back to the Case Study…
35 y.o. male with PMH of type I diabetes mellitus and GERD presents with 2 days of nausea, vomiting, abdominal pain, shortness of breath, cough and fever.
Exam: Temp 38C, BP 132/76, HR 103, RR 32, SpO2 98%, Wt 70Kg, Ht 175cm BMI 22.9
Gen: Appears ill, sleepy and confused
HEENT: dry mucus membranes, sunken eyes
Lungs: right upper lobe crackles, tachypneic, Kussmaul pattern
Heart: tachycardic, regular rhythm, normal S1,S2 w/o murmurs. No LE edema. JVP is normal
Abdomen: BS present, mildly tender to palpation diffusely, percussion w/o localizing pain, no organomegaly
Skin: clammy, no jaundice, no abnormal lesions
Neurologic: confused, sleepy, CN II-XII grossly intact, no focal motor or sensory deficits
Clinical Features - DKA
Image courtesy of healthy-ojas.com
Clinical Features
DKA HHS
Image modified from “DKA versus HHS” by Dr. Kamal Mohd
CO2 + H2O H2CO3 H+ + HCO3
Clinical Features – Respiratory Compensation
Image courtesy of studyblue.com
Clinical Features
Image courtesy of en.wikipedia.org
What does our guy have… DKA or
HHS?
What is the underlying etiology of
his DKA?
Pneumonia
Back to the Case Study…
Typical Lab Findings
Image courtesy of Dharmraj Singh from Perioperative Diabetes mellitus management,
Institute of medical sciences,BHU, Varanasi
Treatment
Image courtesy dearnurses.com
Treatment
Overall Goals - DKA Stabilize hemodynamics
Improve tissue perfusion and correct hypovolemia
Improve cellular response to insulin
Gradual reduction in the serum glucose and plasma osmolality
Cease ketogenesis
Reverse AG metabolic acidosis
Correction of electrolyte imbalance
Prevent complications of overtreatment
Treat the disease process that precipitated the hyperglycemic crisis
Protocol for the management of adult patients with DKA *DKA diagnostic criteria: blood glucose >250 mg/dl, arterial pH <7.3, bicarbonate <15 mEq/l,
and moderate ketonuria or ketonemia.
American Diabetes Association Dia Care 2004;27:s94-s102
Treatment – Allina Protocol for DKA
Developed by the Clinical Decision Support and Endocrinology Expert Group at AllinaHealth
Treatment
Volume Expansion Improve tissue perfusion and correct hypovolemia
Volume repletion resulting in correction of hyperosmolality
Improves sensitivity to low dose insulin therapy
Gradual reduction in the serum glucose, plasma osmolality, AGMA
By increasing GFR improved excretion of BG and ketoacids
In the absence of cardiac compromise, isotonic saline is used
initially for the 1-2 hrs
If in hypovolemic shock, then fluid replacement should be rapid
Otherwise, goal is 15-20 ml/kg lean body weight per hour
Usually 1L in average sized person
Maximum is <50 ml/kg in the first 4 hrs to prevent complications due
to rapidly correcting hyperosmolality
Treatment
Volume Expansion Subsequent choice for fluid replacement depends on the state of
hydration, serum electrolyte levels, and urinary output
0.45% NaCl is appropriate if the corrected serum sodium is
normal or elevated
0.9% NaCl at a similar rate is appropriate if corrected serum
sodium is low (<135 mEq/L)
The addition of dextrose when the BG is 200 mg/dl (DKA) and 250-
300 mg/dl (HHS)
Prevents hypoglycemia
Allow further time for AGMA to resolve (DKA)
Decreases risk of developing cerebral edema
In HHS, maintain BG at this level until resolution of hyperosmolality,
mental status improves and vitals are stable.
Treatment
Volume Expansion Successful progress is determined by
Hemodynamic improvement
Achieving stable goal UOP
Improvement in labs
Signs and symptoms
Fluid replacement should correct the estimated deficits within the
first 24 h
DKA: 6L fluid deficit
HHS: 9L fluid deficit
Recommend monitoring serum osmolality in patients with renal or
cardiac compromise
Monitor for iatrogenic fluid overload and other complications
Treatment
Potassium Total body depletion in both DKA and HHS
Mild to moderate hyperkalemia on labs is common
Serum potassium is decreased by
Insulin, improvement in acidosis, volume expansion
Prevent hypokalemia by replacing potassium serum levels
decrease to <5.3 mEq/l
20–30 mEq potassium/L of IVF should maintain a serum potassium
concentration within the goal range (4 –5 mEq/l)
It may take more potassium replacement though
Rarely, DKA patients may present with significant hypokalemia
To avoid life threatening hypokalemia, start treatment with IVF
containing potassium rather than insulin
Continue infusion until potassium is >3.3 mEq/l
Then start insulin
Treatment
Phosphate Total body depletion in both DKA and HHS
May be normal or increased at presentation
Likely potassium, phosphate decreases with insulin therapy
RCTs have failed to show any clinical benefit to replacing
phosphate
Overcorrection of phosphate may lead to severe hypocalcemia
If serum phosphate concentration <1.0 mg/dl, judicial correction is
recommended to prevent cardiac/skeletal muscle weakness and
respiratory depression
To Be NaHCO3 Or Not To Be?
Bicarbonate Bicarbonate use in DKA remains controversial
If potassium is low on admission, the use of bicarbonate will drive K into the
cells further worsening hypokalemia
At a pH >7.0, insulin blocks lipolysis and resolves ketoacidosis without any
added bicarbonate
A prospective RCT in 21 patients failed to show help or harm in M&M when
the pH was 6.9 - 7.1
However, no prospective randomized studies using bicarbonate in DKA with
pH values <6.9
Given that severe acidosis may lead to a myriad of adverse vascular
effects, adult patients with a pH <6.9 should receive bicarbonate
Treatment
Insulin Therapy Do all patient with DKA need to be treated in the ICU on an insulin
drip?
RCT studies show benefit to treating uncomplicated DKA patients
out of the ICU with subcutaneous rapid-acting insulin. Initial injection of 0.2 units/kg followed by 0.1 unit/kg/hr or an initial
dose of 0.3 units/kg followed by 0.2 units/kg every 2 h until blood
glucose was <250 mg/dl
Then the insulin dose was decreased by half to 0.05 or 0.1 unit/kg,
respectively, and administered every 1 or 2 h until resolution of DKA.
Outcomes: No differences in LOS, total amount of insulin used until
resolution of hyperglycemia or ketoacidosis
No difference in the number of hypoglycemic events among
treatment groups.
The use of insulin analogs allowed treatment of DKA in out of the ICU or
in the emergency department
Avoiding intensive care admissions saved 30% in the cost of
hospitalization
Treatment
Insulin Therapy Unless DKA is uncomplicated and mild/moderate, regular insulin by
infusion is preferred
Bolus with regular insulin at 0.1 U/kg if K is > 3.3 mEq/l
Follow with a continuous infusion at 0.1U/kg/hr
Goal BG decrease of 50-75 mg/dl/hr with low dose insulin.
If BG does not decrease at that rate in the 1st hour, double the insulin
rate every hour until goal is met.
Decrease insulin rate to 0.05-0.1 U/kg/hr when BG reaches
200 mg/dl in DKA
300 mg/dl in HHS
This is the time to add dextrose to IVF to prevent
Hypoglycemia
Allow for acidosis to correct
Correct hyperosmolality
Mental status improvement
Treatment
Insulin - Phase I Initial goal is to stop
ketogenesis to prevent
worsening acidosis
Decrease
counterregulatory
hormone imbalance
Second goal is to correct
hyperglycemia
Goal 50-75 mg/dl/hr
Need to follow closely for
hypokalemia
Monitor AGMA or b-OHB
Follow until BG <250mg/dl,
then go to Phase II
Treatment
Insulin - Phase II Goal is to prevent
hypoglycemia
Correct hyperosmolality
Prevent rebound ketosis
Allow for adequate time
for clinical recovery
Treatment
Monitoring Hourly glucose until stable
Basic metabolic profile (Na, K, acidosis, AG, renal function)
Venous pH in DKA (similar to arterial pH by 0.03 units lower)
AGMA or b-OHB
Volume status, UOP, plasma osmolality
Hemodynamics
Complications of treatment
Clinical improvement (e.g. improved mentation, initiating diet)
Improvement in the underlying condition that caused
hyperglycemic crisis
Treatment
Measuring Ketones Ketonemia typically takes longer to clear than hyperglycemia.
Direct measurement of β-OHB in the blood is the preferred method
Nitroprusside method measures acetoacetic acid and acetone
β-OHB, the strongest and most prevalent acid in DKA
It is not measured by the nitroprusside method
During therapy, β-OHB is converted to acetoacetic acid, which
may lead the clinician to believe that ketosis has worsened
Allina measures β-OHB with an enzymatic assay
Serial measurements give an indication of response to treatment
Many experts recommend simply following the AG on the BMP
Treatment
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients
with diabetes. Diabetes Care 2001; 24:131-53
Treatment
Overall Goals - HHS Stabilize patients hemodynamics
Improve tissue perfusion and correct hypovolemia
Gradual reduction in the serum glucose and plasma osmolarity
Correction of electrolyte imbalance
Prevent complications of overtreatment
Treat the disease process that precipitated the hyperglycemic crisis
Protocol for the management of adult patients with HHS *Diagnostic criteria: blood glucose >600 mg/dl, arterial pH >7.3, bicarbonate >15 mEq/l,
mild ketonuria or ketonemia, and effective serum osmolality >320 mOsm/kg H2O.
American Diabetes Association Dia Care 2004;27:s94-s102
Treatment – Allina Protocol for HHS
Treatment
Treatment
Insulin - Phase I Notice that potassium
replacement in the IVF
is up to the discretion
of the physician based
on labs.
This is similar to the
DKA protocol but
there is less guidance
on the HHS protocol
for KCL dosing based
on labs.
Begin Phase II when
BG reaches 250-300
mg/dl
Treatment
Treatment
Endpoints Criteria for resolution of DKA is glucose <200 mg/dl and 2 of the following (ADA
guidelines)
Serum bicarbonate ≥15 mEq/l
AG correction (usually <12 mEq/l)
Venous pH >7.3
When the patient is able to eat
Combination of subcutaneously administered short- or rapid-acting and
intermediate- or long-acting insulin should be started
Intravenous insulin infusion should be continued for 1–2 h after the
subcutaneous.
Hyperglycemia or recurrence of ketoacidosis may occur if insulin infusion is
discontinued too soon after giving subcutaneous insulin
Endpoints for HHS include
Improved mentation
Volume repletion
Taking PO diet
Complications
Hypoglycemia
Over aggressive insulin therapy
Hyperglycemia
Insufficient overlap of insulin infusion and subcutaneous insulin
Hypokalemia
Insufficient repletion or use of bicarbonate
Non-anion gap metabolic acidosis (hyperchloremic acidosis)
Not a true complication
Results from urinary excretion of keto anions and loss of
bicarb equivalent in exchange for retention of chloride
Also excessive chloride in IVF during volume expansion Pulmonary edema from aggressive IVF repletion
Complications
Cerebral Edema Both DKA and HHS patients are at risk
More common in children (has been reported in 20 y.o.’s)
Rare but mostly fatal
Signs and Symptoms include
Deterioration in the level of consciousness, lethargy, decreased
arousal, and headache
Seizures, incontinence, pupillary changes, bradycardia, and
respiratory arrest.
Deterioration may be rapid and symptoms progress as brain stem
herniates.
Mortality reaches 70% once the clinical symptoms (excluding lethargy
and behavioral changes)
Only 7–14% of patients recovering without permanent morbidity
Complications
Cerebral Edema May result from osmotically driven movement of water into the CNS when the
plasma osmolality decreases too rapidly.
One study in children with DKA used MRI to assess cerebral water diffusion and
cerebral vascular perfusion during treatment.
Cerebral edema was not a function of cerebral tissue edema but rather a
function of increased cerebral perfusion.
No data in adults and cannot clearly extrapolate from children
Preventive measures include (no matter if hyperosmolar or not),
Gradual replacement of sodium and water deficits by adding dextrose to
IVF when BG reaches 200 mg/dl in DKA and 300 mg/dl in HHS.
In HHS, a BG of 250–300 mg/dl should be maintained until hyperosmolarity
and mental status improves and the patient becomes clinically stable.
Max reduction in plasma osmolality of 3 mosmol/kg/hr (theoretical)
Summary
DKA and HHS are life threatening disorders of diabetes
Both present with profound hypovolemia from free water loss
DKA is associated with AGMA, but HHS is not
Both may have significant total body electrolyte depletion Initial goals of treatment
Stabilization of hemodynamics
Correction of life threatening electrolyte disorders
Volume repletion
Cessation of ketogenesis and correction AGMA (DKA)
Correction of BG
Avoidance of complications
Treat underlying precipitating factors for hyperglycemic crisis Education on prevention of hyperglycemic crisis