Acute Complications of Diabetes by yurtgc548


									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

Diabetic Ketoacidosis

•   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

• 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

• 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

• 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

• 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
   – Depletion of baseline hepatic glycogen stores tends to favor
   – Low insulin levels decrease the ability of the brain and cardiac and
     skeletal muscle to use ketones as an energy source, also increasing
   – Persistently elevated serum glucose levels eventually causes an
     osmotic diuresis
   – Resulting volume depletion worsens hyperglycemia and ketonemia
•   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

•   Presence of concurrent hyperchloremic metabolic acidosis can be detected by
    noting a bicarbonate level lower than explainable by the amount the anion gap has

•   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

                 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
         – Results in a decrease in buffering capacity
              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

                  Causes of DKA
• 25% have no precipitating causes found

• Errors in insulin use, especially in younger population

• Omission of daily insulin injections

• Stressful events:
   –   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

• Initially polyuria and polydipsia are only symptoms until
  ketonemia and acidosis develop
                Clinical Features
• As acidosis progresses
   – Patient develops a compensatory augmented ventilatory
   – 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

            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

• 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
          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
• 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
• 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
• Total body potassium is depleted by renal

• Measured levels usually normal or


• Osmotic diuresis leads to excessive renal losses of
  NaCl in urine

• Hyperglycemia artificially lowers the serum sodium

• 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
           Electrolyte Loss:
• Osmotic diuresis contributes to urinary
  losses and total body depletion of:
  – Phosphorus
  – Calcium
  – Magnesium

                 Other values elevated:
•   Creatinine
    – Some elevation expected due to prerenal azotemia
    – May be factitiously elevated if laboratory assays for Cr and Acetoacetate

•   LFTs
    – Due to fatty infiltration of the liver which gradually corrects as acidosis is

•   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 in
      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
            Differential Diagnosis
• Any entity that causes a high-anion-gap metabolic
   –   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
   – Serum glucose levels are generally much higher (>600 mg/dL)
   – Have little to no anion-gap metabolic acidosis
•   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
           Treatment Goals:
• Volume repletion

• Reversal of metabolic consequences of insulin

• Correction of electrolyte and acid-base

• Recognition and treatment of precipitating

• Avoidance of complications                      25
• 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

• Need frequent monitoring of electrolytes (every 1-2 hours) to
  meet goals of safely replacing deficits and supplying missing

• Resolving hyperglycemia alone is not the end point of
   – 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
            Fluid Administration
• Recommended regimen:
  –   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
         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

• 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

• 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

• 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
• 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
• During initial therapy the serum potassium
  concentration may fall rapidly due to:
  –   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
  – Not given in first L of NS as severe hyperkalemia may
    precipitate fatal ventricular tachycardia and ventricular
    fibrillation                                                34
• 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
• 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
• Osmotic diuresis may cause significant
  magnesium depletion

• Symptomatic hypomagnesemia in DKA is
  rare as is need of IV therapy

• 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
  – 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
Complications related to therapy
• Hypoglycemia

• Hypophosphatemia


• Cerebral edema

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
  – 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
                  Cerebral edema
• Symptoms include:
   –   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

• 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

         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
• 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
• Key features
  – Ingestion of large quantities of alcohol
  – Relative starvation
  – Volume depletion

• Pathophysiologic state occurs with:
  – Depletion of NAD
  – Aerobic metabolism in the Krebs cycle is inhibited
  – Glycogen stores are depleted and lipolysis is

• Occurs in patients with:
  –   Recently intoxicated
  –   Volume-contraction
  –   Poor nutrition
  –   Underlying liver disease
• Insulin secretion is suppressed

• Glucagon, catecholamines, and growth hormone are all

• 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

                     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

• EtOH levels usually low or undetectable
  – Some may have elevated levels

• Elevated anion gap caused by ketones is essential in
  – 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
• 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

• ABG not needed to arrive at correct diagnosis
          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

• 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
• 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

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

               Initial studies
• Electrolytes
• 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
         • 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
• 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

• Insulin
  – No proven benefit
  – May be dangerous as patients have depleted
    glycogen stores and normal or low glucose

• 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

• 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
•   Nitroprusside tests useful because as become more positive signifies

•   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

Hyperosmolar Hyperglycemic

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
   – 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

       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
        HHNS and DKA both
• Hyperglycemia

• Hyperosmolarity

• Severe volume depletion

• Electrolyte disturbances

• Occasionally acidosis

• Acidosis in HHNS more likely due to:
  – Tissue hypoperfusion
    • Lactic acidosis
  – Starvation ketosis
  – Azotemia

     HHNS and DKA Lipolysis
• DKA patients have much higher levels of
  – Release and subsequent oxidation of free fatty acids
    to ketone bodies
     • β hydroxybutyrate and Acetoacetate
     • Contribute additional anions resulting in a more profound

• Inhibition of lipolysis and free fatty acid
  metabolism in HHNS is poorly understood

• See table 214-1 on page 1307
       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 non-
  ambulatory with inadequate hydration status

• Fundamental risk factor for developing HHNS is impaired
  access to water
       HHNS: Pathophysiology
• With poorly controlled DM II, inadequate utilization of
  glucose due to insulin resistance results in

• 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

       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
         HHNS: Pathophysiology
• During osmotic diuresis, urine produced is markedly

• 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
  approximately 8-12 L in a 70 kg person                    77
      HHNS: Pathophysiology
• Absence of ketosis in HHNS not clearly
  – 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
        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

        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

• 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
• 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 b blockers predispose the
  development of 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
                 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 non-
  diabetics who present with an acute medical
  insult such as CVA, severe burns, MI, infection,
  pancreatitis or other acute illness
            HHNS: Physical findings
•   Non-specific

•   Clinical signs of volume depletion:
     –   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

         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:
  –   Tremor
  –   Clonus
  –   Hyperreflexia
  –   Hyporeflexia
  –   Positive plantar response
  –   Reversible hemiplegia or hemisensory defects without
      CVA or structural lesion                          87
       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                                    88
              Laboratory tests
• Essential
  – Serum glucose
  – Electrolytes
  – Calculated and measured serum osmolality
  – BUN
  – Ketones
  – Creatinine
  – CBC

                        Laboratory tests
• Consider
  –   Urinalysis and culture
  –   Liver and pancreatic enzymes
  –   Cardiac enzymes
  –   Thyroid function
  –   Coagulation profiles
  –   Chest x-ray
  –   ECG

• Other
  –   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
             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

• 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
•   Serum sodium is suggestive but not a reliable indicator of degree of volume

•   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                                                              92
• 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

• See formula page 1309

• Normal serum osmolarity range is approximately 275 to 295

• Values above 300 mOsm/kg are indicative of significant 93
  hyperosmolarity and those above 320 mOsm are commonly
•   Hypokalemia is most immediate electrolyte based risk and should be

•   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

•   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
    and insulin therapy cannot be overemphasized
• BUN and Cr
  – Both prerenal azotemia and renal azotemia are
    common with BUN/Cr ratios often exceeding 30/1

  – Leukocytosis is variable and a weak clinical
  – When present usually due to infection or
•   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

•   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                                                                   96
• Improvement in tissue perfusion is the key to effective

• 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

• 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                        98
                 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

• 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
• 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

•   Little credible data on incidence or clinical indicators that may predispose
    to cerebral edema in HHNS patients                                      100
                    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

• 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

• 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
• 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
• 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
• 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
•   Want one unit of regular insulin for every mL of NS in infusion

•   Steady states utilizing infusion pumps occur within 30 minutes of

•   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.

• Need to track pH, vital signs and key lab values
  in the ED for appropriate management and
  disposition of these patients

  – Most require for initial 24 hours of care

  – 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
•   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

•   5. T/F: Volume repletion should precede insulin therapy in HHNS

    Answers: T,T,T,T,T

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