Hyperglycaemic Emergencies
Dr Sath Nag
Consultant Endocrinologist
James Cook University Hospital
Hyperglycemic Crises
Diabetic Ketoacidosis
(DKA)
Hyperglycemic Hyperosmolar State
(HHS)
Younger, type 1 diabetes
Older, type 2 diabetes
No Hyperosmolality
Hyperosmolar state
Volume depletion
Volume depletion
Electrolyte disturbances
Electrolyte disturbances
Acidosis
No significant acidosis
Pre-insulin era
• Mortality from DKA
100 %
• Childhood diabetes
• Treated with low carb
diet
• Death from starvation,
tuberculosis and coma
Crude and Age-Adjusted Death Rates for Hyperglycemic
Crises / 100,000 Diabetic Population, United States,
1980–2009
Death Rates for Hyperglycemic Crises as
Underlying Cause
Deaths per 100,000
Rate per 100,000 Persons with Diabetes
By Age, United States, 2009
Age (years)
CDC. Diabetes complications. Mortality due to hyperglycemic crises. Available5from:
https://www.cdc.gov/diabetes/statistics/mortalitydka/fratedkadiabbyage.htm.
Pathogenesis of Hyperglycemic Crises
DKA
HHS
Hyperglycemia
osmotic diuresis
Dehydration
LipolysisIncreased FFA
Increased
glucose
production
Increased
ketogenesis
Insulin
Deficiency
Counterregulatory
Hormones
Decreased
glucose
uptake
Metabolic
acidosis
Electrolyte
abnormalities
Umpierrez G, Korytkowski M. Nat Rev Endocrinol. 2016;12:222-232.
Hypertonicity
Insulin Deficiency
Hyperglycemia
Hyperosmolality
Glycosuria
Dehydration
Renal Failure
Shock
Electrolyte
Losses
CV
Collapse
Insulin Deficiency
Lipolysis
↑FFAs
Ketones
Acidosis
CV
Collapse
Insulin Deficiency
Hyperglycemia
Hyperosmolality
Glycosuria
∆ MS
Lipolysis
↑FFAs
Ketones
Dehydration
Renal Failure
Shock
Electrolyte
Losses
Acidosis
CV
Collapse
Electrolyte and Fluid Deficits in
DKA and HHS
Parameter
DKA*
HHS*
Water, mL/kg
100 (7 L)
100-200 (10.5 L)
Sodium, mmol/kg
7-10 (490-700)
5-13 (350-910)
Potassium, mmol/kg
3-5 (210-300)
5-15 (350-1050)
Chloride, mmol/kg
3-5 (210-350)
3-7 (210-490)
Phosphate, mmol/kg
1-1.5 (70-105)
1-2 (70-140)
Magnesium, mmol/kg
1-2 (70-140)
1-2 (70-140)
Calcium, mmol/kg
1-2 (70-140)
1-2 (70-140)
* Values (in parentheses) are in mmol unless stated otherwise and refer to the
total body deficit for a 70 kg patient.
Chaisson JL, et al. CMAJ. 2003;168:859-866.
Characteristics of DKA and HHS
Diabetic Ketoacidosis (DKA)
Hyperglycemic Hyperosmolar State
(HHS)
Absolute insulin deficiency, resulting in Severe relative insulin deficiency,
• Severe hyperglycemia
resulting in
• Ketone production
• Profound hyperglycemia and
• Systemic acidosis
hyperosmolality (from urinary free
water losses)
• No significant ketone production or
acidosis
Develops over hours to 1-2 days
Develops over days to weeks
Most common in type 1 diabetes, but
increasingly seen in type 2 diabetes
Typically presents in type 2 or
previously unrecognized diabetes
Higher mortality rate
Differentiating DKA and HHS
Diabetic Ketoacidosis (DKA)
Hyperglycemic Hyperosmolar State
(HHS)
Plasma glucose > 13 mmol/l
Plasma glucose > 30 mmol/l
Arterial pH <7.3
Arterial pH >7.3
Bicarbonate <15 mEq/L
Bicarbonate >15 mEq/L
Moderate ketonuria or ketonemia
Minimal ketonuria and ketonemia
Anion gap >12 mEq/L
Serum osmolality >320 mosm/L
Serum osmolality
• Defined as the
concentration of solutes per
litre of solution
• Na,K,Cl,HCO3,glucose and
urea osmotically important
body fluid solutes
• Ranges from 280 to 300
mOsm/L
• Measure of solute/water
ratio
Hyperosmolality and Mortality in Hyperglycemic
Crises
Odds Ratios for Mortality
DKA-HHS
independently
associated with
2.4 fold increased
mortality
Pasquel FJ, et al. Presented at 76th Annual ADA Scientific Sessions, New Orleans, LA. June 10-14, 2016. Abstr 1482-P.
Management of DKA and HHS
• Replacement of fluids losses
• Correction of hyperglycemia/metabolic
acidosis
• Replacement of electrolytes losses
• Detection and treatment of precipitating
causes
• Prevention of recurrence
Diabetic Ketoacidosis:
Pathophysiology
Unchecked gluconeogenesis
→
Hyperglycemia
Osmotic diuresis
→
Dehydration
Unchecked ketogenesis
→
Ketosis
Dissociation of ketone bodies into
hydrogen ion and anions
→
Anion-gap metabolic
acidosis
Precipitating event (infection, lack of insulin administration)
Management of DKA
Hyperosmolar
Hyperglyacemic State (HHS)
Definition of HSS
• Hypovolaemia
• Marked hyperglycaemia ( > 30 mmol/L)
without significant hyperketonaemia (<3
mmol/L)
• No significant acidosis (pH>7.3, bicarbonate
>15 mmol/L)
• Osmolality usually > 320 mosmol/kg
Clinical Presentation of HHS
• Compared to DKA, in HHS there is greater
severity of:
– Dehydration
– Hyperglycemia
– Hypernatremia
– Hyperosmolality
• Acute glucose toxicity
• Beta cell exhaustion and transient
insulin deficiency leading to mild
acidosis
Who is affected?
• Generally occurs in older patients who
are known to have diabetes
• Can be first presentation of Type 2 DM
• Now occurring in young adults and
children
• Mortality
• 15 – 20%
• 5% in DKA
Fluid and Electrolyte Management in
HHS
• More free water and greater volume
replacement than needed for patients with
DKA
• Caution in the elderly with preexisting heart
disease
• Potassium
– Usually not significantly elevated on
admission (unless in renal failure)
– Replacement required during treatment
Typical fluid deficit
Mechanisms
Osmolality
• Useful guide to:
• Severity
• Monitoring response to treatment
• Estimated by equation:
• 2Na+ + glucose + urea*
*Urea not an osmolyte but a useful indicator of dehydration
Early HHS
• ECF is hyperosmolar
• Shift of water from
ICF maintains ECF
volume
• Pulse and blood
pressure reasonable
Late HHS
• Both ECF and ICF
are hyperosmolar
• ECF and ICF volume
are reduced
• Clinical signs of
dehydration likely
Case Study
• 73 year old lady admitted unwell
• Type 2 diabetes with modest control on
Metformin and Gliclazide (HBA1c 8.9%).
She weighs 70 kg.
• Unwell for more than a week with a
chesty cough and in the last 72 hours
has been drowsy and confused and
drinking very little.
What is the osmolality?
•U&Es
•Na 160 mmol/L
•K 5.2 mmol/L
•HCO3 22 mmol/L
•Urea 31 mmol/L
•Creatinine 163 umol/L
•Glucose 59 mmol/L
•What is the
osmolarity?
410 (285 -300 mmol/kg)
2Na+ + glucose + urea
Laboratory glucose.
Glucometer unreliable
What is the likely fluid
deficit?
•
7 – 15 litres
•
(100 – 220 ml per kg body weight)
•
Assume 12 litres for this exercise
Treatment goals
Primary
Secondary
PREVENT
•Normalise osmolality
•Thromboembolism
•Replace fluid loss
•Cerebral oedema /
pontine myelinolysis
•Normalise glucose
•Foot ulceration
High-dependency / level 2 care
• Osmolality greater
than 350 mosmol/kg
• Serum creatinine >
200 µmol/L
• Sodium above 160
mmol/L
• Macrovascular
event( MI,CVA)
• pH <7.1
• Glasgow Coma
Scale (GCS) less
than 12
• Hypokalaemia or
hyperkalemia
Type of fluid
• Goal of the therapy is volume expansion
and restoration of peripheral perfusion
• No evidence for the use of Ringer’s
lactate (Hartmann’s solution) in HHS
• As majority of electrolyte losses are Na+,
Cl- and K+ the base fluid that should be
used is 0.9% NaCl with K+
Isotonic vs hypotonic fluids
• Rapid changes in osmolality harmful
• 0.9 % saline is hypotonic compared to
plasma in HSS
• With saline plasma glucose will fall by
dilution(5 mmol per hour)
• Osmolarity of ECF falls and water shifts
into hyperosmolar ICF
Inevitable rise of sodium
when you start treatment
•Sodium will rise by around
2mmol/l for every 5 mmol/L
drop in glucose
•A rise in sodium is okay as
long as osmolality is
dropping
•Aim to take 72 hours to
normalise osmolality and
electrolytes
General principles
• Safe rate of fall of glucose 4-6 mmol/hr
• Rate of fall of Sodium should NOT exceed
10 mmol/l in 24 hours
• Target glucose 10-15 mmol/l
• Complete normalisation of osmolality and
electrolytes may take 72 hours
General principles
• Aim of treatment is to replace 50% of
estimated fluid loss within the first 12 hours
and remainder in the following 12 hours
• Rehydration rate influenced by
• Initial severity, renal impairment,
comorbidities
• IVT to achieve positive fluid balance 2-3
litres by 6 hours and 3-6 litres by 12
hours
Use of hypotonic fluids
• No evidence to use hypotonic fluids
<0.45 % NaCl
• Only use 0.45 % Saline if osmolality not
declining despite fluid replacement with
0.9 % NaCl and glucose not falling
adequately
Changes with treatment of HSS
Role of Insulin
• Insulin NOT required initially unless
• co-existent ketoacidosis suspected
• 3β-hydroxy butyrate > 1 mmol/L(indicative of
relative hypoinsulinaemia)
• Commence insulin when glucose is no
longer falling with saline replacement.
• 0.05 units per kg per hour
• 3.5 units per hour in this case
• Patients with HHS are Insulin sensitive
Anticoagulation and Foot care
•High risk of VTE
• Similar to patients with
sepsis
•Treat with prophylactic
low molecular weight
heparin
• No evidence for full
anticoagulation
• Foot care
Recovery phase
• Full metabolic recover takes > 24 hours
• Rapid correction harmful
• Switch from IV to subcutaneous insulin
• May well be able to switch to OHAs or
even diet alone after period of stablity
Summary
• HHS is a life-threatening emergency
• Management involves
– Fluid and electrolyte management
– Prevention of metabolic complications
during recovery
• Patient education and discharge
planning should aim at prevention of
recurrence