Hyperglycemic Hyperosmolar Syndrome (HHS) or HyperOsmolar NonKetotic (HONK) crisis

What is hyperosmolar hyperglycemic state (HHS) and what are its key clinical hallmarks in veterinary patients?

• Hallmarks:

  • Severe hyperglycemia (typically >600 mg/dL; often 600–1600 mg/dL).

  • Hyperosmolality (usually >325–330 mOsm/kg in dogs; >330–350 mOsm/kg in cats; some refs use >350 mOsm/kg for all).

  • Minimal to absent ketones (no or only small ketonemia/ketonuria).

  • Significant systemic illness and/or neurologic compromise (lethargy → seizures/coma).

  • pH: arterial >7.3; venous >7.25.

  • Serum bicarbonate >15 mmol/L (no marked ketoacidosis).

  • Often neurologic abnormalities present.

• Clinically significant HHS is a medical emergency with guarded prognosis; many patients need 24-h critical care.

How can HHS overlap with diabetic ketoacidosis (DKA), and why is overdiagnosis of HHS a concern?

• A hybrid HHS + DKA state can occur:

  • BG >600 mg/dL, serum osmolality >320–350 mOsm/kg plus ketoacidosis (pH <7.3, low bicarbonate, high anion gap, ketonemia/ketonuria).

• Many DKA patients are hyperosmolar, so hyperosmolality alone ≠ HHS.

• HHS diagnosis should be reserved for patients with:

  • Marked hyperglycemia, marked hyperosmolality, minimal/no ketosis, severe dehydration/hypovolemia ± neurologic signs.

• Overdiagnosing HHS:

  • May cause overly guarded prognosis and owners declining care.

  • May lead to over-cautious therapy (late insulin, under-resuscitation) → longer stay and higher cost.

Why is corrected sodium important in HHS, and what are the key formulas?

Hyperglycemia pulls water from cells → dilutional hyponatremia, masking true hypernatremia and free water deficit.

A normal measured Na with severe hyperglycemia may actually represent hypernatremia once corrected.

Correct Na slowly: 0.5–1 mEq/L/h, max 10–12 mEq/L/24 h to reduce neurologic risk.

Which counterregulatory hormones oppose insulin, and what is their general role?

• Key counterregulatory hormones:

  • Glucagon

  • Epinephrine

  • Cortisol

  • Growth hormone (GH)

• Common roles:

  • Increase blood glucose (via glycogenolysis and/or gluconeogenesis).

  • Promote fat utilization and lipolysis.

  • Activate in states of hypoglycemia or systemic stress; in HHS/DKA they exacerbate metabolic derangements.

How do growth hormone, cortisol, and epinephrine specifically affect glucose and fat metabolism?

• Growth hormone (GH):

  • Secreted from anterior pituitary in hypoglycemia.

  • Inhibits cellular glucose utilization and promotes fat use; effects are slow (hours).

• Cortisol:

  • Secreted from adrenal cortex in response to hypoglycemia and stress.

  • Similar to GH: decreases glucose utilization, increases lipolysis; slow onset (hours).

• Epinephrine:

  • From adrenal medulla during sympathetic activation/stress.

  • Rapid hepatic glycogenolysis → ↑ BG within minutes.

  • Direct lipolytic effect via hormone-sensitive lipase → ↑ FFAs.

What is the role of glucagon in diabetes mellitus and HHS?

• Secreted by pancreatic α-cells when BG decreases.

• Stimulates hepatic glycogenolysis and gluconeogenesis → ↑ BG within minutes.

• In DKA/HHS, elevated glucagon contributes to:

  • Persistent hyperglycemia.

  • Enhanced lipolysis and ketogenesis (unless partially suppressed by residual insulin in HHS).

• Human HHS patients have higher hepatic insulin and lower glucagon concentrations than DKA patients; higher insulin:glucagon ratio helps prevent ketoacidosis.

How does the pathogenesis of HHS differ from DKA in terms of insulin and glucagon?

• Both start with absolute or relative insulin deficiency + ↑ counterregulatory hormones (glucagon, epinephrine, cortisol, GH) triggered by stress or concurrent disease.

• DKA:

  • Marked insulin deficiency → uncontrolled lipolysis, large FFA flux → ketogenesis and ketoacidosis.

• HHS:

  • Patients have small but sufficient insulin to:

    • Inhibit lipolysis and ketogenesis,

    • But not enough to prevent severe hyperglycemia.

  • Hepatic glucagon resistance and hyperosmolar state both further inhibit lipolysis and ketosis.

• Result: Hyperglycemia + hyperosmolality + dehydration, but minimal ketones.

How does hyperglycemia interact with GFR and osmotic diuresis in HHS pathogenesis?

• Early: hyperglycemia → osmotic diuresis with increased GFR → limits BG rise initially.

• Over time:

  • Ongoing osmotic diuresis + poor intake/other fluid losses → hypovolemia.

  • Hypovolemia → reduced GFR → less renal glucose excretion → worsening hyperglycemia.

• Hyperglycemia + renal free water loss → hypernatremia and hyperosmolality.

• Progressive hyperosmolality causes cerebral dehydration → neurologic signs, which further reduce voluntary water intake, worsening the cycle.

What are idiogenic osmoles and why do they matter in HHS treatment?

• In chronic hyperosmolality, brain cells produce intracellular solutes (“osmolytes” or idiogenic osmoles) to match ECF osmolality and limit cell shrinkage.

• If ECF osmolality is corrected too quickly (eg, aggressive fluids/insulin):

  • ECF becomes relatively hypo-osmotic, while intracellular osmoles remain high.

  • Water shifts into brain cells → cerebral edema.

• Practical implication: slow correction of Na, glucose, and osmolality:

  • Na ↓ ≤0.5–1 mEq/L/h,

  • Glucose ↓ ≤50–75 mg/dL/h,

  • Osmolality ↓ ≈2–5 (up to 8) mOsm/kg/h.

Which concurrent diseases and medications commonly precipitate HHS in dogs and cats?

• Common comorbidities in cats:

  • Chronic kidney disease, congestive heart failure, respiratory disease, infections, neoplasia, GI disease.

• Common comorbidities in dogs:

  • Acute pancreatitis, urinary tract infection, hyperadrenocorticism; renal failure, CHF, pulmonary disease, neoplasia, lower urinary tract disease.

• Mechanisms:

  • ↓ GFR (renal failure, CHF).

  • ↓ water intake (nausea, lethargy).

  • ↑ losses (vomiting, diarrhea).

  • ↑ stress hormones → insulin resistance.

What are the common physical examination findings in HHS patients?

• Moderate to severe dehydration.

• Perfusion deficits:

  • Pale mucous membranes, CRT >2 s.

  • Tachycardia (or bradycardia in cats with severe poor perfusion).

  • Weak/absent pulses, cold extremities.

  • Hypotension, altered mentation.

• Hypothermia (especially cats).

• Neurologic findings (often symmetric):

  • From depressed → obtunded → stuporous → comatose.

  • Abnormal PLRs, cranial nerve deficits.

  • Circling, seizures.

• Plantigrade stance may be seen in diabetic neuropathy.

• Respiratory changes:

  • Kussmaul-type respirations (slow, deep) if concurrent ketoacidosis or severe lactic acidosis.

  • Tachypnea or increased effort.

• Abdominal pain if concurrent abdominal disease (eg, pancreatitis).

Why can HHS patients still be acidotic, and how is lactic acidosis diagnosed?

• Despite minimal ketosis, some HHS patients have metabolic acidosis due to:

  • Lactic acidosis from tissue hypoxia/hypoperfusion.

  • Accumulation of uremic acids in azotemia.

  • Occult ketoacidosis missed by urine strip (which doesn’t detect BHB).

• Lactic acidosis:

  • Lactate >2.5 mmol/L and pH <7.35 are typical.

  • Confirm with plasma lactate measurement (POC analyzers).

• Presence of acidosis alone shouldn’t rule out HHS; evaluate lactate, ketones, and perfusion.

What are the limitations of urine reagent strips for ketones, and how do blood BHB assays improve detection?

• Urine/serum reagent strips use nitroprusside reaction → detect acetoacetate ± acetone, not BHB.

  • Can underestimate ketosis, especially early DKA where BHB predominates.

  • False positives: N-acetylcysteine, captopril, penicillamine.

  • False negatives: early disease (serum ketones precede urine), old or air-exposed strips.

• Blood BHB (lab assay or portable meter):

  • Earlier and more accurate detection of ketoacidosis.

  • In cats: BHB >2.4 mmol/L is sensitive for ketoacidemia.

  • In dogs: BHB >3.5 mmol/L predicts high risk of DKA; BHB <2.8 mmol/L makes DKA unlikely.

• Take-home: Use BHB assays where available to distinguish HHS vs HHS–DKA overlap.

What are the overarching treatment goals for HHS patients?

• Restore intravascular volume and perfusion (correct hypovolemia/shock).

• Gradually correct dehydration and free water deficit over ~24–48 h.

• Correct electrolyte disturbances, especially Na, K, P.

• Reduce blood glucose and serum osmolality slowly:

  • BG ↓ ≤50–75 mg/dL/h.

  • Na ↓ ≤0.5–1 mEq/L/h.

  • Osmolality ↓ ≈2–5 (up to 8) mOsm/kg/h.

• Address concurrent disease (infection, pancreatitis, CHF, etc.).

• Avoid rapid shifts in osmolality that risk cerebral edema or cardiovascular collapse.

What is the recommended approach to initial IV fluid resuscitation in HHS?

• Use an isotonic crystalloid (0.9% NaCl or a high-Na balanced solution like Plasma-Lyte 148 or Norm-R).

• Shock bolus:

  • 10–15 mL/kg in cats; up to 15–30 mL/kg in dogs, reassessing after each bolus.

• Repeat boluses until perfusion improves (MM, CRT, HR, pulses, BP, lactate).

• Reassess Na and osmolality after initial resuscitation.

• 0.9% NaCl osmolarity ≈308 mOsm/L (highest common isotonic option, helps avoid overly rapid osm drop).

How is persistent hypernatremia managed in HHS patients after initial resuscitation?

• Correct Na slowly: 30 mEq/L decline would require ~30–60 h (0.5–1 mEq/L/h); use midpoint (e.g. 45 h) as a planning horizon.

• Provide free water via:

  • Enteral water (feeding tube) if GI tract functional.

  • IV hypotonic fluids (e.g. 0.45% NaCl) as part of total fluid plan.

• Adjust fluids if Na falling too quickly: reduce hypotonic fluid rate, switch to higher-Na fluid, or slow overall fluid rate.

• Recheck Na and osmolality at least q4h.

How should fluid therapy be modified in HHS patients with CHF or oliguric/anuric renal failure?

• CHF:

  • Avoid standard “maintenance” rates; rehydrate slowly and cautiously.

  • Consider forced enteral water via nasogastric tube if not vomiting.

  • Monitor for volume overload: weight gain, chemosis, wet MM, nasal discharge, tachypnea, cough, edema.

  • Use CHF-specific therapy as needed (diuretics, inotropes, inodilators).

• Oliguric/anuric renal failure:

  • Place urinary catheter to monitor urine output.

  • Once euvolemic, titrate fluids to match input/output plus minimal additional deficit replacement.

  • Consider renal replacement therapy where available.

Why are potassium deficits important in HHS, and how is potassium supplementation managed?

• Insulin deficiency and hyperosmolality → K shifts out of cells, so serum K may be normal or high, but total body K is depleted.

• Rehydration, correction of acidosis, and insulin therapy drive K back into cells, potentially causing rapid hypokalemia.

• General approach:

  • If hyperkalemic, start fluids without K; recheck in 2–4 h.

  • If normo- or hypokalemic, supplement K from the start.

  • Often use KCl added to IV fluids or CRI via syringe pump.

  • Max rate: 0.5 mEq/kg/h.

• Monitor K every 4–6 h initially, then q8–12 h, adjusting supplementation to keep K in normal range; more frequent checks if using higher rates (≥0.4 mEq/kg/h).

What is the significance of phosphorus depletion in HHS and how is it supplemented?

• Osmotic diuresis + insulin therapy → intracellular phosphate depletion and falling serum phosphorus.

• Severe hypophosphatemia (<1.5 mg/dL) can cause RBC lysis and neurologic signs (including seizures).

• Many HHS patients, especially with renal failure, present hyperphosphatemic, so supplement only when indicated.

• General guidelines:

  • If hypophosphatemic, start supplementation with fluids; if normophosphatemic, start when insulin begins.

  • Use potassium phosphate 0.03–0.12 mmol/kg/h (considered alongside K supplementation because K-phos contains K).

  • Monitor P q8–12 h, adjust as needed.

When should insulin be started in HHS, and how should dosing differ from DKA protocols?

• Do NOT start insulin until hypovolemia is corrected and the patient is hemodynamically more stable.

• Delay is often ≥4–6 h (or longer) after starting fluids.

• Insulin is less urgent in HHS than DKA because ketosis is minimal, and fluids alone can substantially reduce BG.

• Start insulin when:

  • Volume resuscitation is adequate.

  • BG no longer declines at desired rate (<50 mg/dL/h) with fluids alone.

• Use regular insulin (CRI or IM/SC protocols), but reduce DKA doses by ~50% to avoid rapid osm changes.

• BG should fall no more than 50–75 mg/dL/h.

• When BG <200–250 mg/dL, add 2.5–5% dextrose to fluids and continue insulin to resolve residual hyperosmolality and any ketosis.

How should blood glucose be monitored during HHS treatment, and what is the role of CGM?

• BG monitoring:

  • Every 1–2 h in first 24 h, especially after starting insulin.

  • Then q2–4 h as patient stabilizes and insulin/dextrose regimen is established.

• Sampling: central venous catheter preferred; do not infuse insulin, K, P, or dextrose through the same line used for sampling.

• CGM/FGMS devices:

  • Can reduce venipunctures and improve trend recognition.

  • However, some systems in cats with DK(A) under-report BG and show inter-individual variability, so periodic cross-checks with blood meter are recommended

• In people, maintaining BG around ~300 mg/dL during initial HHS management has been suggested to reduce cerebral edema risk; similar cautious approach is reasonable in vet patients

What supportive measures and concurrent disease treatments are important in HHS?

• Antiemetics (eg, maropitant, ondansetron) for vomiting.

• Analgesia (multimodal) especially if pancreatitis or abdominal pain.

• Broad-spectrum antibiotics if infection suspected (fever, leukocytosis, positive urine culture, GI compromise).

• CHF therapy: appropriate diuretics, inotropes, inodilators depending on pathology.

• GI/enteropathy management and pancreatic diets as needed.

• Nutritional support:

  • Introduce enteral nutrition once normothermic, normotensive, hydrated, and electrolytes stabilizing.

  • If not eating, consider nasogastric or esophageal feeding tubes.

  • If enteral feeding not tolerated, parenteral nutrition can be considered with careful monitoring (as PN overdose has induced HHS in a reported dog).

What is an appropriate monitoring schedule for sodium, osmolality, potassium, and phosphorus in HHS?

• Sodium + corrected Na:

  • At least q4 h for first 24 h, then q4–12 h.

• Osmolality:

  • Measured or calculated with each Na/BG assessment (use corrected Na).

  • Aim for osm decrease ≤2–5 (up to 8) mOsm/kg/h.

• Potassium:

  • q4–6 h early, then q8–12 h, adjust supplementation accordingly.

• Phosphorus:

  • q6–12 h during supplementation.

What is the overall prognosis for HHS in dogs and cats, and which factors are associated with outcome?

• Historically: guarded to poor.

  • Reported survival to discharge: ~35–66% overall.

  • One dog series: ~62% survived to discharge; abnormal mentation, coma, and low venous pH predicted poor outcome. PubMed

• Cats: older study showed 35% discharge and ~12% long-term survival. More recent data: ~65.5% survival to discharge, and survival was not significantly different between HHS and DKA cats. PMC+1

  • Worse prognosis associated with: lower body temperature, more severe azotemia, severe hyperglycemia, and hyponatremia