Transcript Slide 1

Acute Complications of Diabetes
Jane D’Isa-Smith, D.O.
December 13, 2005
Tintinalli Chapters 211, 213, 214
Prepared by David R. Fisher, D.O
1
Diabetic Ketoacidosis
2
Introduction
• DKA is an acute life threatening complication of DM
• ¼ of hospital admissions for DM
• Occurs predominantly in type I though may occur in II
• Incidence of DKA in diabetics 15 per 1000 patients
• 20-30% of cases occur in new-onset diabetes
• Mortality less than 5%
• Mortality higher in elderly due to underlying renal disease or coexisting
infection
3
Definition
• Exact definition is variable
• Most consistent is:
– Blood glucose level greater than 250 mg/dL
– Bicarbonate less than 15 mEq/L
– Arterial pH less than 7.3
– Moderate ketonemia
4
Pathophysiology
• Body’s response to cellular starvation
– Brought on by relative insulin deficiency and counter regulatory or catabolic
hormone excess
– Insulin is responsible for metabolism and storage of carbohydrates, fat and
protein
• Lack of insulin and excess counter regulatory hormones (glucagon,
catecholamines, cortisol and growth hormone) results in:
–
–
–
–
–
Hyperglycemia (due to excess production and underutilization of glucose)
Osmotic diuresis
Prerenal azotemia
Ketone formation
Wide anion-gap metabolic acidosis
• Clinical manifestations related to hyperglycemia, volume depletion and
acidosis
5
Pathophysiology
• Free fatty acids released in the periphery are bound to
albumin and transported to the liver where they undergo
conversion to ketone bodies
– The metabolic acidosis in DKA is due to β-hydroxybutyric acid and
acetoacetic acid which are in equilibrium
– Acetoacetic acid is metabolized to acetone, another major ketone
body
– Depletion of baseline hepatic glycogen stores tends to favor
ketogenesis
– Low insulin levels decrease the ability of the brain and cardiac and
skeletal muscle to use ketones as an energy source, also increasing
ketonemia
– Persistently elevated serum glucose levels eventually causes an
osmotic diuresis
– Resulting volume depletion worsens hyperglycemia and ketonemia
6
Electrolytes
•
Renal potassium losses already occurring from osmotic diuresis worsen due to
renin-angiotensin-aldosterone system activation by volume depletion
•
In the kidney, chloride is retained in exchange for the ketoanions being excreted
•
Loss of ketoanions represents a loss of potential bicarbonate
•
In face of marked ketonuria, a superimposed hyperchloremic acidosis is also
present
•
Presence of concurrent hyperchloremic metabolic acidosis can be detected by
noting a bicarbonate level lower than explainable by the amount the anion gap has
increased
•
As adipose tissue is broken down, prostaglandins PGI2 and PGE2 are produced
– This accounts for the paradoxical vasodilation that occurs despite the profound levels of
volume depletion
7
DKA in Pregnancy
• Physiologic changes in pregnancy makes more prone
to DKA
– Maternal fasting serum glucose levels are normally lower
• Leads to relative insulin deficiency and an increase in baseline free
fatty acid levels in the blood
– Pregnant patients normally have increased levels of counter
regulatory hormones
– Chronic respiratory alkalosis
• Seen in pregnancy
• Leads to decreased bicarbonate levels due to a compensatory renal
response
– Results in a decrease in buffering capacity
8
DKA in Pregnancy
• Pregnant patients have increased incidence of
vomiting and infections which may precipitate DKA
• Maternal acidosis:
– Causes fetal acidosis
– Decreases uterine blood flow and fetal oxygenation
– Shifts the oxygen-hemoglobin dissociation curve to the right
• Maternal shifts can lead to fetal dysrhythmia and
death
9
Causes of DKA
• 25% have no precipitating causes found
• Errors in insulin use, especially in younger population
• Omission of daily insulin injections
• Stressful events:
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–
–
–
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–
–
–
–
Infection
Stroke
MI
Trauma
Pregnancy
Hyperthyroidism
Pancreatitis
Pulmonary embolism
Surgery
Steroid use
10
Clinical Features
• Hyperglycemia
• Increased osmotic load
– Movement of intracellular water into the vascular compartment
– Ensuing osmotic diuresis gradually leads to volume loss and
renal loss of sodium, chloride, potassium, phosphorus, calcium
and magnesium
• Patients initially compensate by increasing their fluid
intake
• Initially polyuria and polydipsia are only symptoms until
ketonemia and acidosis develop
11
Clinical Features
• As acidosis progresses
– Patient develops a compensatory augmented ventilatory
response
– Increased ventilation is stimulated physiologically by acidemia to
diminish PCO2 and counter the metabolic acidosis
• Peripheral vasodilation develops from prostaglandins
and acidosis
– Prostaglandins may contribute to unexplained nausea, vomiting
and abdominal pain
– Vomiting exacerbates the potassium losses and contributes to
volume depletion, weakness and weight loss
12
Clinical Features
• Mental confusion or coma may occur with serum
osmolarity greater than 340 mosm/L
• Abnormal vital signs may be the only significant
finding at presentation
• Tachycardia with orthostasis or hypotension are
usually present
• Poor skin turgor
• Kussmaul respirations with severe acidemia
13
Clinical Features
• Acetone presents with odor in some patients
• Absence of fever does not exclude infection as a
source of the ketoacidosis
• Hypothermia may occur due to peripheral
vasodilatation
• Abdominal pain and tenderness may occur with
gastric distension, ileus or pancreatitis
– Abdominal pain and elevated amylase in those with
DKA or pancreatitis may make differentiation difficult
– Lipase is more specific to pancreatitis
14
Clinical Suspicion
• If suspect DKA, want immediately:
– Acucheck
– Urine dip
– ECG
– Venous blood gas
– Normal Saline IV drip
• Almost all patients with DKA have glucose
greater than 300 mg/dL
15
Acidosis
• Elevated serum β-hydroxybutyrate and acetoacetate cause
acidosis and ketonuria
• Elevated serum ketones may lead to a wide-anion gap
metabolic acidosis
• Metabolic acidosis may occur due to vomiting, osmotic
diuresis and concomitant diuretic use
• Some with DKA may present with normal bicarbonate
concentration or alkalemia if other alkalotic processes are
severe enough to mask acidosis
– In which case the elevated anion gap may be the only clue to the
presence of an underlying metabolic acidosis
16
ABGs
• Help determine precise acid-base status in order to
direct treatment
– Venous pH is just as helpful
– Studies have shown strong correlation between arterial and
venous pH in patients with DKA
• Venous pH obtained during routine blood draws can be used to
avoid ABGs
• Decreased PCO2 reflects respiratory compensation
for metabolic acidosis
• Widening of anion gap is superior to pH or
bicarbonate concentration alone
– Widening is independent of potentially masking effects
concurrent with acid base disturbances
17
Potassium
• Total body potassium is depleted by renal
losses
• Measured levels usually normal or
elevated
18
Sodium
• Osmotic diuresis leads to excessive renal losses of
NaCl in urine
• Hyperglycemia artificially lowers the serum sodium
levels
• Two corrections:
– Standard-1.6 mEq added to sodium loss for every 100 mg
of glucose over 100 mg/dL
– True-2.4 mEq added for blood glucose levels greater than
400 mg/dL
19
Electrolyte Loss:
• Osmotic diuresis contributes to urinary
losses and total body depletion of:
– Phosphorus
– Calcium
– Magnesium
20
Other values elevated:
• Creatinine
– Some elevation expected due to prerenal azotemia
– May be factitiously elevated if laboratory assays for Cr and Acetoacetate
interfere
• LFTs
– Due to fatty infiltration of the liver which gradually corrects as acidosis is
treated
• CPK
– Due to volume depletion
• Amylase
• WBCs
– Leukocytosis often present due to hemoconcentration and stress response
– Absolute band count of 10,000 microL or more reliably predicts infection in21
this population
ECG changes
• Underlying rhythm is sinus tachycardia
• Changes of hypo/hyperkalemia
• Transient changes due to rapidly changing
metabolic status
• Evaluate for ischemia because MI may
precipitate DKA
22
Differential Diagnosis
• Any entity that causes a high-anion-gap metabolic
acidosis
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–
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–
Alcoholic or starvation ketoacidosis
Uremia
Lactic acidosis
Ingestions (methanol, ethylene glycol, aspirin)
• If ingestion cannot be excluded, serum osmolarity or drug-level
testing is required
• Patients with hyperosmolar non-ketotic coma tend to:
– Be older
– Have more prolonged course and have prominent mental status
changes
– Serum glucose levels are generally much higher (>600 mg/dL)
23
– Have little to no anion-gap metabolic acidosis
Studies
• Diagnosis should be suspected at triage
• Aggressive fluid therapy initiated prior to receiving lab results
• Place on monitor and have one large bore IV with NS running
• Rapid acucheck, urine dip and ECG
• CBC
• Electrolytes, phosphorus, magnesium, calcium
• Blood cultures
• ABG optional and required only for monitoring and diagnosis of
critically ill
– Venous pH (0.03 lower than arterial pH) may be used for critically ill
24
Treatment Goals:
• Volume repletion
• Reversal of metabolic consequences of insulin
insufficiency
• Correction of electrolyte and acid-base
imbalances
• Recognition and treatment of precipitating
causes
• Avoidance of complications
25
Treatment
• Order of therapeutic priorities is volume first, then insulin
and/or potassium, magnesium and bicarbonate
• Monitor glucose, potassium and anion gap, vital signs, level
of consciousness, volume input/output until recovery is well
established
• Need frequent monitoring of electrolytes (every 1-2 hours) to
meet goals of safely replacing deficits and supplying missing
insulin
• Resolving hyperglycemia alone is not the end point of
therapy
– Need resolution of the metabolic acidosis or inhibition of ketoacid
production to signify resolution of DKA
– Normalization of anion gap requires 8-16 hours and reflects
26
clearance of ketoacids
Fluid Administration
• Rapid administration is single most important step in treatment
• Restores:
– Intravascular volume
– Normal tonicity
– Perfusion of vital organs
• Improve glomerular filtration rate
• Lower serum glucose and ketone levels
• Average adult patient has a 100 ml/Kg (5-10 L) water deficit and a
sodium deficit of 7-10 mEq/kg
• Normal saline is most frequently recommended fluid for initial
volume repletion
27
Fluid Administration
• Recommended regimen:
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First L of NS within first 30 minutes of presentation
First 2 L of NS within first 2 hours
Second 2 L of NS at 2-6 hours
Third 2 L of NS at 6-12 hours
• Above replaces 50% of water deficit within first
12 hours with remaining 50% over next 12 hours
• Glucose and ketone concentrations begin to fall
with fluids alone
28
Fluid Administration
• Add D5 to solution when glucose level is
between 250-300 mg/dL
• Change to hypotonic ½ NS or D5 ½ NS if
glucose below 300 mg/dL after initially using NS
• If no extreme volume depletion, may manage
with 500 ml/hr for 4 hours
– May need to monitor CVP or wedge pressure in the
elderly or those with heart disease and may risk
ARDS and cerebral edema
29
Insulin
• Ideal treatment is with continuous IV
infusion of small doses of regular insulin
– More physiologic
– Produces linear fall in serum glucose and
ketone body levels
– Less associated with severe metabolic
complications such as hypoglycemia,
hypokalemia and hypophosphatemia
30
Insulin
• Recommended dose is 0.1 unit/kg/hr
• Effect begins almost immediately after
initiation of infusion
• Loading dose not necessary and not
recommended in children
31
Insulin
• Need frequent glucose level monitoring
• Incidence of non-response to low-dose
continuous IV administration is 1-2%
• Infection is primary reason for failure
• Usually requires 12 hours of insulin infusion or
until ketonemia and anion gap is corrected
32
Potassium
• Patients usually with profound total body hypokalemia
• 3-5 mEq/kg deficient
• Created by insulin deficiency, metabolic acidosis, osmotic
diuresis, vomiting
• 2% of total body potassium is intravascular
• Initial serum level is normal or high due to:
–
–
–
–
Intracellular exchange of potassium for hydrogen ions during acidosis
Total body fluid deficit
Diminished renal function
Initial hypokalemia indicates severe total-body potassium depletion and
requires large amounts of potassium within first 24-36 hours
33
Potassium
• During initial therapy the serum potassium
concentration may fall rapidly due to:
–
–
–
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Action of insulin promoting reentry into cells
Dilution of extracellular fluid
Correction of acidosis
Increased urinary loss of potassium
• Early potassium replacement is a standard modality of
care
– Not given in first L of NS as severe hyperkalemia may
precipitate fatal ventricular tachycardia and ventricular
fibrillation
34
Potassium
• Fluid and insulin therapy alone usually lowers the
potassium level rapidly
– For each 0.1 change in pH, serum potassium concentration
changes by 0.5 mEq/L inversely
• Goal is to maintain potassium level within 4-5 mEq/L and
avoid life threatening hyper/hypokalemia
• Oral potassium is safe and effective and should be used
as soon as patient can tolerate po fluids
• During first 24 hours, KCl 100-200 mEq usually is
required
35
Phosphate
• Roll of replacement during treatment of
DKA is controversial
• Recommended not treating until level less
than 1 mg/dL
• No established roll for initiating IV
potassium phosphate in the ED
36
Magnesium
• Osmotic diuresis may cause significant
magnesium depletion
• Symptomatic hypomagnesemia in DKA is
rare as is need of IV therapy
37
Bicarbonate
• Role in DKA debated for decades
• No clinical study indicates benefit of treating
DKA with bicarbonate
• Routine use of supplemental bicarbonate in DKA
is not recommended
• Routine therapy works well without adding
bicarbonate
38
Complications and Mortality
• Complications related to acute disease
– Main contributors to mortality are MI and
infection
– Old age, severe hypotension, prolonged and
severe coma and underlying renal and
cardiovascular disease
– Severe volume depletion leaves elderly at risk
for vascular stasis and DVT
– Airway protection for critically ill and lethargic
patients at risk for aspiration
39
Complications related to therapy
• Hypoglycemia
• Hypophosphatemia
• ARDS
• Cerebral edema
40
Complications related to therapy
• Cerebral edema
– Occurs between 4 and 12 hours after onset of therapy
but may occur as late as 48 hours after start
treatment
– Estimated incidence is 0.7 to 1.0 per 100 episodes of
DKA in children
– Mortality rate of 70%
– No specific presentation or treatment variables predict
development of edema
– Young age and new-onset diabetes are only identified
potential risk factors
41
Cerebral edema
• Symptoms include:
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Severe headache
Incontinence
Change in arousal or behavior
Pupillary changes
Blood pressure changes
Seizures
Bradycardia
Disturbed temperature regulation
• Treat with Mannitol
– Any change in neurologic function early in therapy should prompt
immediate infusion of mannitol at 1-2 g/kg
42
Disposition
• Most require admission to ICU:
– Insulin drips
• If early in the course of disease and can
tolerate oral liquids, may be managed in
ED or observation unit and discharged
after 4-6 hours of therapy
• Anion gap at discharge should be less
than 20
43
Alcoholic Ketoacidosis
44
Alcoholic Ketoacidosis
• Wide anion gap acidosis
• Most often associated with acute cessation of alcohol
consumption after chronic alcohol abuse
• Metabolism of alcohol with little or no glucose sources
results in elevated levels of ketoacids that typically
produce metabolic acidosis present in the illness
• Usually seen in chronic alcoholics but may be seen in
first time drinkers who binge drink, especially in those
with volume depletion from poor oral intake and vomiting
45
Epidemiology
• No gender difference
• Usually presents between age 20 to 60
• Many with repeated episodes of ketoacidosis
• Incidence is unknown but mirrors incidence of alcoholism
• Usually self-limited
• Poor outcomes may occur
• 7-25% of deaths of known alcoholics due to AKA
46
Pathophysiology
• Key features
– Ingestion of large quantities of alcohol
– Relative starvation
– Volume depletion
47
Pathophysiology
• Pathophysiologic state occurs with:
– Depletion of NAD
– Aerobic metabolism in the Krebs cycle is inhibited
– Glycogen stores are depleted and lipolysis is
stimulated
• Occurs in patients with:
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Recently intoxicated
Volume-contraction
Poor nutrition
Underlying liver disease
48
Pathophysiology
• Insulin secretion is suppressed
• Glucagon, catecholamines, and growth hormone are all
stimulated
• Aerobic metabolism is inhibited and anaerobic
metabolism causes lipolysis and ketones are produced
• β-hydroxybutyrate is increased
• More ketones are produced with malnourishment and
vomiting or with hypophosphatemia
49
Clinical Features
• Usually occurs after episode of heavy drinking followed by
decrease in alcohol and food intake and vomiting
• Nausea, vomiting and abdominal pain of gastritis and
pancreatitis may exacerbate progression of illness
• With anorexia continuing, symptoms worsen leading to seeking
medical help
• Symptoms are nonspecific and diagnosis is difficult without labs
• No specific physical findings solely with AKA
– Most commonly tachycardia, tachypnea, diffuse mild to moderate
abdominal tenderness
– Volume depletion resulting from anorexia, diaphoresis and vomiting may
explain the tachycardia and hypotension
50
Clinical Features
• Most are alert
– Mental status changes in patients with
ketoacidosis should alert to other causes:
•
•
•
•
•
Toxic ingestion
Hypoglycemia
Alcohol-withdrawal seizures
Postictal state
Unrecognized head injury
51
Labs
• EtOH levels usually low or undetectable
– Some may have elevated levels
• Elevated anion gap caused by ketones is essential in
diagnosis
– Since β hydroxybutyrate predominates, degree of ketonemia
may not be appreciated
– Initial anion gap is 16-33 usually, mean of 21
• Frequently mild hypophosphatemia, hyponatremia
and/or hypokalemia
– Severe derangements are rare
52
Labs
• Most have elevated bilirubin and liver enzymes
due to liver disease from chronic EtOH use
• BUN and creatine kinase are frequently
elevated due to relative volume depletion
• Serum lactate mildly elevated
• Glucose usually mildly elevated
– Some have hypoglycemia
– Rarely glucose greater than 200 mg/dL
53
Acid-Base Balance
• Need to evaluate the anion gap in every patient
at risk for AKA
– Diagnosis can easily be missed otherwise
• Anion gap greater than baseline or 15 signifies a
wide-anion-gap acidosis regardless of
bicarbonate concentration or pH, even if
alkalemic
• ABG not needed to arrive at correct diagnosis
54
Acid-Base Balance
• Serum pH usually acidemic (55% of time)
though may be normal or alkalemic early in
course of disease
• Degree of acidosis typically less than in DKA
• Since volume loss is virtually always present,
some degree of metabolic acidosis is present
55
Ketones
• Clinical application is variable
• Most ketones in AKA are β-hydroxybutyrate
– The serum and urine nitroprusside test for ketones detects
acetoacetate and may show only mildly elevated ketones
• As treatment progresses the acetoacetate will
increase and indicates improving condition
• Most suggest measuring β-hydroxybutyrate and
acetoacetate only if diagnosis is unclear or other
methods are not available to follow patient’s
response to therapy
56
Diagnosis
• May be established with classic
presentation of:
– The chronic alcoholic with:
•
•
•
•
Recent anorexia
Vomiting
Abdominal pain
Unexplained metabolic acidosis with a positive
nitroprusside test, elevated anion gap and a low or
mildly elevated serum glucose level
57
Classic Presentation is Uncommon
• Difficult to establish diagnosis
• Blood alcohol level may be zero
• May not provide history of alcohol consumption
• Urine nitroprusside testing may be negative or weakly
positive despite significant ketoacidosis
• pH may vary from significant acidemia to mild alkalemia
• Wide anion gap is variable
58
Initial studies
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•
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•
•
•
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•
Electrolytes
BUN
Creatinine
Liver enzymes
Pancreatic enzymes
WBC count
Hematocrit
Urinalysis
Calculate anion gap
Serum lactic acid level and serum osmolarity
may be helpful if diagnosis is in doubt
• ABG is unnecessary unless a primary
respiratory acid-base disturbance is suspected
59
Differential diagnosis
Very broad
– Same as for wide-anion-gap metabolic acidosis
• Lactic acidosis
• Uremia
• Ingestions such as:
– Methanol
– Ethylene glycol
• Methanol and ethylene glycol do not produce ketosis but do have severe
acidosis
• Absence of urinary ketones cannot exclude diagnosis of AKA if concurrent
methanol or ethylene glycol ingestion is suspected
– Isopropyl alcohol ingestion
• Produces ketones and may have mild lactic acidosis
– Salicylate poisoning
•
•
•
•
Sepsis
Renal failure
DKA
Starvation ketosis
60
Concurrent Illnesses Promoting Alcohol
Cessation and Anorexia
• Need to evaluate for these illnesses:
– Pancreatitis
– Gastritis
– Upper GI bleeding
– Seizures
– Alcohol withdrawal
– Pneumonia
– Sepsis
– Hepatitis
61
Treatment
• Glucose administration and volume repletion
– Fluid of choice is D5NS
– Glucose stimulates insulin production, stopping
lipolysis and halts further formation of ketones
– Glucose increases oxidation of NADH to NAD and
further limits ketone production
• Patients are not hyperosmolar
• Cerebral edema is not a concern with large
volumes of fluid administration
62
Treatment
• Insulin
– No proven benefit
– May be dangerous as patients have depleted
glycogen stores and normal or low glucose
levels
63
Treatment
• Sodium bicarbonate is not indicated
unless patients are severely acidemic with
pH 7.1 or lower
– This level of acidemia not likely explained by
AKA alone
– Vigorous search for alternate explanation
must be undertaken
64
Treatment
• Hypophosphatemia
– Frequently seen in alcoholic patients
– Can retard resolution of acidosis
• Phosphorous is necessary for mitochondrial
utilization of glucose to produce NADH oxidation
– Phosphate replacement is generally
unwarranted in ED unless levels less than 1
are encountered
– Oral replenishment is safe and effective
65
Treatment
• Nitroprusside tests useful because as become more positive signifies
improvement
• To prevent theoretical progression to Wernicke’s disease, all patients
should receive 50-100 mg of thiamine prior to administration of glucose
• Concomitant administration of magnesium sulfate and multivitamins
should be considered and guided by laboratory results
• Acidosis may clear within 12-24 hours
• If uncomplicated ED course, may be safely discharged if resolution of
acidosis over time and patient able to tolerate oral fluids
• If complicated course, underlying illness or persistent acidosis, admit for
further evaluation and treatment
66
Hyperosmolar Hyperglycemic
State
67
Hyperosmolar Hyperglycemic State
• Syndrome of severe hyperglycemia, hyperosmolarity and
relative lack of ketonemia in patients with poorly
uncontrolled DM type II
• ADA uses hyperosmolar hyperglycemic state (HHS) and
hyperosmolar hyperglycemic non ketotic syndrome
(HHNS)
– Both commonly used and appropriate
• Frequently referred to as non ketotic hyperosmolar coma
– Coma should not be used in nomenclature
– Only 10 % present with coma
68
HHNS: Epidemiology
• HHNS is much less frequent than DKA
• Mortality rate higher in HHNS
– 15-30 % for HHNS
– 5% for DKA
• Mortality for HHNS increases substantially
with advanced age and concomitant
illness
69
Hyperosmolar Hyperglycemic State
• Defined by:
– Severe hyperglycemia
• With serum glucose usually greater than 600 mg/dL
– Elevated calculated plasma osmolality
• Greater than 315 mOsm/kg
– Serum bicarbonate greater than 15
– Arterial pH greater than 7.3
– Serum ketones that are negative to mildly positive
• Values are arbitrary
– Profound metabolic acidosis and even moderate
degrees of ketonemia may be found in HHNS
70
HHNS and DKA both
• Hyperglycemia
• Hyperosmolarity
• Severe volume depletion
• Electrolyte disturbances
• Occasionally acidosis
71
HHNS
• Acidosis in HHNS more likely due to:
– Tissue hypoperfusion
• Lactic acidosis
– Starvation ketosis
– Azotemia
72
HHNS and DKA Lipolysis
• DKA patients have much higher levels of
lipolysis
– Release and subsequent oxidation of free fatty acids
to ketone bodies
• β hydroxybutyrate and Acetoacetate
• Contribute additional anions resulting in a more profound
acidosis
• Inhibition of lipolysis and free fatty acid
metabolism in HHNS is poorly understood
• See table 214-1 on page 1307
73
HHNS: Pathophysiology
• Three main factors:
– Decreased utilization of insulin
– Increased hepatic gluconeogenesis and glycogenolysis
– Impaired renal excretion of glucose
• Identification early of those at risk for HHNS is most
effective means of preventing serious complications
• Must be vigilant on helping those who are nonambulatory with inadequate hydration status
• Fundamental risk factor for developing HHNS is impaired
access to water
74
HHNS: Pathophysiology
• With poorly controlled DM II, inadequate utilization of
glucose due to insulin resistance results in
hyperglycemia
• Absence of adequate tissue response to insulin results in
hepatic glycogenolysis and gluconeogenesis resulting in
further hyperglycemia
• As serum glucose increases, an osmotic gradient is
produced attracting water from the intracellular space
and into the intravenous compartment
75
HHNS: Pathophysiology
• Initial increase in intravascular volume is accompanied
by a temporary increase in the GFR
• As serum glucose concentration exceeds 180 mg/dL,
capacity of kidneys to reabsorb glucose is exceeded and
glucosuria and a profound osmotic diuresis occurs
• Patients with free access to water are often able to
prevent profound volume depletion by replacing lost
water with large free water intake
• If water requirement is not met, volume depletion occurs
76
HHNS: Pathophysiology
• During osmotic diuresis, urine produced is markedly
hypertonic
• Significant loss of sodium and potassium and modest loss of
calcium, phosphate, magnesium and urea also occur
• As volume depletion progresses, renal perfusion decreases
and GFR is reduced
• Renal tubular excretion of glucose is impaired which further
worsens the hyperglycemia
• A sustained osmotic diuresis may result in total body water
losses that often exceeds 20-25% of total body weight or
77
approximately 8-12 L in a 70 kg person
HHNS: Pathophysiology
• Absence of ketosis in HHNS not clearly
understood
– Some degree of starvation does occur but a clinically
significant ketoacidosis does not occur
• Lack of ketoacidosis may be due to:
– Lower levels of counter regulatory hormones
– Higher levels of endogenous insulin that strongly
inhibits lipolysis
– Inhibition of lipolysis by the hyperosmolar state
78
HHNS: Pathophysiology
• Controversy how counter regulatory hormones
glucagons and cortisol, growth hormone and epinephrine
play in HHNS
– Compared to DKA, glucagon and growth hormone levels are
lower and this may help prevent lipolysis
• Compared to DKA, significantly higher levels of insulin
are found in peripheral and portal circulation in HHNS
– Though insulin levels are insufficient to overcome
hyperglycemia, they appear to be sufficient to overcome lipolysis
• Animal studies have shown the hyperosmolar state and
severe hyperglycemia inhibit lipolysis in adipose tissue
79
HHNS: Clinical Features
• Typical patient is usually elderly
– Often referred by a caretaker
• Abnormalities in vital signs and or mental status
• May complain of:
–
–
–
–
–
–
Weakness
Anorexia
Fatigue
Cough
Dyspnea
Abdominal pain
80
HHNS
• Many have undiagnosed or poorly
controlled type II diabetes
– Precipitated by acute illness
• Pneumonia and urinary tract infections account for
30-50% of cases
– Noncompliance with or under-dosing of insulin
has been identified as a common precipitant
also
81
HHNS
• Those predisposed to HHNS often have some level of
baseline cognitive impairment such as senile dementia
– Self-referral for medical treatment in early stages is rare
• Any patient with hyperglycemia, impaired means of
communication and limited access to free water is at
major risk for HHNS
• Presence of hypertension, renal insufficiency or
cardiovascular disease is common in this patient
population and medications commonly used to treat
these diseases such as  blockers predispose the
development of HHNS
82
HHNS
• An insidious state goes unchecked
– Progressive hyperglycemia
– Hyperosmolarity
– Osmotic diuresis
• Alterations in vital signs and cognition
follow and signal a severity of illness that
is often advanced
83
HHNS Causes
• A host of metabolic and iatrogenic causes have
been identified
–
–
–
–
–
–
–
–
–
Diabetes
Parental or enteral alimentation
GI bleed
PE
Pancreatitis
Heat-related illness
Mesenteric ischemia
Infection
MI
84
HHNS Causes
•
•
•
•
•
•
Severe burns
Renal insufficiency
Peritoneal or hemodialysis
Cerebrovascular events
Rhabdomyolysis
Commonly prescribed drugs that may
predispose to hyperglycemia, volume depletion
or other effects leading to HHNS
• HHNS may unexpectedly be found in nondiabetics who present with an acute medical
insult such as CVA, severe burns, MI, infection,
pancreatitis or other acute illness
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HHNS: Physical findings
• Non-specific
• Clinical signs of volume depletion:
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Poor skin turgor
Dry mucus membranes
Sunken eyeballs
Hypotension
• Signs correlate with degree of hyperglycemia and hyperosmolality and
duration of physiologic imbalance
• Wide range of findings such as changes in vital signs and cognition to
clear evidence of profound shock and coma may occur
• Normothermia or hypothermia is common due to vasodilation
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HHNS: Physical findings
• Seizures
– Up to 15% may present with seizures
– Typically focal
– Generalized seizures that are often resistant to
anticonvulsants may occur
• Other CNS symptoms may include:
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Tremor
Clonus
Hyperreflexia
Hyporeflexia
Positive plantar response
Reversible hemiplegia or hemisensory defects without
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CVA or structural lesion
HHNS: Physical findings
• Degree of lethargy and coma is
proportional to the level of osmolality
– Those with coma tend to have:
• Higher osmolality
• Higher hyperglycemia
• Greater volume contraction
• Not surprising that misdiagnosis of stroke
or organic brain disease is common in the
elderly
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Laboratory tests
• Essential
– Serum glucose
– Electrolytes
– Calculated and measured serum osmolality
– BUN
– Ketones
– Creatinine
– CBC
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Laboratory tests
• Consider
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Urinalysis and culture
Liver and pancreatic enzymes
Cardiac enzymes
Thyroid function
Coagulation profiles
Chest x-ray
ECG
• Other
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CT of head
LP
Toxicology
ABG
• Of value only if suspicion of respiratory component to acid-base abnormality
• Both PCO2 and pH can be predicted from bicarbonate concentration
obtained from venous electrolytes
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Electrolyte abnormalities
• Electrolyte abnormalities usually reflect a contraction alkalosis due to
profound water deficit
• 50% of patients with HHNS will have increased anion gap metabolic acidosis
– Lactic acidosis, azotemia, starvation ketosis, severe volume contraction
• Acute or concurrent illnesses such as ischemic bowel will contribute anions
such as lactic acid causing varying degrees of an anion gap metabolic
acidosis
• Initial serum electrolyte determinations can be reported as seemingly normal
because the concurrent presence of both metabolic alkalosis and acidosis
may result in each canceling out the other’s effect
• Lack of careful analysis of serum chemistries may lead to delayed
appreciation of the severity of underlying abnormalities, including volume
loss
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Sodium
•
Serum sodium is suggestive but not a reliable indicator of degree of volume
contraction
•
Though patient is total body sodium depleted, serum sodium (corrected for glucose
elevation) may be low, normal or elevated
•
Measured serum sodium is often reported as factitiously low due to dilutional effect
of hyperglycemia
•
Need to correct the sodium level
•
Serum sodium decreases by 1.6 mEq for every 100 mg/dL increase in serum
glucose above 100 mg/dL
•
See formula page 1309
•
Elevated corrected serum sodium during sever hyperglycemia is usually
explainable only by profound volume contraction
•
Normal sodium level or mild hyponatremia usually but not invariably suggests
modest dehydration
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Osmolarity
• Serum osmolarity has also been shown to correlate with
severity of disease as well as neurologic impairment and coma
• Calculated effective serum osmolarity excludes osmotically
inactive urea that is usually included in laboratory measures of
osmolarity
• See formula page 1309
• Normal serum osmolarity range is approximately 275 to 295
mOsm/kg
• Values above 300 mOsm/kg are indicative of significant
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hyperosmolarity and those above 320 mOsm are commonly
Potassium
• Hypokalemia is most immediate electrolyte based risk and should be
anticipated
• Total body deficits of 500-700 mEq/l are common
• Initial values may be reported as normal during a period of severe volume
contraction and with metabolic acidosis when intravascular hydrogen ions
are exchanged for intracellular potassium ions
• Presence of acidemia may mask a potentially life-threatening potassium
deficit
• As intravascular volume is replaced and acidemia is reversed, potassium
losses become more apparent
• Patients with low serum potassium during the period of severe volume
contraction are at greatest risk for dysrhythmia
• Importance of potassium replacement during periods of volume repletion
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and insulin therapy cannot be overemphasized
Labs
• BUN and Cr
– Both prerenal azotemia and renal azotemia are
common with BUN/Cr ratios often exceeding 30/1
• WBC
– Leukocytosis is variable and a weak clinical
indicator
– When present usually due to infection or
hemoconcentration
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Phosphate
• Hypophosphatemia may occur during periods of prolonged hyperglycemia
• Acute consequences such as CNS abnormalities, cardiac dysfunction, and
rhabdomyolysis are rare and are usually if level is <1.0 mg/dL
• Routine replacement of phosphate and magnesium usually unnecessary
unless severe
• Both electrolytes tend to normalize as metabolic derangements are
addressed
• When necessary, gradual replacement minimizes risks of complications
such as renal failure or hypocalcemia
• Metabolic acidosis is of a wide-anion-gap type, often due to lactic acidosis
from poor tissue perfusion, resulting in uremia, mild starvation ketosis or all
three
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Treatment
• Improvement in tissue perfusion is the key to effective
recovery
• Treat hypovolemia, identify and treat precipitating causes,
correct electrolyte abnormalities, gradual correction of
hyperglycemia and osmolarity
• Cannot overstate importance of judicious therapeutic plans
that adjusts for concurrent medical illness such as LV
dysfunction or renal insufficiency
• Due to potential complications, rapid therapy should only be
reserved for potentially life-threatening electrolyte
abnormalities only
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• Figure 214-1
Fluid resuscitation
• Initial aim is reestablishing adequate tissue perfusion and
decreasing serum glucose
• Replacement of intravascular fluid losses alone can account for
reductions in serum glucose of 35-70 mg/hr or up to 80 % of
necessary reduction
• Average fluid deficit is 20-25% of total body water or 8-12 L
• In elderly 50% of body weight is due to total body water
• Calculate the water deficit by using patient’s current weight in
kilograms and normal total body water
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Fluid resuscitation
• One-half of fluid deficits should be replaced over the initial 12
hours and the balance over the next 24 hours when possible
• Actual rate of fluid administration should be individualized for
each patient based on presence of renal and cardiac
impairment
• Initial rates of 500-1500 ml/hr during first 2 hours followed by
rates of 250-500 ml per hour are usually well tolerated
– Patients with cardiac disease may require a more conservative rate of
volume repletion
• Renal and cardiovascular function should be carefully
monitored
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• Central venous and urinary tract catheterization should be
Fluid resuscitation
• Rate of fluid administration may need to be limited in children
• A limited number of reports of cerebral edema occurring during or soon
after the resuscitation phase of patients with both DKA and HHNS have
been described
• Most cases have occurred in children with DKA and mechanism is unclear
• One review showed cerebral edema was found with similar frequency
before treatment with replacement fluids
• New study shows rehydration of children with DKA during first 4 hours at a
rate greater than 50 mL/kg was associated with increased risk of brain
herniation
• Little credible data on incidence or clinical indicators that may predispose
to cerebral edema in HHNS patients
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Fluid resuscitation
• Current recommendations based on available data include limiting rate of
volume depletion during first 4 hours to <50 ml/kg of NS
• Mental status should be closely monitored during treatment
• CT of brain should be obtained with any evidence of cognitive impairment
• Most authors agree use of NS is most appropriate initial crystalloid for
replacement of intravascular volume
• NS is hypotonic to the patient’s serum osmolality and will more rapidly
restore plasma volume
• Once hypotension, tachycardia and urinary output improve, ½ NS can be
used to replace the remaining free water deficit
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Potassium
• Potassium deficits are most immediate electrolyte-based
risk for a bad outcome
• On average potassium losses range from 4-6 mEq/kg
though may be as high as 10mEq/kg of body weight
• Initial measurements may be normal or even high with
acidemia
• Patients with levels <3.3 are at highest risk for cardiac
dysrhythmia and respiratory arrest and should be treated
with urgency
• Insulin therapy precipitously lowers intravascular
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Potassium
• When adequate urinary output is assured, potassium
replacement should begin
• Should replace at 10-20 mEq/hr though if life threatening
may require 40 mEq/hr
• Central line needed if given more than 20 mEq/hr
• Some believe potassium through central line poses risk for
conduction defects and should be avoided if good
peripheral line sites are available
• Monitoring of serum potassium should occur every hour
until a steady state has been achieved
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Sodium
• Sodium deficits replenished rapidly since given NS or ½ NS
during fluid replacement
• Phosphate and Magnesium should be measured
• Current guideline recommend giving 1/3 of potassium
needed as potassium phosphate to avoid excessive chloride
administration and to prevent hypophosphatemia
• Unless severe, alleviation of hypophosphatemia or
hypomagnesemia should occur after the patient is admitted
into the ICU setting
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Insulin
• Volume repletion should precede insulin therapy
• If given before volume repletion, intravascular volume is
further depleted due to shifting of osmotically active glucose
into the intracellular space bringing free water with it and this
may precipitate vascular collapse
• Absorption of insulin by IM or SC route is unreliable in patients
with HHNS and continuous infusion of IV insulin is needed
• No proven benefit to bolus of insulin
• Continuous infusion of 0.1U/kg/hour is best
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Insulin
• Want one unit of regular insulin for every mL of NS in infusion
• Steady states utilizing infusion pumps occur within 30 minutes of
infusion
• Decrease plasma glucose by 50-75 mg/dL per hour along with
adequate hydration
• If adequate hydration, may double infusion rate until 50-75 mg/dL/hr
is achieved
• Some patients are insulin resistant and require higher doses
• Once level less than 300 mg/dL, should change IV solution to D5 ½
NS and insulin infusion should be reduced to half or 0.05 U/kg/hr.
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Disposition
• Need to track pH, vital signs and key lab values
in the ED for appropriate management and
disposition of these patients
• ICU
– Most require for initial 24 hours of care
• SDU
– Patients with no significant co morbid conditions and
who demonstrate a good response to initial therapy
as evidenced by documented improvement in vital
signs, urine output, electrolyte balance and mentation
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Questions
•
1. T/F: The venous pH is just as helpful as arterial pH in patients with DKA
and may be obtained during routine blood draws.
•
2. T/F: Alcoholic ketoacidosis is usually seen in chronic alcoholics but may
be seen in first time drinkers who binge drink, especially in those with
volume depletion from poor oral intake and vomiting.
•
3. T/F: In treating DKA, the order of therapeutic priorities is volume first,
then insulin and/or potassium, magnesium and bicarbonate.
•
4. T/F: DKA patients have much higher levels of lipolysis, resulting in
release and subsequent oxidation of free fatty acids to ketone bodies
contributing additional anions resulting in a more profound acidosis than in
HHNS.
•
5. T/F: Volume repletion should precede insulin therapy in HHNS
Answers: T,T,T,T,T
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