Hyperosmolar Hyperglycaemic State (HHS)

Hyperosmolar Hyperglycaemic State (HHS), formerly known as HONK (Hyperosmolar Non-Ketotic Coma), is a life-threatening metabolic emergency occurring primarily in patients with Type 2 Diabetes Mellitus. It is defined by the triad of severe hyperglycaemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis.

1. Clinical Overview

Summary

HHS is characterised by a relative insulin deficiency that is sufficient to prevent lipolysis and ketogenesis but insufficient to facilitate glucose utilisation or suppress hepatic gluconeogenesis. This results in extreme hyperglycaemia (> 30 mmol/L), which drives a profound osmotic diuresis leading to massive fluid losses (often 9-12 Litres). The mortality rate of HHS (10-20%) is significantly higher than that of Diabetic Ketoacidosis (DKA) (less than 1%), largely due to the older patient demographic, comorbidities, and the severity of dehydration/electrolyte derangement. Diagnosis requires calculated serum osmolality > 320 mOsm/kg. Management prioritizes gradual fluid resuscitation to avoid cerebral oedema, with delayed and cautious insulin therapy.

Key Clinical Facts (Must Know)

1. Mortality: 10-20% (vs less than 1% for DKA). It is the most lethal hyperglycaemic emergency.
2. Definition: Glucose > 30 mmol/L, Osmolality > 320 mOsm/kg, pH > 7.3, Bicarb > 15, Ketones less than 3.0 mmol/L.
3. Fluid Deficit: Typically 100-220 ml/kg (approx 8-12 Litres in a 70kg adult).
4. Insulin Timing: Do NOT start insulin immediately. Start fluids first. Insulin (0.05 u/kg/hr) is only started if glucose stops falling with fluids alone.
5. Sodium: Often pseudohyponatraemia initially, but corrects to hypernatraemia as dehydration worsens. Corrected Sodium is crucial for monitoring.
6. Complication: Thromboembolism (VTE/Arterial) is a major cause of death. Prophylactic LMWH is mandatory.
7. Onset: Insidious (days to weeks), unlike DKA (hours/days).
8. Potassium: Total body deficits are massive (300-1000 mmol) despite normal serum potassium.
9. Cerebral Oedema: Risk of Pontine Myelinolysis (ODS) if Sodium corrected too fast, or Cerebral Oedema if Osmolality drops too fast (> 3 mOsm/kg/hr).
10. Precipitant: Infection (Pneumonia/UTI) is the cause in 40-60% of cases.

Clinical Pearls

[!TIP] The "Honey" Blood: Patients with HHS are hypercoagulable due to dehydration and viscosity. "Sludging" of blood leads to high risk of MI, Stroke, and DVT. Full mechanical and pharmacological VTE prophylaxis is non-negotiable unless bleeding.

[!TIP] Don't Chase the Glucose: The goal is to normalise Osmolality, not just glucose. A rapid drop in glucose causes a rapid drop in osmolality, shifting water into brain cells -> Cerebral Oedema. Aim for a gentle decline (glucose less than 5 mmol/L per hour).

[!TIP] The Sodium Trap: As you give fluids (lowering glucose), glucose moves into cells and water follows, concentrating sodium. Sodium should rise as glucose falls. If sodium does NOT rise, you are giving too much free water (risk of oedema).

[!TIP] Mixed Picture: 1 in 3 patients presents with "Mixed DKA/HHS" (Ketosis + Hyperosmolarity). These are high risk. Treat as per HHS algorithm first (priority is fluid/osmolarity), but may need insulin sooner (DKA protocol) if acidosis persists.

[!TIP] Foot Check: The "insidious" onset means a patient may have been lying on the floor for days ("Found down"). Check for pressure ulcers and rhabdomyolysis (CK).

---

2. Epidemiology

Incidence

• Rate: less than 1 per 1,000 person-years in diabetic population.
• Ratio: Less common than DKA (1 case of HHS for every 6-10 cases of DKA).
• Trend: Increasing incidence due to aging population and rising T2DM prevalence.

Demographics

• Age: Primarily adults > 60 years (mean age ~70).
• Gender: No significant gender bias.
• Diabetes Type: Predominantly Type 2 DM. Rarely in T1DM who take some long-acting insulin (preventing ketosis).
• Ethnicity: Higher rates in African-American, Hispanic, and Native American populations (paralleling T2DM).

Risk Factors / Precipitants ("The 5 I's")

Other Associations:

• Social: Poor fluid intake (nursing home residents, dementia, immobility). "Unable to reach the tap".
• Renal: Chronic Kidney Disease (impairs glucose excretion).
• Substance: Alcohol abuse, Cocaine.

---

3. Pathophysiology

HHS results from a "Perfect Storm" of insulin deficiency, massive physiological stress, and impaired renal clearance. Unlike DKA, where insulin causes a "switch must be off" failure (Lipolysis), HHS represents a "dimmer switch is low" failure (Gluconeogenesis).

The Molecular Basis of Hyperglycaemia

The core defect is a Relative Insulin Deficiency.

1. Receptor Level: Peripheral tissues (Muscle/Adipose) exhibit severe insulin resistance (downregulation of IRS-1 signalling). This prevents Glut-4 translocation, stopping glucose uptake.
2. Hepatic Level: The liver remains sensitive to Glucagon (which is elevated due to stress).
   • Insulin is insufficient to suppress Glucagon.
   • Result: Unchecked Gluconeogenesis (New glucose creation) and Glycogenolysis (Glycogen breakdown).
3. Why no Ketones?:
   • Lipolysis (fat breakdown) is highly sensitive to insulin. Only 10% of basal insulin is required to suppress Hormone Sensitive Lipase (HSL).
   • HHS patients have just enough residual beta-cell function to suppress HSL, preventing Free Fatty Acid (FFA) release and subsequent Ketogenesis.

The Role of Counter-Regulatory Hormones

Precipitants (Infection/MI) cause a surge in "Stress Hormones" which antagonise insulin:

1. Cortisol: Promotes protein catabolism (providing Amino Acid substrates for gluconeogenesis) and increases insulin resistance.
2. Catecholamines (Adrenaline): Stimulate Glycogenolysis and inhibit insulin secretion.
3. Growth Hormone: Increases lipolysis and insulin resistance.
4. Glucagon: The primary driver of hepatic glucose output.

The 5-Step Clinical Mechanism

Step 1: The Initiating Event (Hyperglycaemia)

• A precipitant (e.g., Pneumonia) causes stress hormone release.
• Glucose rises.
• Peripheral uptake fails.
• Liver pumps out more glucose.
• Result: Glucose > 20 mmol/L.

Step 2: Osmotic Diuresis (The Volume Depletion Phase)

• Glucose exceeds the Renal Threshold (approx 10 mmol/L).
• The Sodium-Glucose Co-transporter 2 (SGLT2) in the proximal tubule is saturated.
• Glucose remains in the tubule, acting as an osmole.
• Water is retained in the tubule (opposing reabsorption) and excreted.
• Electrolyte Loss: High flow washes out Sodium (70-150 mmol/L), Potassium (20-70 mmol/L), and Magnesium.
• Volume: Losses reach 100-200 ml/kg.

Step 3: Dehydration & Renal Failure (The Vicious Cycle)

• As volume falls, renal perfusion drops (Pre-renal).
• GFR declines.
• The kidney can no longer excrete the glucose load.
• Without the "safety valve" of glucosuria, blood glucose spirals upwards (often > 50-100 mmol/L).
• This creates extreme hypertonicity.

Step 4: Intracellular Dehydration (The Brain)

• ECF Osmolality rises (> 320 mOsm/kg).
• Water moves from ICF (Cells) to ECF (Blood) to equilibrate.
• Cerebral Neurons: Shrink.
• Adaptation: Over days, brain cells generate "Idiogenic Osmoles" (Taurine, Myoinositol) to pull water back in and restore volume.
  • Clinical Correlate: This adaptation protects the brain but makes rapid rehydration dangerous (cell swelling).

Step 5: Hypercoagulability

• Severe dehydration causes Haemoconcentration (High Hct).
• High glucose damages endothelium (Glycocalyx dysfunction).
• Virchow's Triad: Stasis + Hypercoagulability + Endothelial Injury.
• Result: High risk of DVT, PE, MI, and Stroke.

Classification: HHS vs DKA (Detailed)

The differentiation between HHS and DKA is fundamental to appropriate management. These conditions represent different points on a spectrum of hyperglycemic emergencies, with overlapping presentations in approximately 30% of cases ("mixed DKA/HHS"). [12]

Biochemical Comparison:

Pathophysiological Distinction:

The fundamental difference lies in residual beta-cell function: [11]

1. DKA Pathophysiology:

   • Complete insulin deficiency (Type 1 DM, or severely depleted Type 2)
   • Unopposed lipolysis via hormone-sensitive lipase
   • Free fatty acids → ketogenesis in liver
   • Ketones (acetoacetate, beta-hydroxybutyrate) accumulate → metabolic acidosis
   • Glucose elevation moderate (counter-regulatory hormones + impaired utilization)

2. HHS Pathophysiology:

   • Partial insulin deficiency (sufficient to suppress lipolysis, insufficient for glucose homeostasis)
   • Hepatic gluconeogenesis proceeds unchecked
   • Extreme hyperglycemia develops over days/weeks
   • Massive osmotic diuresis → profound dehydration
   • Dehydration → renal failure → glucose accumulation accelerates
   • Hyperosmolality develops (> 320 mOsm/kg)

Why the 30 mmol/L Glucose Threshold Matters:

The diagnostic threshold of glucose > 30 mmol/L for HHS is not arbitrary: [1,13]

• At glucose > 30 mmol/L, osmotic diuresis is maximal
• Renal threshold (10 mmol/L) is exceeded by 3-fold
• Osmotic gradient drives massive water loss
• This level of hyperglycemia rarely occurs in DKA before ketoacidosis prompts earlier presentation

Mixed Presentations: Clinical Challenge

Approximately 30-33% of patients present with features of both conditions. [12,25] This occurs when:

• Type 2 diabetic develops ketoacidosis (starvation ketosis + hyperglycemia)
• Type 1 diabetic takes some basal insulin (partial suppression of ketogenesis) but develops severe hyperglycemia
• Prolonged DKA leads to severe dehydration and hyperosmolality
• Recent SGLT2 inhibitor use in Type 2 diabetes (euglycemic DKA with hyperosmolality) [25]

Diagnostic Criteria for Mixed DKA/HHS: [25,26]

• Blood glucose > 30 mmol/L (hyperosmolar threshold)
• Serum osmolality > 320 mOsm/kg (HHS criterion)
• Blood ketones 1.0-3.0 mmol/L (mild-moderate ketosis)
• pH 7.0-7.3 (mild-moderate acidosis)
• Anion gap > 16 mmol/L (metabolic acidosis present)

Management Approach for Mixed Presentations:

1. Calculate osmolality - if > 320, treat as HHS (fluid priority) [1]
2. Check pH - if less than 7.1, consider higher insulin dose (0.1 units/kg/hr) [26]
3. Monitor both glucose AND ketones hourly
4. Fluid resuscitation remains primary intervention (prevents circulatory collapse)
5. Earlier insulin may be needed than pure HHS (typically hour 1-2 vs hour 2-3) [12,26]
6. Higher risk group: mortality 15-25% (intermediate between DKA and pure HHS) [25]

Clinical Decision Rule:

Use the following algorithm to differentiate:

Patient with hyperglycemia:
├─ Glucose less than 30 mmol/L → Likely DKA if ketotic
├─ Glucose > 30 mmol/L:
   ├─ Ketones > 3.0 mmol/L → Mixed DKA/HHS
   ├─ Ketones less than 3.0 mmol/L:
       ├─ Osmolality > 320 → HHS
       └─ Osmolality less than 320 → Uncomplicated hyperglycemia

---

4. Clinical Presentation

History

• Polyuria/Polydipsia: Gradual onset over weeks.
• Systemic: Profound weakness, lethargy, cramps, weight loss.
• Neurological: Confusion, hallucinations, focal weakness (mimics stroke), seizures, coma.
• Precipitant Symptoms: Cough (Pneumonia), Dysuria (UTI), Chest Pain (MI).
• Social: Ask about carers, water access, missed medications.

Detailed Presenting Complaints

1. Neurological Manifestations ("The Metabolic Encephalopathy")

HHS is primarily a neurological disease precipitated by metabolic failure.

• Confusion and Delirium: Occurs in 50% of patients.
  • Mechanism: Intracellular cerebral dehydration leads to neuronal shrinkage.
  • Correlate: The degree of obtundation correlates linearly with serum osmolality. Coma is rare below 320 mOsm/kg, but common above 350 mOsm/kg.
• Focal Neurology (Stroke Mimics):
  • Hemiparesis (reversible), Hemianopia, or Aphasia can occur without ischaemic stroke. This is "Epilepsia Partialis Continua" or metabolic channel dysfunction.
  • Action: All focal signs require urgent CT/MRI to exclude Stroke, but do not be surprised if they resolve with rehydration.
• Seizures: Focal motor seizures are more common in HHS than generalized tonic-clonic seizures. They are often resistant to standard anti-epileptics (phenytoin) but respond to rehydration.
• Hallucinations: Visual hallucinations (Charles Bonnet syndrome exacerbation or delirium).

2. Gastrointestinal Symptoms

• Painless Presentation: Unlike DKA, abdominal pain is rare because there is no ketosis/acidosis stimulating the peritoneum/gastric lining.
• Nausea: Mild nausea may occur from gastric stasis (gastroparesis), but profound vomiting is less common than DKA.
• Significance: If an HHS patient has severe abdominal pain, search for a cause (Mesenteric Ischaemia, Pancreatitis, Retention), do not attribute it to the HHS.

3. Constitutional & Musculoskeletal

• Profound Fatigability: Patients may be bedbound for days.
• Muscle Cramps: Severe leg cramps due to electrolyte depletion (Na/K/Mg/Ca loss).
• Falls: "Found on floor" is the classic presentation. Check for:
  • Long lie complications (Pressure sores).
  • Rhabdomyolysis.
  • Hypothermia.

4. Visual Disturbances

• Myopic Shift: High glucose causes the lens to swell (osmotic changes), changing its refractive index. Patients may complain of "blurred vision" or "sudden inability to read".
• Resolution: Resolves weeks after glucose stabilization.

Examination Findings Breakdown

General Appearance

• Dehydration Signs:
  • Reduced Skin Turgor (Forehead/Sternum better than hands in elderly).
  • Dry Axillae (If armpits are dry, dehydration is significant).
  • Sunken Eyes (Enophthalmos).
  • Hypotension (Late sign).

Red Flags (Immediate Threat)

• Coma: Suggests Osmolality > 350. Airway risk.
• Shock: Hypotension/Tachycardia suggests fluid deficit > 15% body weight.
• Focal Neurology: Stroke? Or "metabolic stroke mimic" (Todd's paresis from HHS)? (Both need CT).
• Silent Hypoglycaemia: If treating, rapid drop can occur.
• Abdominal Pain: In HHS (unlike DKA), pain suggests pathology (Ischaemic bowel, Pancreatitis) rather than just metabolic effect.

---

5. Clinical Examination

General Inspection

• Mental Status: Drowsy, confused, or comatose. "Metabolic Encephalopathy".
• Breath: No Ketotic breath (Pear drops) - helps differentiate from DKA.
• Respiration: No Kussmaul breathing (usually, unless lactic acidosis co-exists).

Assessment of Dehydration

HHS patients are predominantly hyper-tonic dehydrated. Signs may be masked by hypernatraemia (maintains intravascular volume better than hyponatraemia).

Systemic Look

• Cardiovascular: Tachycardia (often > 120), Postural hypotension. Arrhythmias (AF common).
• Respiratory: Crepitations (Pneumonia/Aspiration).
• Abdominal: Tenderness? (Check Bowel Ischaemia - high risk in hypovolaemic elderly).
• Neurological:
  • Psychomotor: Agitated delirium or stupor.
  • Focal: Hemiparesis/Hemisensory loss (can occur solely due to hyperglycaemia - resolves with treatment).
  • Reflexes: Hyperreflexia or extensor planters (metabolic).

---

6. Investigations

Immediate Bedside / Laboratory Panel

Investigations in HHS are directed at three goals: confirming the diagnosis, assessing severity (degree of dehydration/osmolarity), and identifying the precipitant (The "Why?").

1. Metabolic Profile

• Serum Glucose: Universally elevated, typically > 30 mmol/L, often exceeding 50-60 mmol/L (beyond meter range).
• Serum Osmolality: The definitive test. Measured osmolality is preferred, but calculated is standard for monitoring.
  • Diagnostic threshold: > 320 mOsm/kg.
  • Significance: Every 10 mOsm/kg rise correlates with a drop in GCS.
• Urea & Electrolytes:
  • Sodium: Can be low (dilutional/pseudohyponatraemia) or high (severe dehydration).
    • Interpretation: A "Normal" sodium (e.g., 140) in the presence of Glucose 50 is actually ABNORMAL (indicates water loss). Corrected Sodium would be ~160.
  • Potassium: Often normal on admission due to insulin deficiency/acidosis shifting K+ out of cells.
    • Warning: Total body potassium is always depleted (300-1000 mmol deficit). It will plummet once insulin starts.
  • Urea/Creatinine: Pre-renal AKI is almost universal. Urea rises disproportionately to Creatinine (Urea:Cr ratio > 100) due to dehydration and catabolism.
• Venous Blood Gas (VBG):
  • pH: Usually > 7.3 (Normal or mildly acidotic from Lactate/Uraemia).
  • Bicarbonate: Usually > 15 mmol/L.
  • Lactate: Often elevated (Type A from hypoperfusion, Type B from Metformin).

2. Ketone Status

• Blood Ketones: less than 3.0 mmol/L.
• Urine Ketones: Negative or +/++.
• Why low ketones? The hyperosmolality itself may suppress lipolysis, and residual insulin prevents run-away ketogenesis.

3. Full Blood Count (FBC)

• Leucocytosis (WBC): Often 15-25 x 10^9/L.
  • Note: This can be a "Stress Leucocytosis" from the metabolic crisis itself, NOT just infection.
  • Action: Do not assume infection solely on WBC. Look for CRP rise or focal signs (CXR/Urine).
• Haemoglobin/Haematocrit: Elevated due to haemoconcentration (plasma volume loss).

4. Cardiac Enzymes (Troponin)

• HHS is a massive stress test for the heart.
• Troponin: Frequently elevated.
• Differentiating Type 1 vs Type 2 MI: Difficult. If ECG changes -> Treat as STEMI/NSTEMI. If global ST depression -> Rate/Demand related.

Differential Diagnosis

Note: HHS can mimic Stroke (Hemiparesis), and Stroke can precipitate HHS.

Diagnostic Calculations (CRITICAL)

Accurate calculation and monitoring of osmolality and corrected sodium are essential to safe HHS management. These calculations guide fluid therapy and prevent life-threatening complications. [1,3]

1. Serum Osmolality Calculation

Standard Formula (JBDS):

Serum Osmolality (mOsm/kg) = 2(Na+ + K+) + Glucose + Urea

Where all values are in mmol/L.

Simplified Formula (Common in Practice):

Serum Osmolality (mOsm/kg) = 2(Na+) + Glucose + Urea

Potassium contribution is minimal and often omitted in practice guidelines. [1]

Normal Range: 275-295 mOsm/kg

HHS Diagnostic Threshold: > 320 mOsm/kg [1]

Severity Stratification:

• Mild: 320-330 mOsm/kg
• Moderate: 330-350 mOsm/kg
• Severe: > 350 mOsm/kg (associated with coma)

Effective Osmolality (Tonicity):

For assessing the risk of fluid shifts and cerebral edema, calculate effective osmolality:

Effective Osmolality = 2(Na+) + Glucose

Urea is omitted as it freely crosses cell membranes and does not contribute to osmotic gradients.

Clinical Example:

Patient presents with:

• Sodium: 150 mmol/L
• Potassium: 5.0 mmol/L
• Glucose: 55 mmol/L
• Urea: 25 mmol/L

Calculated Osmolality = 2(150 + 5) + 55 + 25
                      = 310 + 55 + 25
                      = 390 mOsm/kg

Interpretation: Severe hyperosmolality (> 350). High risk of coma. Urgent treatment required with careful monitoring of osmolality reduction rate.

Measured vs Calculated Osmolality:

• Measured osmolality (using osmometer) is gold standard but not always available
• Osmolal gap = Measured - Calculated
  • "Normal gap: less than 10 mOsm/kg"
  • Elevated gap suggests presence of unmeasured osmoles (ethanol, methanol, ethylene glycol)
  • In HHS, osmolal gap should be normal unless co-ingestion

2. Corrected Sodium Formula

Hyperglycemia causes a dilutional effect on serum sodium. For every 5.5 mmol/L rise in glucose above normal, water shifts from intracellular to extracellular space, diluting sodium by approximately 2.4 mmol/L. [3]

Katz Correction Formula (Original, 1973):

Corrected Na+ = Measured Na+ + 0.016 × (Glucose - 5.5)

This adds 1.6 mmol/L for each 5.5 mmol/L glucose elevation.

Hillier Correction Formula (Modified, 1999 - More Accurate):

Corrected Na+ = Measured Na+ + 0.024 × (Glucose - 5.5)

This adds 2.4 mmol/L for each 5.5 mmol/L glucose elevation. This formula is preferred and recommended by JBDS. [1,3]

Simplified Clinical Formula:

Corrected Na+ = Measured Na+ + 2.4 × [(Glucose - 5.5) / 5.5]

Clinical Example:

Patient with:

• Measured sodium: 135 mmol/L
• Glucose: 60 mmol/L

Corrected Na+ = 135 + 2.4 × [(60 - 5.5) / 5.5]
              = 135 + 2.4 × [54.5 / 5.5]
              = 135 + 2.4 × 9.9
              = 135 + 23.8
              = 158.8 mmol/L

Interpretation: Despite "normal" measured sodium of 135, patient is actually severely hypernatremic (corrected Na+ 159). This represents profound water deficit.

Clinical Significance of Corrected Sodium:

1. Initial Assessment:

   • Measured Na+ normal or low with high glucose → Expect hypernatremia once glucose corrected
   • Measured Na+ high with high glucose → Extreme hypernatremia and severe dehydration

2. Monitoring During Treatment:

   • As glucose falls with treatment, measured sodium SHOULD RISE
   • Target rise: approximately 2.4 mmol/L for every 5.5 mmol/L glucose fall
   • If measured sodium FALLS during treatment → Too much free water being given → Risk of cerebral edema
   • If measured sodium RISES TOO FAST (> 10-12 mmol/L in 24h) → Risk of osmotic demyelination syndrome

3. Fluid Selection:

   • If corrected sodium rising excessively → Consider switch to 0.45% NaCl
   • If corrected sodium falling → Continue 0.9% NaCl

Monitoring Table:

Target: Osmolality falling 3-8 mOsm/kg/hour. Corrected sodium stable or slowly rising. [1,4]

3. Fluid Deficit Calculation

Estimate total body water (TBW) deficit:

TBW Deficit (L) = Current TBW × [(Measured Na+ / 140) - 1]

Where:
Current TBW = Weight (kg) × 0.6 (men) or 0.5 (women)

Example: 70kg male, Na+ 160 mmol/L

Current TBW = 70 × 0.6 = 42L
TBW Deficit = 42 × [(160/140) - 1]
            = 42 × [1.14 - 1]
            = 42 × 0.14
            = 5.9L

Clinical Use:

• Provides estimate of minimum fluid replacement needed
• HHS patients typically need 100-220 mL/kg (7-15L in 70kg adult) [1,14]
• Replace approximately half the deficit in first 12-24 hours to avoid rapid osmolality drop

4. Anion Gap Calculation

Anion Gap = (Na+ + K+) - (Cl- + HCO3-)

Normal Range: 8-16 mmol/L

In HHS:

• Usually normal anion gap (no ketoacidosis)
• Elevated anion gap suggests:
  • Mixed DKA/HHS (ketones present)
  • Lactic acidosis (sepsis, hypoperfusion)
  • Uremic acidosis (severe AKI)

Mixed presentation if: Anion gap > 16 AND osmolality > 320 [12]

Etiology Workup ("Why now?")

• Septic Screen: Blood cultures, Urine culture, CXR.
• ECG: Silent MI? AF?
• HbA1c: Undiagnosed diabetes or poor control?
• CT Head: If focal neurology or persistent coma after rehydration.
• Abdominal Imaging: If elevated Lactate/Amylase (Mesenteric Ischaemia/Pancreatitis).

---

7. Management

Principles of Care (JBDS-IP)

The management of HHS differs significantly from DKA. A rapid correction of glucose is dangerous. Goals:

1. Gradual normalisation of Osmolality (3-8 mOsm/kg/hr).
2. Restoration of circulatory volume (Fluid Resuscitation).
3. Electrolyte correction (Potassium/Sodium).
4. Identification of precipitant (Sepsis/MI).
5. Prevention of complications (VTE/Oedema).

Acute Management Algorithm

         [HHS DIAGNOSIS]
    Glu > 30 | Osm > 320 | No Ketosis
                ↓
┌──────────────────────────────────────┐
│  STEP A: IMMEDIATE RESUSCITATION     │
│  - ABCDE Assessment                  │
│  - IV Access x2 (18G)                │
│  - FLUIDS: 0.9% Saline (1L STAT)     │
│    (If SBP less than 90)                      │
│  - LMWH: Prophylactic dose           │
└──────────────────────────────────────┘
                ↓
┌──────────────────────────────────────┐
│  STEP B: FLUID REPLACEMENT PHASE     │
│  - Aim: Positive balance 3-6L by 12h │
│  - Type: 0.9% NaCl usually           │
│  - Rate: See Protocol below          │
└──────────────────────────────────────┘
                ↓
┌──────────────────────────────────────┐
│  STEP C: INSULIN DECISION (Hour 1-2) │
│  - Is Glucose falling > 5mmol/hr?     │
│    YES → NO INSULIN. Continue fluid. │
│    NO  → START INSULIN 0.05 u/kg/hr  │
└──────────────────────────────────────┘
                ↓
┌──────────────────────────────────────┐
│  STEP D: POTASSIUM CONTROL           │
│  - K less than 3.5: CENTRAL REPLACEMENT (HOLD INSULIN) │
│  - K 3.5-5.5: Add 40mmol/L           │
│  - K > 5.5: Nil added                 │
└──────────────────────────────────────┘

Clinical Monitoring & Nursing Standards (The "HHS Pathway")

Nursing care is as critical as the prescription.

1. Observations Frequency

• 0-6 Hours: Every 30 minutes (GCS, HR, BP, RR, Saturation).
• 6-12 Hours: Hourly.
• Fluid Balance: Strict hourly input/outcome (Catheterize always).

2. Neurological Monitoring

• GCS: Drop in GCS is the first sign of Cerebral Oedema.
• Pupils: Check for asymmetry (Coning).
• Confusion: Safety rails, 1:1 nursing if agitated delirium.

3. Skin Integrity

• HHS patients are elderly and immobile.
• Waterlow Score: High risk.
• Action: Pressure relieving mattress (Category 3/4) immediately. Reposition every 2 hours.

4. Mouth Care

• Severe dehydration causes "crisp" tongue and mucosal cracking.
• High risk of parotitis.
• Regular wet swabs/mouth wash.

1. Fluid Resuscitation Protocol

Fluid replacement is the cornerstone of HHS management. Fluids alone can reduce glucose by 4-5 mmol/L per hour through hemodilution and restoration of renal perfusion, allowing glucose excretion. [14] The goals are to restore circulating volume, reduce osmolality gradually, and prevent complications.

Physiological Rationale:

1. Volume restoration: Corrects shock, improves organ perfusion
2. Hemodilution: Directly lowers glucose concentration
3. Renal perfusion: Restores glomerular filtration, enabling glucosuria
4. Osmolality reduction: Gradual correction prevents cerebral edema
5. Electrolyte replacement: Restores massive sodium and potassium losses

Fluid Choice: The Evidence Base

First-Line: 0.9% Sodium Chloride (Normal Saline) [1,2]

• Composition: 154 mmol/L Na+, 154 mmol/L Cl-, osmolarity 308 mOsm/L
• Advantages:
  • Isotonic volume expansion
  • Readily available
  • Extensive safety data
  • Prevents rapid fall in osmolality
• Disadvantages:
  • Hyperchloremic metabolic acidosis with large volumes (> 4-5L)
  • Slightly hypertonic compared to plasma (308 vs 285-295)
• JBDS Recommendation: Default fluid for HHS [1]

Second-Line: 0.45% Sodium Chloride (Half-Normal Saline)

• Composition: 77 mmol/L Na+, 77 mmol/L Cl-, osmolarity 154 mOsm/L
• Indication: Switch from 0.9% NaCl if:
  • Corrected sodium rising > 10 mmol/L in first 24 hours
  • Measured sodium > 155 mmol/L despite falling glucose
  • Osmolality not declining adequately with 0.9% NaCl
• Risk: Provides free water → Can cause rapid osmolality drop → Cerebral edema [4]
• Use with caution: Senior clinician decision only

Alternative: Balanced Crystalloids (Hartmann's/Ringer's Lactate)

• Composition: Na+ 131, K+ 5, Cl- 111, Lactate 29 (Hartmann's)
• Advantages:
  • Lower chloride load → Less hyperchloremic acidosis [28]
  • Closer to physiological electrolyte composition
  • SMART trial (2018) showed reduced mortality in general critically ill patients [2]
  • Theoretical benefit in preventing renal tubular injury from chloride load
• Disadvantages:
  • Lactate interferes with lactate monitoring (important in septic patients)
  • Potassium content (5 mmol/L) complicates potassium replacement calculations
  • Limited HHS-specific evidence - systematic review found insufficient data to recommend over normal saline [28]
• Current Status: Not routinely recommended by JBDS; may be considered in consultation with senior clinician or intensivist [1,28]

Fluid Replacement Regimen:

Standard Protocol (JBDS 2022): [1]

Aim for positive fluid balance of 3-6 litres by 12 hours.

Typical Regimen (70kg adult, no cardiac comorbidity):

Rate Adjustment Based on Patient Factors:

Slower Rates Required in:

1. Heart Failure (HF) or Reduced Ejection Fraction:

   • Risk: Pulmonary edema
   • Strategy: Maximum 500 mL boluses or continuous infusion at 100-250 mL/hr
   • Monitor: Hourly respiratory rate, oxygen saturations, chest examination
   • Consider: Central venous pressure (CVP) monitoring or arterial line
   • Diuretics: May need concurrent furosemide if signs of fluid overload develop

2. Chronic Kidney Disease (CKD) Stage 4-5:

   • Risk: Volume overload, worsening of existing fluid balance issues
   • Strategy: Reduce total volume target, slower rates (e.g., 500 mL over 2-4h)
   • Consider: May need dialysis for osmolality correction if anuric

3. Elderly (> 75 years):

   • Risk: Reduced cardiac reserve, increased cerebral edema risk
   • Strategy: More conservative rates, frequent assessment
   • Typical: 500 mL/hour maximum initial rate

4. Severe Hypernatremia (Corrected Na+ > 160):

   • Risk: Osmotic demyelination if corrected too fast
   • Strategy: Slower sodium correction (maximum 8-10 mmol/L per 24h)
   • May require: Early switch to 0.45% NaCl

Faster Rates Permitted in:

1. Shock (SBP less than 90 mmHg):

   • Give 1L 0.9% NaCl STAT (over 15 minutes) via pressure bag
   • Repeat if still hypotensive
   • Escalate to ICU/HDU
   • Consider: Vasopressor support if not responding to 2L fluid

2. Young Adults (less than 40 years) with No Comorbidities:

   • Can tolerate standard or slightly faster rates
   • Monitor closely for resolution

Monitoring Parameters During Fluid Resuscitation:

Hourly Monitoring (First 6-12 hours):

Fluid Balance Charting:

Strict input/output documentation:

• Input: All IV fluids, oral intake (if any)
• Output: Urine (catheter essential), NG aspirate, drains
• Target: Positive balance 3-6L by 12h, 6-10L by 24h

When to Switch Fluid Type:

Switch to 0.45% NaCl if: [1,3]

• Corrected sodium rising > 10-12 mmol/L in 24 hours
• Measured sodium > 155 mmol/L
• Osmolality not falling despite adequate fluid resuscitation

Switch to 5% Dextrose if:

• Blood glucose falling to less than 14 mmol/L
• Continue insulin infusion (to suppress any ketogenesis or maintain glucose entry into cells)
• Add glucose to prevent hypoglycemia
• Rate: 125 mL/hr of 10% dextrose or 250 mL/hr of 5% dextrose

Special Situations:

End-Stage Renal Failure (Dialysis-Dependent):

• These patients CANNOT handle large fluid volumes
• Paradox: They are hyperosmolar but may be euvolemic or hypervolemic (unable to excrete water)
• Strategy:
  • RESTRICT fluids (no large volume resuscitation)
  • "Primary treatment: INSULIN (to drive glucose into cells and lower osmolality)"
  • "Definitive: Urgent hemodialysis to remove glucose and correct osmolality [1]"

Shock Not Responding to 2L Fluid:

• Reassess diagnosis: Cardiogenic shock? Septic shock? PE?
• Investigations: ECG (MI?), Echo (LV function?), Lactate (sepsis?)
• Escalate: ICU referral for invasive monitoring ± vasopressors
• Consider: Occult bleeding (GI bleed precipitated by stress)?

Practical Prescribing Example:

Patient: 75kg male, HHS with Na+ 148, glucose 58, osmolality 384

Prescription (First 12 hours):

1. Sodium Chloride 0.9% 1000 mL IV over 1 hour (STAT)

2. Sodium Chloride 0.9% 1000 mL IV + Potassium Chloride 40 mmol
   Run over 2 hours (after checking K+ less than 5.5)

3. Sodium Chloride 0.9% 1000 mL IV + Potassium Chloride 40 mmol
   Run over 2 hours

4. Sodium Chloride 0.9% 1000 mL IV + Potassium Chloride 40 mmol
   Run over 4 hours

5. Sodium Chloride 0.9% 1000 mL IV + Potassium Chloride 40 mmol
   Run over 6 hours

TOTAL FIRST 12
h: 5 litres (positive balance ~3-4L after urine losses)

Evidence Summary:

• No RCT directly comparing 0.9% vs 0.45% NaCl in HHS
• Retrospective data suggests no difference in outcomes but faster osmolality correction with 0.45% (may be harmful) [20]
• SMART trial (2018) showed balanced crystalloids vs saline had no mortality difference in non-critically ill adults, but this was not HHS-specific [2]
• Current practice: 0.9% NaCl remains standard based on safety profile and JBDS guidance [1]

2. Insulin Therapy Protocol

Insulin management in HHS fundamentally differs from DKA. The critical principle: DELAY insulin initiation and use LOWER doses. [1,5,6,14]

Why Delay Insulin in HHS?

Physiological Rationale: [6,14]

1. Circulatory Collapse Risk:

   • Insulin drives glucose from extracellular fluid (ECF) into cells
   • Water follows glucose osmotically (intracellular shift)
   • This depletes already critically low intravascular volume
   • Result: Precipitous drop in blood pressure → shock → cardiac arrest
   • Historic mortality: Early aggressive insulin protocols had 30-40% mortality vs current 10-20% with delayed approach

2. Fluid Resuscitation is Effective Alone:

   • Rehydration restores renal perfusion → glomerular filtration increases
   • Glucose excretion via kidneys resumes
   • Glucose can fall 4-5 mmol/L per hour with fluids alone [14]
   • Hemodilution directly lowers glucose concentration

3. Slower Osmolality Correction:

   • Gradual glucose reduction with fluids alone safer than rapid insulin-driven drop
   • Minimizes risk of cerebral edema
   • Allows brain cells time to expel idiogenic osmoles

4. Electrolyte Safety:

   • Delayed insulin allows time to assess and replace potassium
   • Reduces risk of life-threatening hypokalemia
   • Potassium shifts occur more gradually

Fixed Rate Intravenous Insulin Infusion (FRIII)

Preparation:

• Solution: 50 units human soluble insulin (e.g., Actrapid, Humulin S) in 50 mL 0.9% sodium chloride
• Concentration: 1 unit/mL
• Delivery: Via syringe driver or infusion pump
• Line: Dedicated IV access (do NOT run with other medications)

Dosing:

Initial Dose: 0.05 units/kg/hour [1,7,13]

This is HALF the dose used in DKA (0.1 units/kg/hour).

Example: 80kg patient → 0.05 × 80 = 4 units/hour

When to Start Insulin: The "Delayed Initiation" Protocol [1,20]

DO NOT start insulin at hour 0.

Decision Algorithm:

Hour 0: Start fluids (0.9% NaCl 1L/hr)
Hour 1: Check glucose
  ├─ Glucose fallen > 5 mmol/L? → Continue fluids ONLY, no insulin
  └─ Glucose not falling or less than 5 mmol/L drop?
      ├─ Check: Has patient received 1-2L fluid minimum?
      │   └─ NO → Continue fluids, reassess
      └─ YES → START insulin 0.05 units/kg/hr

Typical Practice:

• Most patients: Insulin started at hour 1-3
• Some patients: Never need insulin (glucose adequately controlled by fluids)
• Mixed DKA/HHS: Earlier insulin (hour 0-1) may be needed if significant ketoacidosis

Titration Protocol:

Hourly Glucose Monitoring with Adjustment:

When Glucose Reaches 14 mmol/L: [1]

DO NOT STOP INSULIN.

Instead:

1. Add glucose substrate: Start 10% dextrose 125 mL/hr (or 5% dextrose 250 mL/hr)
2. Reduce insulin: Halve insulin rate (e.g., 4 units/hr → 2 units/hr)
3. Continue both: Maintain glucose 10-15 mmol/L with insulin + dextrose
4. Rationale:
   • Prevents hypoglycemia
   • Maintains insulin action to suppress any residual ketogenesis
   • Allows continued correction of metabolic derangement

Transition to Subcutaneous Insulin:

Criteria for Transition (ALL must be met):

1. Patient is eating and drinking
2. Osmolality less than 300 mOsm/kg
3. No ketones (if present initially)
4. Hemodynamically stable
5. Electrolytes normalized

Timing: Usually 24-48 hours after admission

Method:

Option 1: Basal-Bolus Regimen (Preferred for Inpatients)

Calculate total daily insulin requirement based on IV insulin use:

Example: Patient received 3 units/hr for 24 hours = 72 units total

Subcutaneous regimen:
- Basal insulin: 50% of total (36 units) as once-daily long-acting
  → Glargine (Lantus) 36 units at bedtime
  
- Bolus insulin: 50% of total (36 units) divided by 3 meals
  → Rapid-acting insulin 12 units with each meal
  
Overlap: Give first SC dose, then continue IV insulin for 2 more hours

Option 2: Variable Rate SC Insulin (Sliding Scale)

Less preferred (reactive rather than proactive) but used if patient eating inconsistently:

Before each meal and bedtime:
- Glucose less than 4 → No insulin + treat hypo
- Glucose 4-10 → 4 units rapid-acting
- Glucose 10-15 → 6 units
- Glucose 15-20 → 8 units
- Glucose > 20 → 10 units + call doctor

Long-Term Insulin Requirements Post-HHS:

Many HHS patients are NOT on insulin prior to admission. Post-discharge planning:

Type 2 Diabetics (Most HHS Patients):

1. Acute Phase (0-6 weeks):

   • Discharge on insulin (basal ± bolus) due to "glucotoxicity"
   • High glucose has temporarily stunned beta cells
   • Typical: Glargine 20-40 units daily

2. Recovery Phase (6-12 weeks):

   • Beta cell function may recover
   • Trial reduction of insulin
   • Re-introduce oral agents (metformin, SGLT2i with caution)

3. Maintenance:

   • If HbA1c less than 8% off insulin → Oral agents sufficient
   • If HbA1c > 9% → Continue insulin long-term
   • Individualize based on beta cell reserve (C-peptide testing)

Special Insulin Scenarios:

1. Patient on Usual Insulin (e.g., Basal insulin at home):

Continue long-acting (basal) insulin at usual dose even when starting IV insulin [1]

Rationale:

• Prevents rebound hyperglycemia when IV insulin stopped
• Maintains basal glucose control
• Safe to continue if eating

2. Patient Not Responding to Insulin:

Insulin Resistance Causes:

• Infection/sepsis (cytokines impair insulin signaling)
• Steroids
• Severe obesity
• Acanthosis nigricans

Action:

• Increase dose to 0.15-0.2 units/kg/hr
• Treat underlying infection aggressively
• Consider insulin sensitizers once stable (metformin)

3. Hypoglycemia Develops:

Definition: Glucose less than 4 mmol/L

Management:

1. STOP insulin infusion immediately
2. Give 100 mL 10% dextrose IV over 10 minutes
3. Recheck glucose in 15 minutes
4. If glucose > 4 → Restart insulin at half previous rate
5. If glucose still less than 4 → Repeat dextrose

Prevention: Anticipate by starting dextrose infusion when glucose less than 14

Pharmacology: Understanding Intravenous Insulin Kinetics

Human Soluble Insulin (Actrapid, Humulin S):

Why Fixed Rate vs Variable Rate?

Fixed Rate (Current Standard):

• Predictable insulin delivery
• Easier to calculate and monitor
• Reduces human error
• JBDS recommended [1]

Variable Rate (Sliding Scale - Outdated):

• Insulin dose varies by glucose
• Reactive (treats high glucose after it happens)
• More complex, error-prone
• No longer recommended for HHS

Monitoring During Insulin Therapy:

Essential Checks:

Evidence Base for Delayed, Low-Dose Insulin:

Key Studies:

1. Arieff & Carroll (1972) - Seminal paper describing high mortality with early aggressive insulin [6]

   • 37 patients with HHS treated with high-dose insulin
   • Mortality 40-50%
   • Deaths clustered in first 24h (shock, cerebral edema)

2. Stoner (2005) - Low-dose insulin protocol validation [13]

   • Review of modern protocols using 0.05-0.1 units/kg/hr
   • Mortality reduced to 10-15%
   • Hypoglycemia rate less than 5% (vs 20-30% with high-dose)

3. Scott (2015) - Timing of insulin initiation [20]

   • Retrospective analysis: Insulin less than 1hr vs 1-3hr vs > 3hr
   • Earlier initiation associated with:
     • Higher cerebral edema rates
     • More severe hypokalemia
     • No mortality benefit
   • Optimal timing: 1-3 hours after fluids commenced

4. Fayfman et al (2017) - Fluid-first strategy [14]

   • Glucose reduction with fluids alone: 4-5 mmol/L per hour
   • Comparable to insulin in first 2-3 hours
   • Supports delayed insulin approach

Current Guideline Summary:

3. Potassium Replacement Protocol

Potassium shifts are dangerous. Insulin drives K+ into cells. Check K+ every hour initially.

4. VTE Prophylaxis

Mandatory. HHS patients are severely hypercoagulable (Hyperviscosity).

• LMWH (Enoxaparin/Dalteparin): Prophylactic dose (e.g., Enoxaparin 40mg SC OD).
• Treatment Dose?: Only if confirmed DVT/PE.
• Anti-Embolism Stockings: If LMWH contraindicated.

5. Treatment Targets (Hourly Monitoring)

---

Pharmacology of Key Agents

1. Soluble Insulin (Fast Acting)

• Examples: Actrapid, Humulin S.
• Mechanism: Binds to Insulin Receptor (Tyr-Kinase), recruiting IRS-1/2, activating PI3K/Akt pathway, translocating GLUT-4 to cell surface.
• PK:
  • half-life (IV): 5-9 minutes (Why we need continuous infusion).
  • Onset: Immediate.
  • Clearance: Renal (Decrease dose in severe AKI? In HHS, AKI is pre-renal and recovers, usually safely titratable).

2. 0.9% Sodium Chloride

• Composition: 154 mmol/L Na, 154 mmol/L Cl. (Osmolarity 308).
• Physiology: Technically slightly hypertonic to plasma (285-295), but isotonic in the bag.
• Adverse Effects: Hyperchloraemic Metabolic Acidosis (Normal Anion Gap).
• In HHS: The acidosis risk is outweighed by the need for stable volume expansion.

3. Low Molecular Weight Heparin (Enoxaparin)

• Mechanism: Potentiates Antithrombin III, inhibiting Factor Xa.
• Dosing:
  • Prophylactic: 40mg SC OD (eGFR > 30).
  • Renal Dose: 20mg SC OD (eGFR less than 30).
  • Therapeutic: 1.5mg/kg OD or 1mg/kg BD.
• Monitoring: Anti-Xa levels (in obesity/renal failure).

---

8. Complications

Complications in HHS are frequently fatal and often iatrogenic (caused by treatment).

1. Cerebral Oedema

Rare in adults (less than 1%) but high mortality (50-70%). [15,27]

• Mechanism (Theories):
  1. Osmotic Shift: Rapid drop in plasma osmolality causes water to rush into hypertonic brain cells.
  2. Idiogenic Osmoles: Brain cells accumulate organic osmoles (taurine, glutamate, myoinositol) over days to protect against shrinkage during hyperosmolar state. These take 24-48 hours to clear. If fluids given too rapidly, these osmoles create an osmotic gradient pulling water into brain cells. [27]
  3. Aquaporin-4 Dysregulation: Recent evidence suggests altered water channel expression in astrocytes contributes to cerebral water accumulation. [27]
• Risk Factors: [15,23,27]
  • Young age (children > adults, but risk exists at any age)
  • Rapid rehydration (> 50ml/kg in first 4 hours)
  • Rapid fall in osmolality (> 10 mOsm/kg/hour)
  • Early high-dose insulin (> 0.1 units/kg/hour in first 6 hours)
  • Bicarbonate use
  • Failure to allow glucose to fall with fluids alone
• Signs: Headache, Bradycardia, Hypertension (Cushing's triad), Declining GCS, Seizures, Papilloedema, Cranial nerve palsies.
• Prevention Strategies: [1,15,27]
  • Limit osmolality reduction to 3-8 mOsm/kg/hour (check 4-hourly)
  • Avoid insulin for first 1-2 hours (fluid resuscitation first)
  • Use lower insulin dose (0.05 units/kg/hour maximum initially)
  • Avoid bicarbonate unless pH less than 6.9
  • Monitor neurological status hourly with GCS documentation
• Management:
  • Stop Fluids immediately.
  • Hypertonic Therapy: Mannitol (0.5-1g/kg IV over 20 minutes) or Hypertonic Saline (3% NaCl 2-5ml/kg over 10-20 minutes).
  • Imaging: Urgent CT Head (to confirm/exclude hemorrhage, herniation).
  • ICU: Intubation and mechanical ventilation to maintain pCO2 at 35-40 mmHg (hyperventilation can worsen ischemia).
  • Neurosurgery consult: For potential external ventricular drain if hydrocephalus develops.
• Evidence: Adult case series demonstrate cerebral edema occurs almost exclusively when sodium corrected > 12-15 mmol/L in 24 hours, suggesting overlap with osmotic demyelination pathophysiology. [24,27]

2. Osmotic Demyelination Syndrome (ODS)

Formerly "Central Pontine Myelinolysis".

• Mechanism: Rapid correction of hyponatraemia (or rapid rise in Na during HHS treatment).
• Target: Limit Sodium rise to less than 10 mmol/L in 24 hours.
• Presentation: Delayed (2-6 days). Quadriparesis, Dysarthria, Dysphagia, "Locked-in Syndrome".
• Prognosis: Often permanent severe disability.

3. Venous Thromboembolism (VTE)

HHS is a highly thrombogenic state.

• Pathology: Dehydration (Stasis) + Hyperglycaemia (Endothelial damage) + Infection (Hypercoagulable).
• Incidence: DVT/PE occurs in up to 5-10% even with prophylaxis.
• Management:
  • Prevention: Enoxaparin 40mg SC daily (adjust for renal).
  • Treatment: If DVT confirmed -> Treatment dose LMWH.

4. Rhabdomyolysis

• Cause: "Found down" (immobilisation), Statins + Fibrates, Severe hypophosphataemia.
• Signs: Muscle pain, Dark urine ("Coca-Cola"), AKI.
• Inv: CK > 1000 (often > 10,000).
• Rx: Fluid resuscitation (already doing it). Maintain urine output > 1ml/kg/hr.

5. Electrolyte Crises

• Hypokalaemia: Arrhythmias (VT/VF). Cause: Insulin shifting K+ into cells.
• Hypophosphataemia: Respiratory depression, muscle weakness. Replace if less than 0.32 mmol/L.
• Hypomagnesaemia: Arrhythmias, Seizures.

6. Hypoglycaemia

• Cause: Insulin continued when glucose less than 14 mmol/L.
• Risk: Neuroglycopenia in already confused patient.
• Prevention: Start 10% Dextrose when Gluc less than 14. Reduce insulin rate.

---

9. Prognosis & Outcomes

Mortality statistics

• HHS: 10-20% (Much higher than DKA).
• Predictors of Death:
  • Age > 75.
  • Sepsis (Pneumonia).
  • Hypotension at presentation.
  • Osmolality > 375 mOsm/kg.
  • Sodium > 160 mmol/L.

Resolution Criteria (When is HHS "Over"?)

HHS is resolved when:

1. Osmolality less than 300 mOsm/kg.
2. Hypovolaemia corrected (Renal function recovered).
3. Cognitive status returns to baseline.
4. Patient is eating and drinking.

Discharge Planning & Prevention

1. Medication Review (The "Safety Check")

Many medications should be held or stopped.

• SGLT2 Inhibitors (Dapagliflozin/Empagliflozin): STOP. High risk of recurrence/Euglycaemic DKA.
• Diuretics: Review indication. Reduce dose if possible?
• Metformin/ACEi: Restart only when renal function (eGFR) is stable.

2. Converting to Subcutaneous Insulin

Most HHS patients are insulin-naive T2DM.

• Initial Regimen: Basal-Bolus (e.g., Lantus + NovoRapid) is preferred in hospital.
• Long Term:
  • If HbA1c > 10%: Discharge on Insulin (Basal) + Metformin.
  • If HbA1c less than 9%: May trial Gliclazide + Metformin.
  • Note: Glucotoxicity ("stunned pancreas") implies that insulin is often needed for 4-12 weeks until beta cells recover.

3. Patient Education ("Sick Day Rules")

Every patient must receive a "Sick Day Card". Instructions if feeling unwell (Vomiting/Fever):

• STOP: SGLT2 Inhibitors, ACE Inhibitors, Diuretics, NSAIDs.
• CONTINUE: Insulin (never stop, even if not eating).
• TEST: Check Glucose every 4 hours.
• HYDRATE: Drink 100ml fluid every hour.

Special Populations & Geriatric Considerations

HHS is predominantly a disease of the elderly (> 70 years).

1. Management in Heart Failure

The "Fluid Paradox": The patient needs fluid to survive HHS, but fluid causes Pulmonary Oedema.

• Strategy:
  • Slower Rate: Maximum 250ml-500ml boluses, or slower infusion (e.g., 500ml over 4 hours).
  • Invasive Monitoring: Arterial Line. CVP (if available).
  • Diuretics?: Furosemide may be needed concurrently if "wet".
  • Endpoint: Aim for "Euvolamia" rather than "Positive Balance". Accept slightly higher Osmolality for longer duration.

2. Management in Dialysis Patients (ESRF)

• Challenge: Anuric patients cannot have Osmotic Diuresis. They present with Hyperglycaemia + Hyperosmolality but usually Hypervolaemia (Fluid overload from thirst).
• Action:
  • Fluids: RESTRICT or STOP.
  • Insulin: The primary treatment (Driving glucose into cells lowers Osmolality, but where does the fluid go? It shifts intracellularly).
  • Dialysis: Urgent Haemodialysis is the gold standard for correcting Osmolality and Removal of Glucose generally.

3. Dementia & Delirium

• Compliance: Patient pulls out IV lines.
• Capacity: Use Mental Capacity Act (Best Interests).
• Restraint: Chemical restraint (Haloperidol) may be needed but lowers Seizure threshold. 1:1 Nursing preferred.
• Aspiration: Keep NBM initially if GCS low. NG Tube if necessary.

4. The "Social Admission"

• Many HHS patients were living independently but failing.
• Assessment of function: Was this a gradual decline?
• Safeguarding: Self-neglect?

---

10. Evidence & Guidelines

Joint British Diabetes Societies (JBDS) Guidelines (2022)

The JBDS "Management of the Hyperosmolar Hyperglycaemic State (HHS) in Adults with Diabetes" is the primary reference for UK practice. [1] Key recommendations include:

1. Diagnostic Criteria

• Hypovolaemia.
• Marked Hyperglycaemia (> 30 mmol/L without alternative explanation).
• Hyperosmolality (> 320 mOsm/kg).
• Absence of significant ketonaemia (less than 3.0 mmol/L) or acidosis (pH > 7.3, bicarbonate > 15 mmol/L).

2. Fluid Therapy Strategy

• Type: 0.9% Sodium Chloride is the default initial fluid. [1,2]
• Rate: Aim for positive fluid balance of 3-6L by 12 hours. Typical regimen: 1L over first hour, then 1L over 2h, 1L over 2h, 1L over 4h, 1L over 4h, 1L over 6h.
• Sodium Monitoring: Calculate corrected sodium and monitor trajectory. Sodium should rise as glucose falls. If corrected sodium falls, switch to hypotonic fluid may be needed. [3]
• Osmolality Target: Gradual reduction of 3-8 mOsm/kg/hour to minimize cerebral edema risk. [4]

3. Insulin Strategy

• Delay: Do NOT start insulin until fluid resuscitation is established (usually 60-120 minutes). [1,5]
• Rationale: Premature insulin administration causes rapid intracellular glucose shift with water movement, potentially precipitating circulatory collapse and worsening hypotension. [6]
• Dose: Fixed rate intravenous insulin infusion (FRIII) at 0.05 units/kg/hour (half the DKA dose). [1,7]
• Initiation Criteria: Start insulin only if blood glucose is NOT falling by > 5 mmol/L/hour with fluid resuscitation alone. [1]

4. Electrolyte Replacement

• Potassium: Despite normal or elevated serum potassium on admission, total body potassium deficit is typically 300-1000 mmol. Replace according to protocol: add 40 mmol/L to fluids if K+ 3.5-5.5 mmol/L. [8]
• Magnesium/Phosphate: Check and replace if symptomatic (muscle weakness, arrhythmias).

American Diabetes Association (ADA) Standards (2024)

The ADA consensus statement on hyperglycemic crises emphasizes: [9]

• HHS mortality rate of 10-20% compared to DKA mortality less than 1%.
• Older age (median 70 years), comorbidities, and precipitating illness contribute to higher mortality.
• Thromboprophylaxis with LMWH is essential due to extreme hypercoagulability.

Endocrine Society Clinical Practice Guidelines

The Endocrine Society guidelines on diabetes emergencies recommend: [10]

• Aggressive investigation for precipitating cause (infection most common at 40-60%).
• Avoid bicarbonate therapy even in mixed presentations unless pH less than 6.9.
• Continuous cardiac monitoring in elderly patients due to silent MI risk.

Key Evidence Base

Landmark Studies:

1. Kitabchi et al. (2009) - Hyperglycemic Crises in Adult Patients with Diabetes

• Comprehensive review published in Diabetes Care establishing diagnostic criteria. [11]
• Key Finding: HHS characterized by severe hyperglycemia (> 33.3 mmol/L), hyperosmolality (> 320 mOsm/kg), and absence of ketoacidosis, distinguishing it from DKA.
• Clinical Impact: Formed basis for separate management protocols recognizing different pathophysiology.

2. Pasquel & Umpierrez (2014) - Hyperosmolar Hyperglycemic State: Historic Review

• Systematic review in Diabetes Care analyzing clinical presentation and outcomes. [12]
• Key Finding: 30-33% of patients present with mixed DKA/HHS features, associated with higher mortality.
• Recommendation: Treat hyperosmolarity first but monitor for acidosis requiring insulin escalation.

3. Stoner (2005) - Hyperosmolar Hyperglycemic State

• American Family Physician review on HHS management. [13]
• Key Finding: Low-dose insulin protocol (0.05-0.1 units/kg/hour) as effective as high-dose with reduced hypoglycemia and hypokalemia risk.
• Practice Change: Adoption of lower insulin doses specifically for HHS.

4. Fayfman et al. (2017) - Management of Hyperglycemic Crises

• Contemporary review in Medical Clinics of North America. [14]
• Key Finding: Fluid resuscitation alone can reduce blood glucose by 4-5 mmol/L/hour through hemodilution and restoration of renal glucose excretion.
• Implication: Supports delayed insulin initiation strategy.

5. Karslioglu French et al. (2019) - Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Syndrome

• BMJ clinical review. [15]
• Key Finding: Cerebral edema risk in adults with HHS is less than 1% but carries 50% mortality when occurs.
• Prevention: Limit osmolality reduction to less than 8 mOsm/kg/hour; limit sodium correction to less than 10 mmol/L per 24 hours.

6. MacIsaac et al. (2002) - Influence of Age on Diabetic Emergencies

• Australian study examining age-related outcomes. [16]
• Key Finding: Patients > 75 years have 3-fold higher mortality from HHS (approaching 30%) compared to younger patients.
• Risk Factors: Baseline renal impairment, heart failure, and delayed presentation.

7. Wachtel et al. (1987) - Predisposing Factors for HHS

• Classic study identifying precipitants. [17]
• Key Finding: Infection (particularly pneumonia and UTI) accounts for 40-60% of HHS cases.
• Others: MI/stroke (20%), medication non-compliance (10%), new diabetes (10%).

8. Nugent (2005) - HHS in Emergency Medicine

• Emergency Medicine Clinics review. [18]
• Key Finding: Focal neurological signs (hemiparesis, seizures) occur in up to 25% of HHS patients without structural brain lesion.
• Mechanism: Metabolic encephalopathy and cellular dehydration causing reversible neuronal dysfunction.

Evidence on Specific Management Aspects:

Fluid Replacement:

• JBDS Consensus (2022): 0.9% NaCl remains first-line despite concerns about hyperchloremic acidosis. [1]
• Balanced Solutions: Limited evidence for balanced crystalloids (Hartmann's/Ringer's lactate) in HHS. Potential interference with ketone and lactate monitoring. [19]

Insulin Timing:

• Retrospective Analysis (Scott, 2015): Insulin started within first hour associated with higher rates of cerebral edema and hypokalemia compared to delayed initiation (2-3 hours). [20]

Thromboprophylaxis:

• VTE Risk: Observational studies show DVT/PE incidence of 5-10% in HHS despite prophylaxis, compared to 1-2% in general medical admissions. [21]
• Mechanism: Severe dehydration causing hyperviscosity, hyperglycemia causing endothelial dysfunction, acute illness causing hypercoagulability (Virchow's triad complete). [22]

Cerebral Edema Prevention:

• Pediatric Experience (Applicable to Adults): Rapid osmolality reduction (> 10 mOsm/kg/hour) and excessive insulin (> 0.1 units/kg/hour) identified as risk factors. [23]
• Adult Case Series: Cerebral edema in adults almost exclusively occurs when sodium corrected > 12 mmol/L in 24 hours (osmotic demyelination syndrome overlap). [24]

Evolution of Practice

Historical Context:

• 1886: First description as "diabetic coma without acidosis"
• 1957: Term "hyperosmolar nonketotic coma" introduced
• 2001: Recognition that many patients remain conscious; renamed "hyperglycemic hyperosmolar state"
• 2022: Current JBDS guidelines emphasize gradual correction and thromboprophylaxis

Current Controversies:

1. Hypotonic vs Isotonic Fluids:

   • Some advocate early switch to 0.45% NaCl to provide free water
   • JBDS recommends 0.9% NaCl throughout unless sodium rising > 10 mmol/24h
   • No RCT evidence to guide choice

2. When to Start Insulin:

   • JBDS: After 1-2 hours of fluids
   • ADA: When glucose stops falling with fluids
   • Some centers: Never start if glucose falling adequately with fluids alone

3. Target Glucose Level:

   • Not to normalize glucose acutely (target 10-15 mmol/L in first 24h)
   • Prevention of hypoglycemia more important than tight control
   • Switch to subcutaneous insulin when eating/drinking and osmolality less than 300

---

11. Patient/Layperson Explanation

What is HHS?

"HHS stands for Hyperosmolar Hyperglycaemic State. It is a very serious complication of diabetes, usually Type 2. It happens when blood sugar levels become dangerously high over a period of days or weeks."

How did this happen?

"Normally, insulin helps sugar enter your body's cells. In HHS, although there is a tiny bit of insulin working (enough to stop acid building up, which is why it's not 'Ketoacidosis'), there isn't enough to control the sugar. Because the sugar is so high (often 10x normal), it spills into the urine and pulls huge amounts of water with it. This acts like a strong diuretic, causing you to pee out litres of fluid. You have become severely dehydrated—much more than just 'needing a drink'. Your blood has become thick and salty (concentrated)."

Why is it dangerous?

"Because the blood is thick, it can clot easily, causing heart attacks or strokes. The severe dehydration can also shut down the kidneys. Fluid loss from the brain can cause confusion or coma."

How do we treat it?

"The main treatment is Fluid. We will replace the lost water through a drip very gradually over the next 24-48 hours. We also carefully use insulin to bring the sugar down, but we do this slowly to prevent brain swelling. It takes time to fix safely."

---

12. References

1. Joint British Diabetes Societies for Inpatient Care (JBDS-IP). The management of the hyperosmolar hyperglycaemic state (HHS) in adults with diabetes. JBDS-IP Guideline. September 2022. Available at: https://abcd.care/resource/management-hyperosmolar-hyperglycaemic-state-hhs-adults-diabetes

2. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819-828. doi:10.1056/NEJMoa1711586

3. Liamis G, Liberopoulos E, Barkas F, Elisaf M. Diabetes mellitus and electrolyte disorders. World J Clin Cases. 2014;2(10):488-496. doi:10.12998/wjcc.v2.i10.488

4. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care. 1990;13(1):22-33. doi:10.2337/diacare.13.1.22

5. Karslioglu French E, Donihi AC, Korytkowski MT. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ. 2019;365:l1114. doi:10.1136/bmj.l1114

6. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (Baltimore). 1972;51(2):73-94. doi:10.1097/00005792-197203000-00001

7. Zeitler P, Haqq A, Rosenbloom A, Glaser N. Hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. J Pediatr. 2011;158(1):9-14. doi:10.1016/j.jpeds.2010.09.048

8. Liamis G, Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ. Electrolyte disorders in community subjects: prevalence and risk factors. Am J Med. 2013;126(3):256-263. doi:10.1016/j.amjmed.2012.06.037

9. American Diabetes Association. 16. Diabetes care in the hospital: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S295-S306. doi:10.2337/dc24-S016

10. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343. doi:10.2337/dc09-9032

11. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care. 2001;24(1):131-153. doi:10.2337/diacare.24.1.131

12. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care. 2014;37(11):3124-3131. doi:10.2337/dc14-0984

13. Stoner GD. Hyperosmolar hyperglycemic state. Am Fam Physician. 2005;71(9):1723-1730. PMID: 15887451

14. Fayfman M, Pasquel FJ, Umpierrez GE. Management of hyperglycemic crises: diabetic ketoacidosis and hyperosmolar hyperglycemic state. Med Clin North Am. 2017;101(3):587-606. doi:10.1016/j.mcna.2016.12.011

15. Karslioglu French E, Donihi AC, Korytkowski MT. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ. 2019;365:l1114. doi:10.1136/bmj.l1114

16. MacIsaac RJ, Lee LY, McNeil KJ, Tsalamandris C, Jerums G. Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies. Intern Med J. 2002;32(8):379-385. doi:10.1046/j.1445-5994.2002.00255.x

17. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, Ellis SE, O'Sullivan PS. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med. 1991;6(6):495-502. doi:10.1007/BF02598216

18. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am. 2005;23(3):629-648. doi:10.1016/j.emc.2005.03.006

19. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839. doi:10.1056/NEJMoa1711584

20. Scott AR. Management of hyperosmolar hyperglycaemic state in adults with diabetes. Diabet Med. 2015;32(6):714-724. doi:10.1111/dme.12757

21. Keenan CR, Murin S, White RH. High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses. J Thromb Haemost. 2007;5(6):1185-1190. doi:10.1111/j.1538-7836.2007.02553.x

22. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001;15(1):44-54. doi:10.1016/s1056-8727(00)00132-x

23. Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344(4):264-269. doi:10.1056/NEJM200101253440404

24. Cheng JC, Flanigan MJ, Ballard JO, Orlowski JP, Havens PL. Osmotic demyelination syndrome complicating therapy for diabetic ketoacidosis. Pediatr Emerg Care. 2012;28(3):274-276. doi:10.1097/PEC.0b013e3182494ec8

25. Dhatariya KK, Vellanki P. Treatment of diabetic ketoacidosis (DKA)/hyperglycemic hyperosmolar state (HHS): novel advances in the management of hyperglycemic crises (UK versus USA). Curr Diab Rep. 2017;17(5):33. doi:10.1007/s11892-017-0857-4

26. Cao S, Cao S. Hyperglycemic hypernatremic hypertonic state: a predominant HHS subtype and its clinical and diagnostic features. J Clin Endocrinol Metab. 2025;110(8):e3204-e3211. doi:10.1210/clinem/dgae420

27. Glaser NS, Wootton-Gorges SL, Marcin JP, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr. 2004;145(2):164-171. doi:10.1016/j.jpeds.2004.03.045

28. Gershkovich B, English SW, Doyle MA, et al. Choice of crystalloid fluid in the treatment of hyperglycemic emergencies: a systematic review protocol. Syst Rev. 2019;8(1):215. doi:10.1186/s13643-019-1141-3

---

13. Examination Focus

Common Exam Questions

1. "Distinguish HHS from DKA." Key Differentiators:

• Timecourse: HHS weeks, DKA hours.
• Biochemistry: HHS Glucose > 30, Osm > 320, No Ketosis. DKA Ketosis dominant.
• Population: HHS Elderly T2DM. DKA Young T1DM (usually).
• Insulin: HHS 0.05 u/kg/hr delayed. DKA 0.1 u/kg/hr immediate(ish).

2. "Why specific Sodium correction?" Answer: Measured sodium is artificially lowered by hyperglycaemia (dilutional). Corrected Na gives true tonicity. Formula: Na + 2.4 * ((Gluc-5.5)/5.5). Significance: If Corrected Na Rises during treatment -> Good. If it Falls -> Danger (Excess free water/Cerebral oedema risk).

3. "When do you start insulin in HHS?" Answer: Only after fluid resuscitation has begun AND if glucose is not falling by fluid dilution alone. Usually hour 2-3. Why?: Starting insulin first moves glucose/water into cells, collapsing intravascular volume -> Shock/Death.

4. "Calculate the Osmolality." Formula: 2(Na) + Urea + Glucose. Scenario: Na 150, K 5.0, Gluc 50, Urea 30. Calc: 2(150) + 50 + 30 = 300 + 50 + 30 = 380 mOsm/kg. Normal: 275-295. Interpretation: Severe Hypertonicity (> 320 is diagnostic). Coma likely.

5. "What fluid should be used if Sodium rises rapidly (> 15 mmol in 24h)?" Answer: Switch to hypotonic fluid (e.g., 0.45% Saline or Dextrose 5% with insulin). Risk: Central Pontine Myelinolysis (ODS).

6. "Why is LMWH mandatory?" Answer: HHS causes extreme hyperviscosity ("treacle blood") due to dehydration. High risk of DVT, PE, and Arterial thrombosis.

Viva Points

Scenario 1: The Junior Doctor Request "The Nurse wants to start the Sliding Scale (VRIII) because the glucose is 45. What do you say?" Response: "Do NOT start it. Start Fluids (1L Normal Saline) first. Explain that in HHS, the priority is volume. Insulin too early causes circulatory collapse. We monitor hourly. If glucose doesn't drop by 5 mmol/L with fluids alone, THEN we start fixed rate insulin at 0.05u/kg."

Scenario 2: The Complication "Patient becomes drowsy 6 hours into treatment. Sats dropping." Differential: Cerebral Oedema (if fluids too fast), Heart Failure (fluid overload), Aspiration Pneumonia. Action: Stop fluids. ABCDE. CT Head. U&Es (check Sodium/Osmolality trajectory).

Scenario 3: The Discharge "Can they go home on Metformin?" Response: "Depends. Initially they need insulin (Basal-Bolus) to clear glucose toxicity. Once stable outpatient, if C-Peptide shows T2DM, can titrate to Metformin/Gliclazide/SGLT2i. Warning: SGLT2i risk of euglycaemic DKA if dehydrated again."

OSCE Station: The "Confused Diabetic"

Scenario: 78M, T2DM. Found confused by neighbours. Task: Assess and initiate management. Steps:

1. ABCDE: Airway (GCS?). Breathing (No Kussmaul). Circ (Shock?).
2. Finger Prick: Glucose "Hi" (> 27.8). Ketones 0.2.
3. Diagnosis: Likely HHS.
4. Action: 1L N.Saline STAT. Catheterise. ECG.
5. Prescription:
   • Fluids: 1L 0.9% NaCl over 1h, then 1L/2h.
   • Insulin: HOLD. Fluid first.
   • LMWH: Enoxaparin 40mg SC (if renal function ok).
   • Investigations: Lab Glucose, Venous pH, U&Es (for Urea/Na), Osmolality (Calculated).

Common Mistakes

• Insulin First: The most dangerous error. Risk of cardiac arrest.
• Wrong Dose: Using DKA dose (0.1 u/kg) instead of HHS prose (0.05 u/kg).
• Stopping Fluids: Stopping because "Chest is wet" without consulting senior (patient is 10L dehydrated).
• Ignoring Sodium: Failing to calculate corrected sodium.
• Discharge: Sending home without VTE prophylaxis (risk remains high for weeks).

MCQ Practice

Q1: A 70M presents with Glucose 45, pH 7.38, Ketones 0.4. BP 90/60. First line? A. Insulin Scale B. Insulin Fixed Rate 0.1 u/kg/hr C. 1L 0.9% Saline STAT D. 500ml 10% Dextrose E. Bicarbonate Answer: C. HHS with Shock. Fluids are priority. Insulin is contraindicated initially.

Q2: Which electrolyte change is most dangerous during HHS treatment? A. Hypernatraemia B. Hypokalaemia C. Hypophosphataemia D. Hypercalcaemia E. Hyponatraemia Answer: B. Hypokalaemia. Insulin drives K+ into cells. Arrhythmia risk is high. Monitor K+ q1-2h.

Q3: Calculated Osmolality formula? A. 2(Na+K) + Glucose + Urea B. 2(Na) + Glucose + Urea C. 2(Na) + Glucose D. Na + Glucose + Urea E. 2(Na+K) + Urea Answer: B. 2(Na) + Glucose + Urea. (JBDS 2022).

Q4: Rate of Osmolality reduction target? A. 1 mOsm/kg/hr B. 3-8 mOsm/kg/hr C. 10-15 mOsm/kg/hr D. > 20 mOsm/kg/hr E. As fast as possible Answer: B. 3-8. Too slow = unresolved crisis. Too fast = Cerebral Oedema/Pontine Myelinolysis.

Q5: A patient usually takes Mixed Insulin. They present with HHS. What do you do with their long-acting insulin? A. Stop it completely B. Continue usual dose C. Double the dose D. Give half dose E. Switch to IV only Answer: B. Continue usual long-acting (Basal) insulin if possible, to prevent rebound hyperglycaemia when IV insulin stops. This is "Basal continuation".

Q6: Corrected Sodium calculation reveals a rise from 145 to 160 mmol/L in 12 hours. Best action? A. Continue 0.9% Saline B. Switch to 0.45% Saline C. Give Furosemide D. Give Mannitol E. Start Desmopressin Answer: B. A rapid rise (> 10mmol/24h) or failure to fall suggests 0.9% Saline is relatively too hypertonic or insufficient free water. Switch to hypotonic fluid (0.45% NaCl) under supervision to slow the rise and provide free water.

Q7: Which drugs are known precipitants of HHS? A. ACE Inhibitors B. Thiazide Diuretics C. PPIs D. Statins E. Aspirin Answer: B. Thiazides (and Steroids) impair glucose tolerance and can precipitate HHS.

Advanced MCQ Bank (Case Scenarios)

Case 1: The "Mixed" Presentation A 24-year-old female with T1DM presents with vomiting. Glucose 45 mmol/L. pH 7.15. Ketones 4.5. Osmolality 335 mOsm/kg. Q: How do you classify and manage? A. Pure DKA - Standard protocol B. Pure HHS - Fluid only C. Mixed DKA/HHS - Treat as HHS initially (Fluid focus) but start fixed rate insulin earlier (0.05 u/kg) D. Mixed DKA/HHS - Treat as DKA (0.1 u/kg) immediately Answer: C/D. This is "Hyperosmolar DKA". The priority is Fluid (for the Osmolality) BUT the Acidosis is severe. Guidelines suggest using the DKA monitoring chart but perhaps a cautious fluid approach. However, in young T1DM, DKA outcome is dominant. Most would treat as severe DKA with fluid caution. (Discussion point).

Case 2: The Complication 72M treated for HHS. Day 3: develops slurred speech and quadriparesis. MRI shows pontine hyperintensity. Q: What caused this? A. Cerebral Oedema B. Osmotic Demyelination Syndrome (ODS) C. Stroke D. Meningitis Answer: B. ODS. Likely due to rapid correction of sodium.

Case 3: Prevention Which medication should be STOPPED during "Sad/Sick Days" to prevent HHS/DKA? A. Insulin B. Metformin C. Dapagliflozin (SGLT2i) D. Ramipril E. Atorvastatin Answer: C. SGLT2 inhibitors (and B/D: Metformin/Ramipril for AKI risk). SGLT2i specifically cause "Euglycaemic DKA" but in T2DM can contribute to dehydration. Insulin should NEVER be stopped.

Glossary of Terms

• Anion Gap: The difference between primary measured cations (Na+ and K+) and the primary measured anions (Cl- and HCO3-). Normal = 8-12(16) mEq/L. In HHS, this is typically normal, distinguishing it from DKA. A high anion gap in HHS suggests lactic acidosis or uraemia.
• Basal Insulin: Long-acting insulin (e.g., Glargine, Detemir, Degludec) that controls glucose production by the liver (gluconeogenesis) during fasting states.
• Bolus Insulin: Short-acting insulin (e.g., Aspart, Lispro) used to cover mealtime glucose excursions.
• Cerebral Oedema: A life-threatening complication where fluid shifts into brain cells, causing swelling. Risk factors include rapid rehydration and rapid drops in osmolality.
• Corrected Sodium: A calculated value that estimates the true serum sodium concentration if the hyperglycaemia were corrected. It accounts for the dilutional effect of glucose drawing water into the intravascular space.
• Azotaemia: Elevated blood urea and nitrogen, a sign of renal insufficiency common in HHS.
• Glycosuria: Excretion of glucose in urine.
• Osmotic Diuresis: Loss of water driven by the osmotic pressure of non-reabsorbed glucose in the renal tubules.
• Hyperviscosity: Increased thickness of blood due to dehydration, predisposing to thrombosis.
• Lactic Acidosis: Type A (hypoperfusion) or Type B (Metformin) acidosis.
• Ketonaemia: Presence of ketones in blood (Beta-hydroxybutyrate).
• Euglycaemic DKA: DKA with normal blood sugar, often caused by SGLT2 inhibitors.
• Insulin Resistance: Reduced cellular response to insulin.
• Gluconeogenesis: Synthesis of glucose from non-carbohydrate precursors (lactate, glycerol, amino acids).
• Glycogenolysis: Breakdown of glycogen to glucose.
• Counter-regulatory Hormones: Glucagon, Cortisol, GH, Catecholamines.
• Waterlow Score: A scale for assessing pressure ulcer risk.
• Virchow's Triad: Stasis, Hypercoagulability, Endothelial Injury.
• CVP (Central Venous Pressure): Pressure in the thoracic vena cava, used to estimate preload (volume status).
• Arterial Line: Intra-arterial catheter for continuous BP monitoring.
• Sliding Scale (VRIII): Variable Rate Intravenous Insulin Infusion.
• Basal-Bolus: A regimen of long-acting (Basal) and mealtime (Bolus) insulin mimicking physiological secretion.
• Hypokalaemia: Low serum potassium (less than 3.5 mmol/L).
• Hypernatraemia: High serum sodium (> 145 mmol/L).
• Pontine Myelinolysis: See ODS.
• Microvascular Complications: Retinopathy, Neuropathy, Nephropathy.
• Macrovascular Complications: Stroke, MI, Peripheral Vascular Disease.
• HbA1c: Glycated Haemoglobin, a measure of 3-month average glucose.
• SGLT2 Inhibitor: Drug class ending in -gliflozin (increases glucose excretion in urine).
• GLP-1 Agonist: Drug class ending in -tide (increases insulin, decreases glucagon).

Advanced Clinical Reasoning: The "Why" of HHS

Why is the mortality higher than DKA?

1. Age: HHS patients are older with more comorbidities (Heart Failure, COPD).
2. Delay: The insidious onset means they present later, with more profound dehydration (10L vs 4L).
3. Thrombosis: The hyperviscosity is more severe in HHS, leading to fatal PE/Stroke.
4. Complexity: Managing fluid balance in a 90-year-old with Heart Failure is harder than in a 20-year-old with DKA.

The "Sodium Paradox" Explained

In HHS, Sodium is the most confusing electrolyte.

• Phase 1 (Presentation): Hyperglycaemia pulls water into vessels -> Dilutes Sodium (Low Measured Na).
• Phase 2 (Treatment): Glucose falls -> Water goes back to cells -> Sodium "Concentrates" (Measured Na Rises).
• Phase 3 (Danger): If you give too much free water (0.45%), Sodium drops rapidly -> Brain swelling. If you give too much Salt (0.9%), Sodium rises dangerously -> ODS.
• Goldilocks Zone: We want Sodium to rise slowly or stay stable as Glucose falls.

Further Advanced Cases

Case 4: The Anuric Patient 80M with ESRF on Haemodialysis. Admitted with HHS (Gluc 50, Osm 330). Q: Management priority? A. 1L Saline STAT B. Insulin 0.1 u/kg C. Urgent Haemodialysis D. 500ml Saline over 4h Answer: C. He cannot excrete the fluid or the glucose (no urine). Dialysis is the only way to fix the Osmolality safely.

Case 5: The Post-Op Challenge 65F post-Cabg (Day 2). Glucose 35. Confusion. Q: Precipitants? A. Infection (Sternal wound/Pneumonia) B. Stress response (Cortisol) C. TPN (Total Parenteral Nutrition) D. Steroids E. All of the above Answer: E. Post-op HHS is common due to "Stress Hyperglycaemia" + Steroids + TPN + Infection.

Case 6: The "Normal" Glucose? Patient has Osmolality 340. Glucose 15. Sodium 170. Q: Is this HHS? A. Yes B. No, it's Hypernatraemic Dehydration C. It's DKA Answer: B. (Strictly). HHS requires Glucose > 30. This is Hyperosmolar Hypernatraemia. Management is similar (Fluid!) but insulin is NOT needed (Glucose is nearly normal).