The Problems with Hyperglycaemia
Understanding the physiology behind Hyperglycaemia and determine the appropriate management of DKA and HHS
So what is Diabetic KetoAcidosis (DKA)?
Clinical Definition is the name – Hyperglycemia, Ketosis and Acidosis
The underlying pathology is a functional/relative lack of insulin over a prolonged period.
So what is Hyperosmolar Hyperglycaemic State?
Criteria as it lacks a true definition:
Hypovolaemia
Marked Hyperglycaemia (>30) without hyperketonaemia (<3) or acidosis (HCO3 >15)
Osmolarity usually >320
Often associated with pre-renal failure
To understand these conditions we need to first understand what insulin does.
So what is insulin
Small protein composed of 2 aminoacid chains, formed in the islets of langerhan in the pancreas from Proinsulin (important as its insulin bound with C-peptide, which has unclear physiological involvement but can be measured to determine how much endogenous insulin production is functioning)
What does insulin do (ie what are the physiological properties, if we are to understand the pathophysiology then we need to know what the hormone does)?
When insulin binds with its membrane receptors:
- Increased glucose uptake (into muscle, adipose and liver)
- Increased membrane permeability to amino acids, K+ and PO4-
- Changes fat metabolism (which is why diabetics have higher atherosclerotic risks)
o Promotes conversion of glucose into fatty acids and inhibitis gluconeogenesis
§ Glucose is first split into pyruvate, which is converted into acetyl CoA, which the substrate for fatty acid
o Inhibits lipase
o Without the insulin the fatty acid transport from the liver is almost blocked (note fatty acids!!)
Absence of Insulin causes:
- lipolysis of stored fat and release of free fatty acid
- Increases plasma cholesterol and phospholipid concentrations
The use of fatty acids as an energy source in an insulin deprived state leads to ketosis and acidsis
- In the liver the mechanism for transporting fatty acids into the mitochondria becomes increasingly activated
- The fatty acids then are beta oxidized rapidly into acetyl CoA (transported to the tissues as acetoacetic acid)
- Lack of insulin reduces the peripheral use of acetoacetic acid
o Incombination of with increased liver production this creates the state of acidosis
Acetoacetic Acid is converted into β-hydroxybutyric acid and acetone. – these are the ketone bodies
Insulin has an anabolic role
– promotes the uptake of amino acid into cells, a role it shares with growth hormone
– Increases translation of messenger RNA, forming new proteins. In the absence of insulin the ribosomes simply stop working
– Inhibits catabolism of proteins
– Depresses gluconeogenesis
From this we can determine the physiological properties of DKA
- Put simply a lack of insulin stops the uptake of glucose, proteins and electrolytes into the cells
- Increasing the use of fatty acids as a fuel source in the liver
- But the fatty acids aren’t taken up as well peripherally
- So we have an increasing amount of ketone bodies, potassium and glucose in the blood
- The high glucose level causes diuresis (once above 15)
o Progressive dehydration but also the electrolytes that would normally be intracellular and is dependent on insulin for uptake and lost with the diuresis
This leads to the physiological state of significant dehydration, ketosis, acidosis and high blood K but total body deplete K
What do we think that Na concentration will be in DKA? And why?
Extracelluar hyperglycaemia causes to water shift from intracellular to extracellular, initially diluting the sodium concentration. Osmotic Diuresis causes the water to be lost in excess to Na.
You end up with an artificially low Sodium Concentration.
So lets bring it back to the clinical situation
How do they present? Can we now explain it?
- Confusion
- Dehydration, volume depletion
- Tachypnoea, kussmal respiration
- Vomiting
- Polyuria, polydipsia
- Abdominal Pain
- Ketone smell
What physiological properties to we see to define DKA?
Ketones >3
Blood glucose >11
HCO3 <15
Why HCO3 not pH?
Respiratory compenstation may mask a metabolic acidosis from the pH, we want to ensure we pick up the acidosis and the best way to do that is to focus on the HOC3
Do you need an ABG in DKA?
ABGs only offer clarification on the PO2 when compared to VBGs, so in most DKA patients serial VBGs is sufficient. Will be writing a post comparing VBGs and ABGs, so have a look at that.
The mortality of DKA in the UK is <1%. This is due to prompt recognition and treatment. Mortality increases with age, morbidity and frailty. Cerebral oedema is the most common cause of death – mostly in children. Other causes are severe hypOkalaemia, ARDS and any comorbid states that may have precipitated the DKA.
How do we treat DKA?
- Fluid, insulin, electrolytes, glucose
What are the priorities of treatment?
Fluid is the most important initial treatment - ‘C’ problem before metabolic correction
The aim is to restore the circulation volume, improve ketone clearance (dilutional) and manage any electrolyte disturbance
Insulin – effective both subcut and IV but subcut gives more rapid resolution
Start at 0.1unit/kg/hr, fixed rate
Potassium – total body deficit but typically high extracellularly - needs monitoring and maintaining as the effects of insulin and fluid replacement reduced the extracellular concentration
To restore and maintain normal insulin metabolism there maybe need to continue the insulin infusion beyond the resolution of the initial hyperglycaemia, at this point there will need to maintain glucose levels with a glucose infusion
It is also worth thinking about other electrolytes, as we have seen patients in DKA are often deplete in all electrolytes due to the diuresis, it is common sense to think about replacing all electrolytes in due course. Potassisum gets a particular focus due to the significance of hyper and hypokalaemia and the way plasma concentrations vary with insulin.
Every trust has their own DKA management proforma to follow but the principles are the same throughout
Likewise the pathophysiology is the same in paeds but we are more careful/precise about the fluid administration due to the cerebral oedema risk:
If they are shocked administer 20ml/kg bolus then administer 10ml/kg boluses up to 40ml/kg
Any bolus given (10ml/kg) when not shocked should be deducted from the deficit calculation
We then try to correct their deficit over 48hrs,
Calculate their fluid deficit = % dehydration x weight in Kg x 10
- Assume 5% dehydration in mild DKA (pH<7.3 or serum bicarbonate <15mmol/L)
- Assume 7% dehydration in moderate DKA (pH<7.2 or serum bicarbonate <10mmol/L)
- Assume 10% dehydration in severe DKA (pH<7.1 or serum bicarbonate <5mmol/L)
But we also need to give their maintenance fluid:
1st 10kg is 100ml/kg/day
2nd 10kg is 50ml/kg/day
Every Kg above 20kg is worth another 20ml/kg/day to a max of 80kg
Then we combine the deficit and maintenance for the 48hrs to calculate the rate of fluid administration:
Hourly rate = (deficit/48hr) + maintenance per hour
Resucitation fluid should be 0.9% NaCL
Then we start with 0.9% NaCl + 20mmol KCL
Then when Blood sugar drops <14mmol/l
- 0.9% saline & 5% glucose with 20mmol KCl in 500ml
With these patients being deficient in all electrolytes it would seem to be logical to use Hartmann’s or other balanced crystalloids to rehydrate and treat the DKA. However, there are some theories suggesting that the lactate in these fluids can lead to erratic blood sugars (lactate is mostly reprocessed through the Cori Cycle which includes gluconeogenesis leading to glucose as the end product).
There is ongoing and completed research suggesting that balanced crystalloids maybe more effective, but there doesnt seem to be enough evidence yet to change practice.
Coming research: https://emj.bmj.com/content/41/2/103.info
Subgroup analysis in the enormous SALT-ED and SMART trials (which if you havent read are worth looking at, the link are to the summaries on The Bottomline): https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2772993
Small number meta analysis: https://www.jwatch.org/na55108/2022/07/26/normal-saline-vs-balanced-crystalloid-diabetic
The background for not using balanced crystalloids seems to come from historic studies measuring interoperative blood sugar levels comparing saline and lactate containing fluid like Ringer’s or Hartmanns. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052582/#:~:text=Lactate%20from%20LR%20infusion%20is,hyperglycemia%20in%20diabetic%20surgical%20patients.
The diabetes society summarises their take on page 18 of their document https://abcd.care/sites/default/files/site_uploads/JBDS_Guidelines_Current/JBDS_02_DKA_Guideline_with_QR_code_March_2023.pdf
If blood sugar <6MMOL/L
- 0.9% saline & 10% glucose with 20mmol KCl in 500ml
Do not stop the insulin infusion
HHS
It’s a spectrum between DKA and HHS, they are not mutually exclusive
Symptoms:
- Dehydration
- Weakness
- Leg cramps
- Vision problems
- Reduced GCS
- DIC, Seizure, rhabdomyolysis
Often has a precipitant - infection, MI, stroke
- The counter regulatory hormones (ie glucagin, catecholaemine, cortisol, and GH) initiate hepatic glucose production through glycogenolysis and gluconeogenesis
“relative insulin deficiency” causes hyperglycaemia
- The amount of functioning insulin suppresses lipolysis and ketogenesis
Hyperglycaemia leads to diuresis – volume depletion and haemconcentration.
- The glycosuria leads ot greater water loss than Na
Prothrombotic environment created by the inflammatory process and cytokines
- Mesenteric artey thrombosis, MI, Low flow syndrome, DIC, CVA and other arterial thrombosis
Initial bedside tests include:
- Capillary blood glucose
- Blood gases to determine pH, bicarbonate and potassium
- Urine dipstick for ketones and urinalysis
- ECG to investigate the possibility of a myocardial infarction, which may be silent
- Measure or calculate osmolality (2 sodium + glucose + urea) frequently to monitor the response to treatment.
The 2012 Joint British Diabetes Societies (JBDS) guideline recommends monitoring serum osmolality to measure the patient’s response to treatment as follows:
- Hourly for the first 6 hours
- 2 hourly from 6 to 12 hours as long as serum osmolality is falling at 3 to 8 mOsm/kg/hour (3-8 mmol/kg/hour)
- 4 hourly after 12 hours if serum osmolality continues to improve.
The aim of treatment is to gradually restore normal osmolarity, fluid status and electrolyte losses and blood glucose
Fluid:
- Mainstay of treatment is 0.9% NaCl
- Avoid hypotonic as its has the potential to correct too quickly
- Just by administering fluid the osmolality will reduce and the Na will correct as more fluid moves intracellularly
- 0.9%NaCl is relatively hypotonic
- We aim for a fall in plasma glucose of 4-6/hr. if the reciprocal Na rise is greater than 2.4 for each 5.5 fall in glucose then there is probably insufficient fluid replacement
- Na shouldn’t change by more than 10 in 24hrs
- Aim to replace 50% of estimated fluid in the first 12hrs
- Target glucose of 10-15 and normalisation of electrolytes and osmolality in 72hrs
- 0.45% NaCl should be used if the osmolality and glucose stops falling
Insulin:
IF there is significant ketonaemia then start insulin, if not don’t
- Insulin without adequate fluid resus could lead to cardiovascular collapse as fluid moves from the intravascular space
- If giving insulin give at the half dose compared to DKA 0.05units.kg/hr
Potassium:
- Are K deplete like DKA and should follow the same principle
Anticoagulation:
- Think about prophylactic LMWH
It’s a spectrum between DKA and HHS, they are not mutually exclusive
Symptoms:
- Dehydration
- Weakness
- Leg cramps
- Vision problems
- Reduced GCS
- DIC, Seizure, rhabdomyolysis
Often has a precipitant - infection, MI, stroke
- The counter regulatory hormones (ie glucagin, catecholaemine, cortisol, and GH) initiate hepatic glucose production through glycogenolysis and gluconeogenesis
“relative insulin deficiency” causes hyperglycaemia
- The amount of functioning insulin suppresses lipolysis and ketogenesis
Hyperglycaemia leads to diuresis – volume depletion and haemconcentration.
- The glycosuria leads ot greater water loss than Na
Prothrombotic environment created by the inflammatory process and cytokines
- Mesenteric artey thrombosis, MI, Low flow syndrome, DIC, CVA and other arterial thrombosis
Initial bedside tests include:
- Capillary blood glucose
- Blood gases to determine pH, bicarbonate and potassium
- Urine dipstick for ketones and urinalysis
- ECG to investigate the possibility of a myocardial infarction, which may be silent
- Measure or calculate osmolality (2 sodium + glucose + urea) frequently to monitor the response to treatment.
The 2012 Joint British Diabetes Societies (JBDS) guideline recommends monitoring serum osmolality to measure the patient’s response to treatment as follows:
- Hourly for the first 6 hours
- 2 hourly from 6 to 12 hours as long as serum osmolality is falling at 3 to 8 mOsm/kg/hour (3-8 mmol/kg/hour)
- 4 hourly after 12 hours if serum osmolality continues to improve.
The aim of treatment is to gradually restore normal osmolarity, fluid status and electrolyte losses and blood glucose
Fluid:
- Mainstay of treatment is 0.9% NaCl
- Avoid hypotonic as its has the potential to correct too quickly
- Just by administering fluid the osmolality will reduce and the Na will correct as more fluid moves intracellularly
- 0.9%NaCl is relatively hypotonic
- We aim for a fall in plasma glucose of 4-6/hr. if the reciprocal Na rise is greater than 2.4 for each 5.5 fall in glucose then there is probably insufficient fluid replacement
- Na shouldn’t change by more than 10 in 24hrs
- Aim to replace 50% of estimated fluid in the first 12hrs
- Target glucose of 10-15 and normalisation of electrolytes and osmolality in 72hrs
- 0.45% NaCl should be used if the osmolality and glucose stops falling
Insulin:
IF there is significant ketonaemia then start insulin, if not don’t
- Insulin without adequate fluid resus could lead to cardiovascular collapse as fluid moves from the intravascular space
- If giving insulin give at the half dose compared to DKA 0.05units.kg/hr
Potassium:
- Are K deplete like DKA and should follow the same principle
Anticoagulation:
- Think about prophylactic LMWH as these patient are procoagulable