Hyperosmolar hyperglycemic state (HHS) (2024)

June 1, 2024 by Josh Farkas

CONTENTS

• Rapid Reference 🚀
• Definition of HHS
• Evaluation for an underlying process
• Treatment
  • Treatment principles
  • Volume resuscitation
  • Insulin
  • Hypertonicity management
• Background:
  • Pathophysiology
    • Osmolality versus tonicity
• Podcast
• Pitfalls

rapid reference

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[1] diagnostic evaluation ⚡️

• Electrolytes (including Ca/Mg/Phos), complete blood count.
• If diagnosis of HHS is unclear: beta-hydroxybutyrate & lactate.
• If infection suspected: blood cultures, urinalysis & culture, CXR.
• If pregnancy possible: urine pregnancy test or serum beta-HCG
• Further evaluation for MI, pancreatitis, abdominal process, or stroke as warranted by the history & physical examination.

[2] start basal insulin immediately ⚡️

• If the patient is chronically on insulin and missed doses: administer their entire home-dose basal insulin dose immediately.
• If the patient is insulin naive: start ~0.3 U/kg glargine q24hr.
• Consider IV thiamine 100 mg daily to prevent Wernicke encephalopathy.

[3] volume & electrolyte repletion ⚡️

• Often start with a liter LR bolus, followed by ~250-500 ml/hr of half-normal saline.
• Aggressive repletion of potassium, magnesium, and phosphate.
  • Target K >5.3 mM.
  • Cycle electrolytes including Ca/Mg/Phos q2-4 hours.

[4] short-acting insulin ⚡️

• Start an insulin infusion at 0.05 U/kg/hr (half of the usual dose used for DKA).
• Titrate insulin to drop the glucose by ~40-80 mg/dL per hour.
• When glucose is approaching ~300 mg/dL, stop the insulin infusion. Then order meal-associated and sliding-scale insulin.

[5] management of hypertonicity

• Management of hypertonicity requires a personalized approach as discussed further below: ⚡️

definition of HHS

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definition of pure HHS (without DKA)

• [1] Profound hyperglycemia (usually >>600 mg/dL or >>33 mM).
• [2] Effective serum osmolality >320 mOsm.
  • Effective osmolarity is defined here as 2[Na] + (glucose in mg/dL)/18. (37758417)
• [3] Absence of substantial ketoacidosis, based on one of the following:
  • Beta-hydroxybutyrate <3 mM (this is the most precise way to define ketoacidosis, but often unnecessary).
  • Anion gap <~15 mM (anion gap is usually sufficient to evaluate for ketoacidosis, in the absence of other factors that elevate the anion gap such as uremia or hyperlactatemia). This may be substantiated by the additional finding that urine ketones are trace/small.

mixed DKA/HHS

• Patients may have a combination of DKA (with beta-hydroxybutyrate >3 mM) and HHS (with hyperosmolarity).
• Treatment can generally be based on which abnormality predominates, for example:
  • Marked ketoacidosis with mildly elevated serum osmolality may be managed using a treatment algorithm for DKA. 📖
  • Marked hypertonicity with mild ketoacidosis may be managed using the algorithm below for HHS (with the modification that the insulin infusion should be initiated immediately). (36370077)

evaluation for an underlying process

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Perhaps the most important aspect of treating DKA or HHS is ensuring that no underlying process is missed (e.g., sepsis, pancreatitis, myocardial infarction, CVA). HHS carries a high mortality (often quoted ~15%) – but this is largely due to comorbid problems and triggers, rather than the HHS itself.(31142480)

common causes of HHS

• [#1] Infection in about half of patients, e.g.:
  • Pneumonia.
  • Skin/soft tissue infection.
  • Urinary tract infection.
• [#2] Insulin nonadherence or inadequate dosing.
• Medications that increase insulin resistance:
  • Steroid initiation.
  • Thiazides.
  • Beta-blockers.
  • Phenytoin.
  • Sympathomimetic agents.
  • Calcineurin inhibitors.
  • HIV protease inhibitors.
  • Antipsychotics.
• Cardiovascular events:
  • Stroke.
  • MI.
  • Pulmonary embolism.
• Gastrointestinal:
  • Pancreatitis.
  • Gastrointestinal hemorrhage.
• Trauma.
• Substance/alcohol use.
• Heat exposure. (25342831)

neurological abnormality in HHS: chicken or egg?

• HHS may cause a range of neurological alterations:
  • Confusion, somnolence, and in extreme cases even coma.
  • Seizure.
  • Acute ballismus or chorea is often associated with HHS. 📖
• However, HHS can also be caused by stroke or CNS infection – so caution is required when attributing neurological abnormalities to HHS. When in doubt, patients should be investigated broadly.
• Red flags that are especially worrisome for a primary neurological disorder:
  • 🚩 Focal neurological signs/symptoms (although these can occur in HHS).
  • 🚩 Severe neurological manifestations with only moderate hypertonicity (e.g., osmolarity ~320-340 mOsm).
  • 🚩 Neurological deterioration despite therapy for HHS.

evaluation for might include

• Infectious workup:
  • Chest radiograph.
  • Blood cultures.
  • Urinalysis.
• CT scan of the abdomen and pelvis; lipase (note that unlike patients with DKA, patients with HHS usually shouldn't have abdominal pain caused by ketoacidosis).
• Evaluation for myocardial ischemia:
  • ECG.
  • Troponin is indicated only if there is clinical suspicion for type-I MI.
• Neurological evaluation (depending on findings, as discussed above).

treatment: key principles of HHS

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less aggressive insulin is needed

• In DKA, aggressive insulin is required to treat ketoacidosis. Subsequently, the insulin infusion and long-acting insulin must be carefully overlap to prevent recurrent ketoacidosis (“re-opening of the gap”).
  • Additionally, in DKA the metabolic acidosis increases insulin resistance – so higher doses of insulin are required. Patients with HHS generally have relatively normal pH, so they may be more insulin sensitive.
• In HHS, there is no ketoacidosis – so insulin dosing is solely directed towards treating the hyperglycemia. This allows us to be much more conservative with insulin dosing. In some cases, an insulin infusion may not be even needed at all (long-acting insulin plus short-acting may be sufficient). All you really need to do is give enough insulin to drop the glucose into a reasonable range.

target moderate hyperglycemia (avoid hypoglycemia)

• Acutely “normalizing” glucose in a patient with longstanding diabetes may induce a stress response, which is potentially detrimental. Furthermore, inducing hypoglycemia in this context is probably extremely dangerous. Finally, excessive lowering of the glucose may increase the risk of cerebral edema.
• The initial glucose target over the first day may be 🎯 180-270 mg/dL (10-15 mM). Over subsequent days, this may be gradually lowered further.

volume resuscitation and electrolyte repletion

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volume resuscitation

• ⚠️ Patients are often profoundly volume depleted, but personalization remains important (especially among patients with heart and/or renal failure).
• [1] Resuscitation is often started with a liter bolus of isotonic fluid (e.g., lactated Ringers or Plasmalyte).
• [2] Subsequently, fluids are often infused in a more controlled fashion (e.g., 250-500 ml/hour). The rate and quantity of volume will depend on the clinical context and hemodynamic assessment.
  • Half-normal saline (0.45% sodium chloride) is often a useful fluid to utilize at this stage, to provide both volume resuscitation and free water. The addition of potassium may be considered in anticipation of ongoing potassium losses (e.g., 0.45% sodium chloride with 20 mEq of KCl).
• [3] Adjust ongoing resuscitation based on:
  • Serial assessment of hemodynamics and urine output.
  • Serial assessment of electrolytes and acid/base status.
  • Serial measurement of tonicity (ideally calculated tonicity will decrease in a controlled fashion). ⚡️

aggressive electrolyte repletion

• Potassium: Potassium should be aggressively repleted as in DKA, with a target potassium >5.3 mM (in patients with normal renal function).
• Magnesium: Magnesium should be aggressively repleted. Maintaining a magnesium level on the high end will tend to prevent Torsade de Pointes if the potassium level falls.
• Phosphate: Phosphate should be repleted as necessary.

insulin

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immediate administration of basal, long-acting insulin

• Dosing:
  • For patients previously on basal insulin, their home-dose basal insulin should be resumed (similar to DKA, dosing details discussed here: 📖).
  • For patients not previously on basal insulin, initiate weight-based, long-acting insulin (~0.3 units/kg glargine s.c. q24h, first dose now).
• Early basal insulin facilitates a smooth transition off the insulin infusion (with reduced incidence of rebound hyperglycemia). In some cases, immediate long-acting insulin plus some doses of short-acting insulin may avoid the need for an insulin infusion.

who needs an insulin infusion?

• Not every patient with HHS necessarily requires an insulin infusion. For some patients, volume resuscitation plus subcutaneous insulin will be adequate. Among patients who are profoundly volume depleted, it's generally advisable to start with volume resuscitation and then assess whether an insulin infusion is needed. (36370077)
• Indications for insulin infusion:
  • [1] For patients who are the borderline of having DKA (e.g., anion gap ~10-14 mEq/L, or beta-hydroxybutyrate level ~2-3 mM), an insulin infusion should be started without delay.
  • [2] Persistent marked hyperglycemia, despite volume resuscitation. In situations where it is unclear whether an insulin infusion is necessary, it may be reasonable to first trial subcutaneous insulin.
• Contraindications: Hypokalemia is a contraindication to insulin infusion.

dose the insulin infusion conservatively

• The starting dose is 0.05 U/kg/hr (half of the initial dose used in DKA).
• The target should be to reduce the glucose by ~40-80 mg/dL per hour (2.2-4.4 mM).
• Stop the insulin when glucose approaches ~300 mg/dL:
  • Dropping the glucose below 🎯 180-270 mg/dL (10-15 mM) may increase the risk of cerebral edema.
  • Following discontinuation of the insulin infusion, transition to a combination of both meal-associated and sliding-scale subcutaneous short-acting insulin.
• If the patient's glucose falls <200 mg/dL (11 mM), stop insulin and initiate a D5W or D10W infusion. Avoid allowing the glucose to fall below 🎯 180-270 mg/dL (10-15 mM) during the first day of therapy. (31142480)

hypertonicity management

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evaluation and understanding of tonicity

Tonicity ≈ 2[Na+K] + (Glucose in mg/dL)/18

• By definition, patients with HHS will start out with an elevated tonicity. One goal of an HHS resuscitation is to safely reduce the tonicity to a normal level.
• Calculated blood tonicity is probably the most important parameter to assess the risk of osmotic shifts over time (physiology is explored further below: ⚡️). (36370077)
• Early in the management of HHS, sodium often increases while glucose decreases and potassium decreases. The key parameter to follow is the calculated tonicity (which ideally should gradually decrease). Failure of the tonicity to decrease suggests that additional water should be provided (e.g., transition from isotonic fluid to half-normal saline, or add a D5W infusion).
• Altered mental status is important to consider in the management of hypertonicity:
  • Altered mental status implies an acute/subacute rise in tonicity, which may argue for a more rapid reduction in tonicity.
  • Normal mental status implies a more chronic rise in tonicity, which may argue for a more gradual reduction in tonicity.

hypertonicity management for patients over ~40 years old

• The risk of cerebral edema due to rapid reduction in tonicity seems to be extremely low in these patients. Consequently, rapid lowering of tonicity is likely safe and is arguably desirable (discussed further here: 📖).
• Altered mental status suggests that the patient has experienced a rapid rise in tonicity, which may theoretically increase the risk of osmotic demyelination syndrome. In this situation, a prompt reduction in tonicity is logical.
• For patients with normal mental status, a reasonable target might be to reduce the serum tonicity by at least 20/day (which is roughly equivalent to dropping the sodium by at least 10 mM/day).
• Logistics:
  • If the patient is thirsty and able to drink water, then allowing free access to water is a simple, kind, and effective approach to correct hypertonicity.
  • If the patient is unable to drink, then water may be provided either via enteral tube or as intravenous D5W or half-normal saline. Estimated free water requirements may be calculated: 🧮

hypertonicity management for patients below ~40 years old

• The risk of cerebral edema is highest among the following patients:
  • (a) Younger age (especially as age approaches a pediatric range).
  • (b) More severe initial hypertonicity.
  • (c) Normal mental status (implying that hypertonicity is chronic).
• For patients <40 years old with a normal mental status, it may be reasonable to target a reduction in serum tonicity by ~20/day:
  • During the initial resuscitation with crystalloid and insulin, serum tonicity may be the best target (calculated using the formula above).
  • After the glucose has normalized, then serum sodium will generally be an accurate reflection of serum tonicity. At this point, it's often easier to simply follow the serum sodium and target a reduction of 10 mM per day in the sodium level.
  • Management here is very similar to the management of chronic hypernatremia: 📖
    • Restrict free water intake.
    • Calculate and gradually administer the amount of free water required to reduce the sodium by 10 mEq/L each day (🧮 using MDCalc).
    • Follow electrolytes and adjust as needed.

pathophysiology

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pathogenesis of classic HHS

• HHS is often triggered by an acute stressor, which increases levels of cortisol and catecholamines (thereby reducing insulin sensitivity).
• HHS occurs in patients with enough insulin to prevent ketoacidosis, but not enough insulin to control hyperglycemia.
  • Higher levels of insulin are required to control hyperglycemia, compared to the amount required to prevent ketogenesis (as seen in the way that many patients in the ICU develop mild insulin resistance and hyperglycemia – without developing ketoacidosis).
• Uncontrolled hyperglycemia causes an osmotic diuresis, with loss of water.
• Patients fail to compensate adequately for water loss by increasing oral water intake (e.g., due to baseline debility, bed-bound status, or a relatively insensitive central drive to maintain normal tonicity).
• Over a period of several days, uncontrolled water loss leads to a hypertonic state. This may lead to altered mental status (which exacerbates the patient's inability to drink an adequate amount of water).
• However, rather than a clean dichotomy between HHS and DKA, there is actually a disease continuum, as shown below:

osmolality versus tonicity

osmolality

• Osmolality is a measurement of the number of particles in a solution.
• This is a physical chemistry property of any water-based solution.
• Osmolality can be precisely measured in the laboratory (based on freezing point depression).
• Osmolality may be approximated as follows:

Osm ≈ 2[Na+K] + [glucose] + [urea]

Osm ≈ 2[Na+K] + (Glucose in mg/dL)/18 + (urea in mg/dL)/2.8

tonicity (aka, effective osmolality)

• Tonicity refers to how much the particles in a solution pull water across a semi-permeable biological membrane. This depends on the number of effective osmoles in the solution.
• Sodium is an effective osmole, because it cannot cross the semipermeable membrane. Therefore, sodium will tend to pull water across the membrane. If you bolus a patient with concentrated sodium solutions, this affects the volume of fluid in their cells.
• Urea is an ineffective osmole, because urea can diffuse freely into cells. Therefore, the urea cannot pull water across the membrane (the urea itself will just freely diffuse into the cells). Thus, if you were to bolus a patient with concentrated urea, this would not affect the volume of fluid in their cells.
• Tonicity is more clinically important than osmolality, because tonicity is what actually determines whether cells swell or shrink.
• Tonicity may be approximated as follows: (36370077)

Tonicity ≈ 2[Na+K] + [glucose]

Tonicity ≈ 2[Na+K] + (Glucose in mg/dL)/18

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Hyperglycemia rarely causes mental status changes unless the serum osmolality is >320 mOsm. Thus, if the serum osmolality is <320 mOsm and mental status is significantly abnormal, look for an alternative explanation (Anna 2015).
• Patients with glucose >600 mg/dL (>33 mM) don't necessarily have HHS, nor do they necessarily need an insulin infusion. Don't assume that every patient with severe hyperglycemia requires ICU admission. As with everything in medicine, the context is king (what else is going on? does the patient appear sick or well?).
• True HHS develops slowly and should be corrected slowly. When in doubt, make small adjustments.
• The morbidity of HHS is due largely to underlying triggers, so search carefully for them (e.g., infection or infarction).
• Don't forget to pay attention to sodium concentration and serum osmolality. Younger patients with HHS are at risk for cerebral edema if their tonicity is reduced too rapidly.

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