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

Death

s p

er

100,0

00

5

Rate per 100,000 Persons with DiabetesBy Age, United States, 2009

Age (years)

CDC. Diabetes complications. Mortality due to hyperglycemic crises. Available from:

https://www.cdc.gov/diabetes/statistics/mortalitydka/fratedkadiabbyage.htm.

Pathogenesis of Hyperglycemic Crises

Umpierrez G, Korytkowski M. Nat Rev Endocrinol. 2016;12:222-232.

Counterregulatory Hormones

InsulinDeficiency

Metabolicacidosis

HypertonicityElectrolyteabnormalities

Increasedglucose

production

Decreasedglucoseuptake

Lipolysis-Increased FFA

Increasedketogenesis

Hyperglycemiaosmotic diuresis

Dehydration

DKA HHS

Electrolyte LossesRenal Failure

Shock CV Collapse

Insulin Deficiency

Hyperglycemia

Hyper-osmolality

Glycosuria

Dehydration

Lipolysis

↑↑↑↑FFAs

Acidosis

Ketones

CV Collapse

Insulin Deficiency

Electrolyte LossesRenal Failure

Shock CV Collapse

Insulin Deficiency

Hyperglycemia

Hyper-osmolality

∆ MS

Lipolysis

↑↑↑↑FFAs

Acidosis

Ketones

CV Collapse

Glycosuria

Dehydration

Electrolyte and Fluid Deficits inDKA 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 hyperglycemia

• Ketone production

• Systemic acidosis

Severe relative insulin deficiency,

resulting in

• Profound hyperglycemia and

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

Odds Ratios for Mortality

Pasquel FJ, et al. Presented at 76th Annual ADA Scientific Sessions, New Orleans, LA. June 10-14, 2016. Abstr 1482-P.

Hyperosmolality and Mortality in Hyperglycemic Crises

DKA-HHS independently

associated with 2.4 fold increased

mortality

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

•Normalise osmolality

•Replace fluid loss

•Normalise glucose

Secondary

PREVENT

•Thromboembolism

•Cerebral oedema / pontine myelinolysis

•Foot ulceration

High-dependency / level 2 care

• Osmolality greater than 350 mosmol/kg

• Sodium above 160 mmol/L

• pH <7.1

• Hypokalaemia or hyperkalemia

• Serum creatinine > 200 µmol/L

• Macrovascular event( MI,CVA)

• Glasgow Coma Scale (GCS) less than 12

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