Hyperosmolar hyperglycemic state

Terminology

New term: Hyperosmolar Hyperglycemic State (HHS)

And I would like first to start by clearing some confusion about the terminology of this condition, which in the past has been given several names including:

• The hyperosmolar non-ketotic coma or HONK
• The hyperosmolar non-ketotic hyperglycemia
• And the hyperosmotic hyperglycemic non-ketotic state

Precipitating factors of HHS

• Infection - most common
• Discontinuation of/inadequate insulin
• Myocardial infarction, stroke
• Medications e.g corticosteroids, thiazides, and sympathomimetic agents

The commonest precipitating factors for HHS include:

• First, infections, which are the most common cause.
• Discontinuation of insulin or inadequate intake of insulin can also be a factor.
• Sometimes the cause is another serious medical event such as myocardial infarction or a stroke.
• And in some patients, medications that cause hyperglycemia can be the reason, such as giving steroids, thiazides, or sympathomimetic agents.

Pathogenesis of HHS

• Less understood than that of DKA
• Insulin enough to suppress ketogenesis but not to prevent hyperglycemia
• 20% of cases of HHS occur in those not previously known diabetic
• Delayed recognition of hyperglycemic symptoms + restricted water intake in the elderly leads to severe dehydration

The pathogenesis of HHS is not as well understood as that of DKA. These patients are also relatively insulin-deficient, but it is thought that they have insulin which is just enough to suppress ketogenesis but not enough to prevent the hyperglycemia. 20% of cases of HHS occur in people who are not previously known to have diabetes. For those who do not know they have diabetes, they may not recognize the symptoms of hyperglycemia, and as HHS usually occurs in elderly patients who have a reduced thirst mechanism and therefore have a restricted water intake, all these factors increase the severity of the dehydration which is usually much more than that seen in DKA.

Pathogenesis of HHS

• Severe hyperglycemia ⇒
• Osmotic diuresis ⇒
• Renal loss of water in excess of sodium ⇒
• Hypernatremia ⇒
• Increased osmolality ⇒

So in HHS, there is usually a severe degree of hyperglycemia. This usually leads to increased osmotic diuresis, which leads to renal loss of water in excess of sodium, leading to hypernatremia and an increase in plasma osmolality.

Diagnosis of HHS

Criteria	Level for HHS diagnosis
Plasma osmolality (Osmolality = 2Na + glucose in mmol/L)	≥320 mOsmol/kg
Hyperglycemia Plasma glucose	≥550 mg/dl
Clinical criteria	Severe dehydration and feeling unwell
Absence of acidosis	pH >7.3 And/Or bicarbonate >15 mmol/l
Absence of ketosis	Urinary ketones ≤ one cross

• Occasional patients may have mixed HHS and DKA

So the criteria for the diagnosis of HHS are:

• First, a high plasma osmolality of more than 320 mosmol per kilogram.
• The plasma osmolality is calculated by adding 2 times the plasma sodium + the glucose level in mmol per liter.
• As I mentioned, the degree of hyperglycemia in HHS is much higher than that in DKA, and the cut-off level for the diagnosis of HHS is a plasma glucose of at least 550 mg per dL.
• These are the laboratory criteria, but the diagnosis of HHS requires a clinical criteria of a severely dehydrated patient who is generally unwell.

The diagnosis of HHS also requires ruling out DKA. And this is by showing that there is no acidosis, confirmed by having a pH level of more than 7.3 or a bicarbonate level of more than 15 mmol/l. And there is usually an absence of ketones in urine, so the urinary ketones should be negative or maximally one cross positive. However, it is also important to remember that it is occasionally possible to have a mixed picture of HHS and DKA.

Investigations

Immediate for diagnosis:

• Plasma glucose
• Sodium with calculation of plasma osmolality (2Na + glucose in mmol/l)
• Potassium and urea
• Venous pH/ bicarbonate (or arterial blood gas if indicated)
• Urine ketones

In terms of investigations for a patient suspected of having HHS:

• The immediate investigations that are needed to confirm the diagnosis are the plasma glucose.
• We should check sodium to calculate the plasma osmolality using this formula.
• We should also check potassium to guide potassium replacement.
• And urea to assess the degree of dehydration.
• Doing venous pH or venous bicarbonate will be important to rule out acidosis.
• Arterial blood gases are only indicated in critically ill patients.
• And checking urine for ketones is also needed to rule out DKA.

Urgent for assessment and treatment:

• Complete blood count
• Creatinine
• Midstream urine
• HbA1c
• Blood film for malaria (if indicated)

Other investigations that will also be needed include:

• A complete blood count to look at the white cell count.
• Creatinine to assess renal function.
• Doing a midstream urine to rule out UTI.
• HbA1c will also be helpful to assess whether the hyperglycemia is a truly acute episode or whether it has been long-standing.
• And a blood film for malaria may be indicated in some patients.

Indications for admission to ICUZ

• Osmolality >350 mOsmol/kg
• Sodium >160 mmol/L
• Glasgow coma scale <10
• Systolic BP<90 mmHg

The indications for admission to ICU include:

• If the osmolality is very high at above 350 mosmol per kg.
• If the sodium is very high at more than 160 mmol/l.
• If there is a reduced level of consciousness with a Glasgow coma scale of less than 10.
• And if there is hypotension with a systolic blood pressure of less than 90 mmHg.

Aims of treatment in HHS

• Replace fluid and electrolyte losses

• Gradually normalize plasma osmolality

• Gradually normalize plasma glucose

• Treat the underlying cause

• Reduce plasma osmolality by 3-8 mOsmol/kg/hour

• Reduce plasma glucose by 55-90 mg/dL/hour

• Target plasma osmolality: <315 mOsmol/kg

• Target plasma glucose: 180-250 mg/dL

The aims of treatment in HHS include:

• First, replacing the fluid and electrolyte losses.
• Plasma osmolality should be normalized but very gradually.
• We should also aim to gradually normalize the plasma glucose.
• And the underlying cause for the HHS should be identified and treated.

So looking at these targets of treatment more specifically:

• The plasma osmolality should be reduced by between 3 and 8 mosmol per kg every hour.
• The target for plasma osmolality to be aimed for is less than 315 mosmol per kg.
• We should aim to reduce the plasma glucose by between 55 and 90 mg per dL.
• With a target plasma glucose of between 180 and 250 mg per dL.

Other goals of treatment in HHS

Prevention of:

• Arterial and venous thrombosis
• Neurological complications e.g cerebral edema/central pontine myelinolysis
• Foot ulceration

There are other goals while we are treating patients with HHS:

• These patients are at high risk from arterial and venous thrombosis, so they should be treated by a prophylactic dose of low molecular weight heparin.
• They are also at risk from neurological complications like cerebral edema and central pontine myelinolysis, and these should be prevented by careful fluid replacement.
• And lastly, there is a risk of foot ulceration, especially in patients who are unconscious and have neuropathy, so foot care is important in these patients.

Monitoring

Hourly:

• Pulse
• BP
• RR
• Fluid input/output
• Capillary glucose

Four Hourly:

• Plasma glucose and sodium (with calculation of plasma osmolality)
• Potassium

Regular monitoring of the patient includes checking hourly the pulse rate, blood pressure, respiratory rate, fluid input and output, and capillary glucose. While checking plasma glucose and sodium to calculate plasma osmolality should be done if possible every 4 hours or as close as possible to that. Potassium should also be checked if possible every 4 hours.

IV fluids

• An adult weighing 70 kg may be up to 10 liters in fluid deficit
• 0.9% normal saline is the fluid of choice
• When glucose reaches 250 mg/dL, change to 10% dextrose at a rate of 125 ml/hour
• The rate of fall of plasma sodium should not exceed 10 mmol/L in 24 hours

Suggested guide for rate of IV saline infusion for most patients with HHS

Element	Rate ml/hour
1st liter over 1 hour	1000
2nd liter over 2 hours	500
3rd liter over 2 hours	500
4th liter over 4 hours	250
5th liter over 4 hours	250

• If systolic BP <90 mmHg, give 500 ml saline over 15 minutes
• Repeat if SBP still <90 mmHg
• In patients with cardiac or renal impairment, adjust rate accordingly
• A urinary catheter may be needed to monitor urine output

Rehydration with IV fluids is the most important element in management of patients with HHS. These patients are usually much more dehydrated than those with DKA, with an adult patient who weighs 70 kg usually needing 10 liters of fluid. Similar to DKA, the fluid of choice is also normal saline. And when the plasma glucose level reaches 250 mg per dL, the fluid should be changed to 10% dextrose and this can be given at a rate of 125 ml per hour. It is important to make sure that the fall in sodium is gradual and should not be more than 10 mmol per liter per 24 hours.

Again, this is a suggested guide for the rate of IV fluid replacement which may be suitable for most adult patients with HHS. One liter should be given over one hour. Then 2 liters to be given over 2 hours each. And then 2 liters to be given over 4 hours each.

And again, of course, these rates are a general guide, and the rate should be adjusted according to the clinical assessment of the severity of the fluid deficit. So for patients who have a systolic BP < 90 mmHg at presentation, 500 ml saline should be given over 10-15 minutes and should be repeated if systolic BP is still below 90 mmHg. Caution should be exercised in those who have cardiac or renal impairment. And in these cases, a urinary catheter may be needed so as to monitor the urine output.

Potassium replacement

If plasma potassium result available quickly on admission, follow the table below:

Serum potassium	Potassium chloride/liter fluid
> 5.5 mmol/L	Give saline with no added KCl
3.3 - 5.5 mmol/L	Add KCl 20 mmol to each 500 ml bag of saline
<3.3 mmol/L	Add KCl 20 mmol to each 500 ml bag of saline and: consider increasing rate of infusion if fluid balance allows withhold insulin until potassium ≥3.3
If plasma potassium result is not available on admission:

• The first 2 bags of 500 ml saline should be without added potassium
• When the potassium result is known, follow the previous table

And similar to the DKA guidelines, the recommendation for potassium replacement will depend on whether the result of plasma potassium is immediately available or not:

• If we can get a plasma potassium done and the result is available quickly, we should follow these recommendations from the joint British societies guideline.
• If the potassium level on admission is more than 5.5 mmol/l, no potassium is added to the saline fluid.
• If the level is between 3.3 and 5.5 mmol/l, 20 mmol of potassium chloride should be added to each 500 ml bag of normal saline.
• And if potassium is very low at less than 3.3 mmol/l, two measures should be taken, first, we should consider increasing the rate of the infusion of the fluid containing potassium.
• And in this situation also, insulin should be withheld until the potassium has risen to above 3.3 mmol/L, as giving insulin will cause further lowering of potassium which can cause life-threatening arrhythmias.

And in case the plasma potassium result is not available on admission, the safe course of action is to give the first two bags without added potassium. And once the result of potassium is known, then one can follow the recommendations in the table I just showed.

Insulin therapy

• Fluid replacement alone (without insulin) will lower plasma glucose

• Start insulin only if:

  • Rate of fall plasma glucose is less than 55 mg/dL/hour
  • Urinary ketones ≥++ (i.e mixed DKA and HHS)

• Aim for a reduction in plasma glucose of 55-90 mg/dL/hour

• Target plasma glucose is 180-250 mg/dL

If syringe infusion pump available:

• Add 50 units of soluble human insulin (e.g actrapid) to 50 ml normal saline, this gives a concentration of 1 unit/ml
• This should be infused into a separate IV line and the solution should be changed every 6 hours
• Infuse at a fixed rate of 0.05 unit/kg/hour, based on estimating patient’s weight (e.g 4 units/hour in an 80 kg person)

If a syringe infusion pump is not available:

• Give a subcutaneous injection of soluble human insulin (e.g actrapid) at a dose of 0.05 unit/kg every hour (or 0.1 unit/kg every 2 hours)
• Reduce the dose to 0.025 unit/kg/hour SC when glucose is <250 mg/dL

The situation regarding insulin therapy in HHS is a little different from DKA. Here, it is expected that IV fluid replacement alone, without insulin, will result in lowering glucose levels. And in HHS, it is recommended that insulin therapy should only be started in these situations:

• First, if the rate of plasma glucose fall is less than the expected rate of 55 mg per dL per hour.
• Or if there are urinary ketones more than 2 crosses, which means the patient has a mixed picture of ketoacidosis and HHS.
• When insulin is given, the aim is to reduce plasma glucose by between 55 and 90 mg per dL.
• And the target is to maintain plasma glucose between 180 and 250 mg per dL.

And similar to DKA, the recommendation to follow will depend on whether a syringe infusion pump is available, which is the ideal situation, or whether it is not available. If a syringe infusion pump is available, then insulin should be given by IV infusion. The insulin used for IV infusion is usually soluble insulin, and this is prepared by adding 50 units to 50 ml of normal saline, which gives a concentration of 1 unit per ml. This should be given through a separate IV line to that used for the IV fluid replacement and the solution should be changed at least every 6 hours. The infusion should be at a fixed rate of 0.05 units per kilogram per hour, which can be based on estimating the patient’s weight, so for example, an 80 kg person can have the insulin infusion at a rate of 4 units per hour, which is a lower rate than that used in patients with DKA because patients with HHS usually need less insulin than those with DKA.

If a syringe infusion pump is not available, the alternative method is to give insulin through the subcutaneous route. And here the soluble human insulin should be given at a dose of 0.05 units per kilogram every hour

HHS- Other management issues

• Seek an infective source based on history/examination + relevant investigations (urine culture, blood film for malaria, etc)

• Give prophylactic dose of low molecular weight heparin

• Take measures to avoid pressure on feet, especially in patients with neuropathy or PVD

It is also important to identify and treat the underlying cause of HHS, infection is a common cause, so a source of infection should be looked for carefully by first taking a good history and performing examination and then direct investigations accordingly such as doing urine culture or a blood film for malaria 

To prevent thrombosis, a prophylactic dose of low molecular weight heparin should be given

And one should also take measures to avoid pressure on feet, this is especially important in those who already have neuropathy or peripheral vascular disease

Resolution of HHS

Stop insulin (IV or SC) when:

• The patient is fully conscious

• Well-hydrated

• Eating and drinking

• Plasma osmolality <315 mOsmol/kg

Resolution from HHS is defined when these criteria are satisfied:

• And the patient should be fully conscious
• Should be well-hydrated
• Should be able to eat and drink
• And the plasma osmolality should be less than 315 mosmol per kg

Management of the recovery period from HHS

• If previously on insulin: restart usual insulin regime

• If previously on diet/oral hypoglycemic drugs: restart if clinically well and stable

• If newly diagnosed diabetes: decide on appropriate treatment (diet, OHAs or insulin) depending on clinical condition and HbA1c

• Educate patient to reduce risk of recurrence of HHS

After recovery from HHS, a decision should be made about the treatment for diabetes

So for those who are already on insulin, they should be restarted on their usual insulin regime

For those who were previously on diet or oral hypoglycemic drugs, if they return to their baseline situation and if their previous diabetes control was satisfactory, they can actually go back to their usual treatment 

For those who are newly diagnosed with diabetes, a decision should be made on the appropriate treatment, depending on their overall clinical condition and the HbA1c level 

Patients who have been admitted with HHS should also receive education to reduce the risk of it happening again