Tulsi Ram Shrestha

DIABETIC KETOACIDOSIS
• Biochemical triad of ketonaemia, hyperglycaemia and acidaemia.
• A medical emergency and remains a serious cause of morbidity,
principally in people with type 1 diabetes
• However, an increasing number of patients presenting with DKA
have underlying type 2 diabetes.
• Lack of a diabetic history does not exclude the diagnosis
 EPIDEMIOLOGY
• 4.6 to 8 episodes per 1000 patients with diabetes in USA.
(Johnson 1980, Faich 1983)
• More than 11% of people with Type 1 diabetes had an episode of
DKA in England between 2004 and 2009. (National Diabetes
Audit 2008–2009)
• Remains a significant clinical problem in spite of improvements in
diabetes care (Fishbein 1995, Umpierrez 19997).
 MORTALITY
• Mortality rates have fallen significantly in the last 20 years from
7.96% to 0.67% (Lin 2005).
• Still high in developing countries and among non hospitalized
patients (Otieno 2005)
• Children and adolescents
• Cerebral oedema
• Adults
• Hypokalaemia
• Acute respiratory distress syndrome
• Comorbidities: MI, sepsis or pneumonia (Hamblin 1989)
 PATHO-
PHYSIOLOG
Y
 PRECIPITATING FACTORS/
CAUSES
• Infection
• Pneumonia, sepsis, UTI
• Lack of insulin
• Insulin pump failure
• Nonadherence to insulin treatment plans
• Other physiologic stressors
• Arterial thrombosis, cerebrovascular accident, Cushing disease, hemochromatosis,
myocardial infarction, pancreatitis, pregnancy, psychological stress, shock/hypovolemia,
trauma
• Drugs
• Antipsychotic agents: clozapine, olanzapine, risperidone
• Others: corticosteroids, glucagon, interferon
 DIAGNOSIS
Cardinal biochemical features
• Hyperketonaemia (≥ 3 mmol/L) and ketonuria (>2+ on standard
urine sticks)
• Hyperglycaemia (blood glucose ≥ 11 mmol/L (~200 mg/dL))
• Metabolic acidosis (venous bicarbonate <15 mmol/L and/or
venous pH < 7.3)
 DIAGNOSTIC CRITERIA
Mild DKA Moderate DKA Severe DKA
Plasma glucose (mg/dL) > 250 > 250 > 250

Arterial pH 7.25-7.30 7.00-7.24 < 7.00

Sodium Bicarbonate (mEq/L) 15 – 18 10 - 15 < 10

Urine Ketones Positive Positive Positive

Serum Ketones Positive Positive Positive

Serum Osmolality (mOsm/kg) Variable Variable Variable

Anion Gap (mmol/L) > 10 > 12 > 12

Mental Status Alert Alert/Drowsy Stupor/Coma

 CLINICAL FEATURES
Symptoms Signs
• Polyuria, thirst • Dehydration
• Weight loss • Hypotension (postural or supine)
• Weakness • Cold extremities/peripheral cyanosis
• Nausea, vomiting • Tachycardia
• Leg cramps • Air hunger (Kussmaul breathing)
• Blurred vision • Smell of acetone
• Abdominal pain • Hypothermia
• Confusion, drowsiness, coma (10%)
 DIFFERENTIAL DIAGNOSIS
• Gastroenteritis • High anion gap metabolic acidosis:
• Hyperosmolar hyperglycemic state • Alcoholic ketoacidosis
• Ethylene glycol intoxication
• Myocardial infarction • Lactic acidosis
• Pancreatitis • Methanol intoxication
• Starvation ketosis • Paraldehyde ingestion
• Rhabdomyolysis
• Salicylate intoxication
• Uremia
 INVESTIGATIONS
• Venous blood • ECG
• Urea • Possible MI
• Na+/ K+ • Infection screen
• Glucose • Full blood count
• Bicarbonate • Blood and urine culture
• Ketones • C-reactive protein
• Urine • Chest X-ray
• Ketones • Amylase/ lipase
• Leucocyte esterase • Rule out Pancreatitis
 NEW PRINCIPLES
• Measurement of blood ketones, venous pH and bicarbonate and their use as
treatment markers
• Monitoring of ketones and glucose using bedside meters
• Replacing ‘sliding scale’ insulin with weight-based fixed rate IV insulin
infusion
• Use of venous blood rather than arterial blood in blood gas analysers
• Monitoring of electrolytes on the blood gas analyser with intermittent
laboratory confirmation
• Continuation of long acting insulin analogues as normal
• Involvement diabetes specialist team as soon as possible
 MANAGEMENT
A. Hour 1: Immediate management upon diagnosis: 0 to 60 minutes.
Aims
• Commence IV 0.9% sodium chloride solution
• Fixed rate IVII but only after fluid therapy has been commenced
• Establish monitoring regime appropriate to patient:
• hourly blood glucose and ketone measurement
• at least 2 hourly serum K+ for the first 6 hours
• Clinical / biochemical assessment of the patient
• Involvement of diabetes specialist team ASAP
Action 1 - Intravenous access and initial investigations
• Rapid ABC (Airway, Breathing, Circulation)
• Large bore iv cannula and iv fluid replacement
• Clinical assessment
• RR; Temp, BP, PR, SpO2
• Glasgow Coma Scale (A drowsy patient in the context of DKA is
serious and the patient requires critical care input. Consider NG tube with
airway protection to prevent aspiration.)
• Full clinical examination
• Initial investigations
• Continuous cardiac monitoring
• Continuous pulse oximetry
• Consider precipitating causes and treat appropriately
• Establish usual medication for diabetes
Action 2 – Restoration of circulating volume

Average loss of fluid and electrolytes in adult DKA of moderate

severity
• Water 6L
• Na+ 500 mmol
• Cl- 400 mmol
• K+ 350 mmol
• Commence crystalloid (NS)
a. If systolic BP < 90 mmHg
• Give 500 mL over 10–15 mins
• Repeat if SBP< 90mmHg
b. If systolic BP ≥ 90 mmHg (for a previously well 70kg adult)
• 1L over 1st hour
• 1L over next 2 hours
• 1L over next 2 hours
• 1L over next 4 hours
• 1L over next 4 hours
• 1L over next 6 hours
Exercise caution in the following patients
• Young people aged 18-25 years
• Elderly
• Pregnant
• Heart or kidney failure
• Other serious co-morbidities
Action 3 - Commence a fixed rate intravenous insulin infusion
• 50 U human soluble insulin in 50 mL 0.9% sodium chloride
• IV infusion at 0.1 U/kg/hr (i.e. 7ml/hr if weight is 70kg)
• Targets
• ↓ blood ketone by 0.5 mmol/L/hour
• ↑ bicarbonate by 3 mmol/L/hour
• ↓ glucose by 3 mmol/L/hour
• K+ 4.0 - 5.0 mmol/L
Action 4 - Potassium replacement
• Serum potassium is often high on admission but falls precipitously upon
treatment with insulin.
• Potassium replacement
Plasma K+ > 5.5 mmol/L Nil
3.5–4.5 mmol/L 20 mmol/L
< 3.5 mmol/L 40 mmol/L
• If K+ < 3.5 mmol/L, K+ replacement before insulin
B. 60 minutes to 6 hours
Aims
• Clear the blood of ketones and suppress ketogenesis
• Achieve the targets
• Fall of ketones of at least 0.5 mmol/L/hr
• Rise of bicarbonate by 3 mmol/L/hr
• Fall of blood glucose by 3 mmol/L/hr
• Maintain serum K+ in normal range
• Avoid hypoglycaemia
Action 1 – Re-assess patient, monitor vital signs
• Urinary catheterization if incontinent or anuric (not passed by 60
min)
• NG tube if patient obtunded or if persistently vomiting
• Accurate fluid balance chart, minimum urine output 0.5ml/kg/hr
• Continuous cardiac monitoring in severe DKA
Action 2 – Review metabolic parameters
• Measure blood ketones and capillary glucose hourly
• Review patient’s response to fixed rate IVII hourly by calculating
rate of change of ketone level fall (or rise in bicarbonate or fall in
glucose).
Assess resolution of ketoacidosis
• If blood ketones not falling by at least 0.5 mmol/L/hr increase
insulin infusion rate by 1 unit/hr increments hourly until ketones
falling at target rates
• If bicarbonate not rising by at least 3 mmol/L/hr increase insulin
infusion rate by 1 unit/hr increments hourly
• If glucose is not falling by at least 3 mmol/L/hr increase insulin
infusion rate by 1 unit/hr increments hourly
• Always check the insulin infusion pump if it’s working and connected and that
the correct insulin residual volume is present
• Measure venous blood gas for pH, bicarbonate and K+ at 60
minutes and 2 hours and 2 hourly thereafter.
• If K+ is outside the reference range, assess the appropriateness
of K+ replacement and check it hourly.
• Continue insulin until ketones < 0.3 mmol/L, venous pH > 7.3
and/or venous bicarbonate >18 mmol/L.
• If glucose falls below 14 mmol/L (~250 mg/dl) add 10% glucose at
125mls/hour with NS.
• Monitor and replace potassium as it may fall rapidly.
Action 3 – Identify and treat precipitating factors
• Infection
• Inadequate insulin treatment or noncompliance
• Infarcts
C. 6 to 12 hours.
Aims
• Ensure that clinical/ biochemical parameters are improving
• Continue IV fluid replacement
• Continue insulin administration
• Assess for complications of treatment
• Continue to treat precipitating factors as necessary
• Avoid hypoglycaemia
Action 1 – Re-assess patient, monitor vital signs
• If patient not improving seek senior advice
• Ensure referral has been made to diabetes team

Action 2 – Review biochemical and metabolic parameters

• At 6 hours check pH, bicarbonate, potassium, blood ketones and
glucose
• Resolution is defined as ketones less than 0.3mmol/L, venous pH
over 7.3
D. 12 to 24 HOURS
Expectation: By 24 hours ketonaemia and acidosis should have
resolved
Aims
• Ensure clinical/ biochemical parameters improving/ have
normalised
• Continue IV fluids if not eating and drinking.
• Continue to treat precipitating factors as necessary
• Subcutaneous insulin if patient is eating and drinking normally
Action 1 – Re-assess patient, monitor vital signs
Action 2 – Review biochemical and metabolic parameters
• At 12 hours check pH, bicarbonate, K+, blood ketones and
glucose
• Resolution is defined as ketones <0.3mmol/L, venous pH>7.3
E. Conversion to subcutaneous insulin.
• When biochemically stable
• Glucose <200 mg/dl
• Anion gap <12 meq/L
• Bicarbonate >18 meq/L
• Ketones < 0.3
• pH > 7.3
• and the patient is ready and able to eat
• Overlap between the insulin infusion and first injection of fast
acting insulin of 1- 2 hours
• Abrupt discontinuation may lead to acute fall in insulin, recurrence
of hyperglycemia and/ or ketoacidosis.
• If unable to take oral nutrition, continue IVII
• In insulin-naïve patients, a multi- dose insulin at a dose 0.5- 0.8
U/ kg including a bolus
 COMPLICATIONS
• Cerebral oedema
• More common in children than in adults
• Occurs within a few hours of initiation of treatment
• Recent studies: cerebral hypoperfusion with subsequent reperfusion (Glaser 2001,
Glaser 2008, Yuen 2008).
• Risk factors (Wolfsdorf 2009, Carlotti 2010)
• Younger age
• New-onset diabetes
• Longer duration of symptoms
• Severe acidosis
• Low initial bicarbonate level
• Low sodium level
• High glucose level at presentation
• Rapid hydration
• Signs of cerebral edema that require immediate evaluation
• Headache
• Persistent vomiting
• Hypertension
• Bradycardia
• Lethargy
• Treatment
• Mannitol (20% 0.5-1 g/kg over 10-15 minutes) or
• Hypertonic saline (3% 2.5-5 ml/kg over 10-15 minutes)
• Acute circulatory failure
• Due to hypovolemia
• May cause acute renal failure
• Corrected by NS
• May need ionotropes in severe hypotension
• Sepsis treated by antibiotics
• Acute gastric dilatation
• Vomiting and abdominal distension
• Auscultation: Succusion splash
• Abdominal Xray: ground glass appearance
• Treated with NG aspiration
• Pulmonary oedema
• Occurs within a few hours of initiation
• Due to rapid infusion of crystalloids over a short period of time (Dixon
2006)
• Elderly patients and those with impaired cardiac function are at particular
risk
• Monitoring of cvp should be considered.
• Hypokalaemia and hyperkalaemia
• Hypoglycemia
• Acute renal failure
• Shock
 CONTROVERSIES
1. Arterial or venous measurements?
• Venous vs arterial pH is 0.02-0.15 pH units and arterial vs
venous bicarbonate is 1.88 mmol/L (Kelly 2006, Gokel 2000).
• Not necessary to use arterial blood to measure acid base status
(Ma 2003)
• Arterial line insertion: only if its use will influence management i.e.
for frequent arterial oxygen level measurements or monitoring
blood pressure in the critically ill patient
2. Blood ketone measurement?
• Frequent repeated measurement of blood ketone has become a
practical option due to availability of bedside meters
• Resolution of DKA depends upon the suppression of ketonaemia
• Measurement of blood ketones now represents best practice in
monitoring the response to treatment.
3. Colloid versus crystalloid?
• Many guidelines suggest that in hypotensive patients initial fluid
resuscitation should be with colloid.
• However, the hypotension results from a loss of electrolyte
solution and it is more physiological to replace with crystalloid.
• A recent Cochrane review did not support the use of colloid in
preference to crystalloid fluid (Perel 2007).
4. Rate of fluid replacement?
• Rapid fluid replacement may lead to cerebral oedema in children
and young adults.
• Paediatric guidelines recommend cautious fluid replacement over
48 hours.
5. 0.9% saline or Hartmann’s solution for resuscitation?
Advantages of NS
• Decades of clinical experience
• Readily available in clinical areas
• Commercially available ready mixed with K+ at required
concentrations, 20mmol/L (0.15%) or 40mmol/L (0.3%)
• Supports safe practice with injectable potassium (NPSA compliant
(NPSA alert 2002)
6. Continuation of long-acting insulin analogues?
• Continuation of SC analogues during the initial management of
DKA provides background insulin when the IV insulin is
discontinued.
• Avoids rebound hyperglycaemia when IV insulin is stopped and
should avoid excess length of stay
7. Fixed-rate intravenous insulin infusion versus variable rate?
• Fixed dose(s) per kg body weight enable rapid blood ketone
clearance
• Fixed rate may need to be adjusted in insulin resistant states if
the ketone concentration is not falling fast enough, and/or the
bicarbonate level is not rising fast enough.
8. Initiating treatment with a bolus of insulin?
• Bolus doesn’t decrease time to normalization of glucose, pH,
bicarbonate level (Goyal et all 2008)
• A bolus dose is not necessary provided that the insulin infusion is
started promptly at a dose of at least 0.1 unit/kg/hour (Kitabchi et
all 2008)
9. Intravenous bicarbonate?
• Adequate fluid and insulin therapy will resolve the acidosis in DKA
and the use of bicarbonate is not indicated (Morris 1986, Hale
1984).
• Excessive bicarbonate may increase CO2 partial pressure in CSF
and may lead to a paradoxical increase in CSF acidosis (Ohman
1971).
• Some evidence suggest bicarbonate treatment leading to
development of cerebral oedema in children and young adults
(Glaser 2001)
10. Use of intravenous phosphate?
• Phosphate deficits in DKA: 1 mmol/kg of body weight
• No evidence of benefit of phosphate replacement (Wilson 1982)
• However, in the presence of respiratory and skeletal muscle
weakness, phosphate measurement and replacement should be
considered (Liu 2004).
 STRATEGIES TO PREVENT DKA

• Diabetic education
• Blood glucose monitoring
• Identification of precipitating factors
• Home monitoring of ketones
• Supplemental short-acting insulin regimens
• Easily digestible liquid diets when sick
• Reducing (not eliminating) insulin when patients are not eating
• Guidelines for when patients should seek medical attention
• Case monitoring of high-risk patients
• Special education for patients on pump management
References
• Davidsons Principles and Practice of
Medicine 22nd Edition
• Joint British Diabetes Societies Inpatient
Care Group guidelines for The
Management of Diabetic Ketoacidosis in
Adults
• British Society for Paediatric Endocrinology
and Diabetes guidelines for the
management of DKA
• American diabetic association guidelines