Fluid Compartments & Distribution

Quick Answer

Answer: Total body water (TBW) comprises approximately 60% of body weight in adult males (42L in a 70kg individual), distributed between the intracellular fluid (ICF) compartment (40% body weight, 2/3 TBW, ~28L) and the extracellular fluid (ECF) compartment (20% body weight, 1/3 TBW, ~14L). The ECF is further subdivided into plasma volume (PV) (~3L, 5% body weight) and interstitial fluid (ISF) (~11-12L, 15% body weight), with a small transcellular fluid component (~1L).

Key physiological principles:

• Starling forces govern fluid movement across capillaries (revised equation: Jv = Lp × S × [(Pc - Pi) - σ(πp - πsg)])
• The glycocalyx layer forms the true semi-permeable barrier, not the endothelium itself
• Osmolality (normally 285-295 mOsm/kg) determines water distribution between ICF and ECF
• Tonicity (effective osmolality) determines cell volume changes
• Crystalloid distribution: 0.9% saline expands plasma by ~25% of infused volume
• Context-sensitive volume kinetics: Fluid distribution varies with haemodynamic state

---

CICM Exam Focus

What Examiners Expect

First Part Written (SAQ):

• Precise definition of fluid compartments with accurate proportions and volumes
• Understanding of Starling forces and the revised Starling equation
• Glycocalyx structure, function, and clinical relevance
• Osmolality vs tonicity distinction with calculation examples
• Distribution of commonly used IV fluids with physiological rationale
• Dilution principle for measuring compartment volumes

First Part Viva:

• Systematic approach to describing fluid compartments
• Ability to draw and explain Starling forces at the capillary level
• Discussion of glycocalyx degradation in critical illness
• Clinical application of osmolar gap calculation
• Explanation of why crystalloids are "context-sensitive"
• Understanding of oedema formation mechanisms

Common SAQ Topics

1. "Describe the distribution of total body water" (appears every 2-3 years)
2. "Explain the factors determining fluid movement across capillary membranes"
3. "Describe the structure and function of the endothelial glycocalyx"
4. "Compare the distribution of crystalloid and colloid solutions"
5. "Define osmolality and tonicity, explaining their clinical significance"

Viva Stem Examples

• "Tell me about body fluid compartments..."
• "Draw a diagram showing Starling forces..."
• "What happens to a litre of normal saline when infused IV?"
• "How would you measure plasma volume?"
• "Explain why patients become oedematous in sepsis..."

---

Key Points

---

Total Body Water

Definition and Composition

Total body water (TBW) represents the sum of all water contained within the body, serving as the universal solvent for biochemical reactions and the medium for nutrient transport, waste removal, and thermoregulation. TBW varies considerably between individuals based on age, sex, and body composition (PMID: 15899331).

Standard Values (70 kg Adult Male):

• Total body water: 42 L (60% of body weight)
• Intracellular fluid: 28 L (40% body weight, 2/3 TBW)
• Extracellular fluid: 14 L (20% body weight, 1/3 TBW)

Factors Affecting Total Body Water

Age:

• Neonates: 75-80% body weight (higher ECF proportion)
• Infants (1 year): 65% body weight
• Adults: 60% (males), 50% (females)
• Elderly (>65 years): 45-55% body weight

The high TBW in neonates reflects the relatively larger ECF compartment, which gradually decreases during the first year of life. The age-related decline in TBW reflects increased adiposity and decreased muscle mass (PMID: 10796607).

Sex:

• Males: ~60% body weight
• Females: ~50% body weight (due to higher adipose tissue proportion)

The sex difference reflects body composition, as adipose tissue contains only 10% water compared to 75% in muscle tissue. This has implications for drug dosing in hydrophilic medications (PMID: 22356994).

Body Composition:

• Lean tissue (muscle): 75% water
• Adipose tissue: 10% water
• Bone: 20% water

Obesity significantly reduces TBW as a percentage of body weight due to increased adipose tissue. A morbidly obese individual may have TBW of only 40% body weight. Conversely, very muscular individuals may have TBW approaching 70% (PMID: 15899331).

Clinical States Affecting TBW:

• Dehydration: Reduced TBW, primarily from ECF
• Overhydration: Increased TBW, distributed across compartments
• Oedema: Increased interstitial fluid volume
• Pregnancy: Increased TBW by 6-8 L (expanded plasma volume)

Water Balance

Daily water turnover in a healthy adult is approximately 2.5 L:

Inputs (~2500 mL/day):

• Oral intake: 1500-2000 mL
• Food water content: 500-800 mL
• Metabolic water (oxidation): 200-300 mL

Outputs (~2500 mL/day):

• Urine: 1000-1500 mL (obligatory minimum ~500 mL)
• Insensible losses (skin, respiration): 800-1000 mL
• Faeces: 100-200 mL
• Sweat: Variable (0-2000+ mL with exercise/fever)

In critically ill patients, additional losses occur through surgical drains, nasogastric tubes, fistulae, and diarrhoea. Fever increases insensible losses by approximately 10% per degree Celsius above 37°C (PMID: 12171839).

---

Fluid Compartments

Intracellular Fluid (ICF)

The intracellular fluid compartment is the largest body fluid compartment, containing two-thirds of total body water. It is bounded by cell membranes that are selectively permeable to water and certain solutes.

Volume and Distribution:

• Total volume: 28 L (40% body weight in 70 kg male)
• Proportion of TBW: 66% (2/3)
• Present in all nucleated cells

Ionic Composition (approximate):

Maintenance of ICF Composition:

The marked difference in ionic composition between ICF and ECF is maintained by:

1. Na⁺/K⁺-ATPase pump: Extrudes 3 Na⁺ for every 2 K⁺ imported, maintaining the sodium and potassium gradients. This electrogenic pump consumes approximately 30% of basal cellular ATP (PMID: 11157865).

2. Cell membrane impermeability: The lipid bilayer is relatively impermeable to charged ions, requiring specific channels or transporters for movement.

3. Gibbs-Donnan equilibrium: Non-diffusible intracellular proteins create an unequal distribution of diffusible ions across the membrane.

4. Secondary active transport: Sodium gradient drives other ion transporters (Na⁺/H⁺ exchanger, Na⁺/Ca²⁺ exchanger, etc.).

Clinical Significance:

• Hypokalaemia reduces the K⁺ gradient, hyperpolarising cells and causing muscle weakness
• Hyperkalaemia depolarises cells, causing cardiac arrhythmias
• Cellular oedema occurs when osmolality decreases (hyponatraemia) or Na⁺/K⁺-ATPase fails (ischaemia)
• Drugs distributing into ICF have larger volumes of distribution

Extracellular Fluid (ECF)

The extracellular fluid compartment surrounds all cells and provides the medium for nutrient delivery, waste removal, and cell-to-cell communication. It comprises one-third of total body water.

Volume and Distribution:

• Total volume: 14 L (20% body weight in 70 kg male)
• Proportion of TBW: 33% (1/3)
• Subdivided into plasma, interstitial fluid, and transcellular fluid

ECF Subdivisions:

Ionic Composition of ECF:

• Sodium: 135-145 mEq/L (primary cation)
• Chloride: 98-106 mEq/L (primary anion)
• Bicarbonate: 22-26 mEq/L
• Potassium: 3.5-5.0 mEq/L
• Calcium: 2.2-2.6 mmol/L (total), 1.1-1.3 mmol/L (ionised)
• Magnesium: 0.7-1.0 mmol/L
• Phosphate: 0.8-1.5 mmol/L
• Protein: 70 g/L (plasma), <10 g/L (interstitial)

Plasma Volume

Plasma is the intravascular component of ECF, serving as the transport medium for blood cells, proteins, nutrients, gases, and waste products.

Volume and Characteristics:

• Volume: 3 L (approximately 5% body weight)
• Proportion of ECF: 25% (1/4)
• Proportion of blood volume: 55% (with 45% cellular component)

Composition:

• Water: 93% by volume
• Proteins: 7% by weight (70 g/L)
  • "Albumin: 35-50 g/L (60% of total protein)"
  • "Globulins: 20-35 g/L"
  • "Fibrinogen: 2-4 g/L"
• Electrolytes, nutrients, hormones, waste products

Plasma Proteins and Oncotic Pressure:

Albumin is the primary determinant of plasma oncotic (colloid osmotic) pressure, contributing approximately 70-80% of the total (~25 mmHg). Each gram of albumin contributes approximately 0.55 mmHg to oncotic pressure. The Gibbs-Donnan effect increases albumin's contribution by an additional 30% due to retention of cations (PMID: 10796607).

Clinical Significance:

• Hypoalbuminaemia reduces oncotic pressure, promoting oedema formation
• Plasma volume is the "sensed" compartment for volume regulation
• Haemorrhage primarily depletes plasma volume
• Colloid solutions preferentially expand plasma volume

Interstitial Fluid (ISF)

Interstitial fluid is the ECF component that directly bathes tissue cells, providing the immediate environment for cellular exchange.

Volume and Characteristics:

• Volume: 11-12 L (approximately 15% body weight)
• Proportion of ECF: 75% (3/4)
• Ultrafiltrate of plasma (similar electrolyte composition, lower protein)

Composition:

• Electrolytes: Similar to plasma (Gibbs-Donnan equilibrium)
• Protein concentration: 10-30 g/L (varies by tissue)
  • "Brain: <10 g/L"
  • "Liver/intestine: 40-60 g/L"
  • "Subcutaneous: 10-20 g/L"
• Interstitial matrix: Collagen, proteoglycans, hyaluronan

Two Phases of Interstitial Fluid:

1. Gel phase (99%): Water bound to glycosaminoglycans (hyaluronan, chondroitin sulfate) in the interstitial matrix. This prevents bulk fluid flow and maintains tissue structure.

2. Free fluid phase (1%): Unbound water that can flow freely. This phase expands significantly in oedema states (PMID: 7890273).

Interstitial Compliance:

The relationship between interstitial fluid volume and pressure is non-linear:

• At normal volumes: Low compliance, small volume changes cause large pressure changes
• In oedema states: High compliance, large volume changes cause small pressure changes

This explains the "safety factor" against oedema - initial fluid accumulation is resisted by increased interstitial pressure. Once compliance increases, oedema accumulates rapidly (PMID: 20418556).

Transcellular Fluid

Transcellular fluid comprises specialised fluid compartments separated from plasma by epithelial cells as well as capillary endothelium.

Volume and Components:

• Total volume: 1-2 L (1-2% body weight)
• Cerebrospinal fluid (CSF): 150 mL
• Synovial fluid: Variable (2-4 mL per joint)
• Pleural fluid: 10-20 mL
• Pericardial fluid: 20-50 mL
• Peritoneal fluid: 50-100 mL
• Aqueous humour: 15-30 mL
• Endolymph/perilymph: 1-2 mL
• Gastrointestinal secretions: Variable (up to 8-10 L/day produced and reabsorbed)

Characteristics:

• Actively secreted by epithelial cells
• Composition differs from plasma (e.g., CSF has lower protein, higher Mg²⁺)
• Can expand significantly in pathological states (ascites, pleural effusion)

Clinical Significance:

• "Third space" losses into transcellular compartments are inaccessible to circulation
• Paracentesis or thoracentesis removes transcellular fluid
• GI fluid losses (vomiting, diarrhoea) represent significant electrolyte and water loss

---

Starling Forces and Transcapillary Fluid Exchange

Classic Starling Hypothesis

Ernest Starling (1896) proposed that fluid movement across capillary membranes is determined by the balance between hydrostatic and oncotic pressures across the capillary wall. The classic Starling equation describes net fluid flux (Jv):

Classic Starling Equation: J_v = K_f[(P_c - P_i) - \sigma(\pi_p - \pi_i)]

Where:

• Jv = Net fluid flux (positive = filtration, negative = absorption)
• Kf = Filtration coefficient (hydraulic conductance × surface area)
• Pc = Capillary hydrostatic pressure
• Pi = Interstitial hydrostatic pressure
• σ = Reflection coefficient (0-1, selectivity to protein)
• πp = Plasma oncotic pressure
• πi = Interstitial oncotic pressure

Classic Starling Forces (Typical Values):

According to the classic model, net filtration occurs at the arteriolar end of capillaries, while absorption occurs at the venular end, creating a continuous cycle of fluid exchange. This model predicted that approximately 90% of filtered fluid is reabsorbed, with 10% returned via lymphatics (PMID: 20418556).

Revised Starling Principle

The classic Starling model has been substantially revised based on experimental evidence demonstrating that:

1. Sustained capillary absorption rarely occurs in most tissues
2. The endothelial glycocalyx, not the endothelium itself, is the primary oncotic barrier
3. The relevant oncotic gradient is between plasma and the subglycocalyx space, not interstitium

Revised Starling Equation (Levick & Michel, 2010): J_v = L_p \times S \times [(P_c - P_i) - \sigma(\pi_p - \pi_{sg})]

Where:

• Lp = Hydraulic conductivity
• S = Surface area
• πsg = Subglycocalyx oncotic pressure (NOT interstitial oncotic pressure)

Key Differences from Classic Model:

1. No sustained absorption: In most tissues, filtration occurs along the entire capillary length, not just the arteriolar end. Absorption only occurs transiently following acute reductions in capillary pressure.

2. Glycocalyx as primary barrier: The endothelial glycocalyx (0.5-3 μm thick) forms the true semi-permeable membrane that excludes proteins. The oncotic pressure difference that opposes filtration is between plasma and the protein-poor subglycocalyx space.

3. Subglycocalyx space: A thin fluid layer between the glycocalyx and endothelial cell surface with very low protein concentration (~10 mOsm/kg oncotic pressure), creating a large oncotic gradient.

4. Interstitial oncotic pressure is irrelevant: Changes in interstitial protein concentration do not directly affect filtration because the glycocalyx maintains a protein-poor subglycocalyx space regardless of interstitial protein levels.

5. Lymphatic return is primary: All filtered fluid returns to the circulation via lymphatics, not through venular reabsorption. Lymph flow = capillary filtration rate in steady state.

This revised understanding has profound implications for fluid resuscitation and understanding oedema formation in critical illness (PMID: 20418556).

Capillary Filtration Coefficient

The filtration coefficient (Kf) represents the product of hydraulic conductivity (Lp) and capillary surface area (S), determining the volume of fluid filtered per unit pressure gradient.

Typical Values:

• Kf varies 10-100 fold between tissues
• Muscle: 0.01 mL/min/mmHg/100g tissue
• Kidney glomerulus: 4-12 mL/min/mmHg (highest in body)
• Intestinal mucosa: High (facilitates absorption)
• Brain: Very low (blood-brain barrier)

Factors Affecting Kf:

• Capillary surface area (recruitment, density)
• Endothelial permeability (inflammation increases)
• Glycocalyx integrity (degradation increases permeability)
• Intercellular junction structure

Reflection Coefficient

The reflection coefficient (σ) describes the membrane's selectivity to a particular solute relative to water, ranging from 0 (freely permeable) to 1 (completely impermeable).

Values for Common Solutes:

• Albumin: σ = 0.9-1.0 (nearly completely reflected)
• Smaller proteins: σ = 0.7-0.9
• Small molecules (glucose, urea): σ ≈ 0.1
• Water: σ = 0 (by definition)

In critical illness, endothelial damage and glycocalyx degradation reduce the reflection coefficient for proteins, allowing protein leak into the interstitium and contributing to oedema formation (PMID: 17483596).

---

Endothelial Glycocalyx

Structure

The endothelial glycocalyx is a gel-like layer covering the luminal surface of all blood vessels, playing a critical role in vascular physiology and barrier function.

Components:

1. Proteoglycans: Core proteins with attached glycosaminoglycan (GAG) chains

   • Syndecans (1-4): Transmembrane proteoglycans anchored to endothelial cytoskeleton
   • Glypicans: GPI-anchored proteoglycans

2. Glycosaminoglycans (GAGs):

   • Heparan sulfate (50-90%): Longest chains, most abundant
   • Chondroitin sulfate: Medium-length chains
   • Hyaluronan: Very long, not attached to core protein

3. Glycoproteins:

   • Selectins (E-selectin, P-selectin): Adhesion molecules
   • Integrins: Cell-matrix adhesion
   • Immunoglobulin superfamily: ICAM-1, VCAM-1, PECAM-1

Dimensions:

• Thickness: 0.5-3 μm (up to 4.5 μm in some vessels)
• Volume: Estimated 700-1700 mL in adult humans
• Highly hydrated (95% water by volume)

The glycocalyx creates a protein-exclusion zone at the endothelial surface, with albumin concentration in the subglycocalyx space being only 10-20% of plasma concentration (PMID: 17483596).

Functions

1. Vascular Permeability Barrier:

• Primary semi-permeable barrier (not endothelium)
• Excludes plasma proteins from subglycocalyx space
• Creates oncotic gradient opposing filtration
• Reflection coefficient for albumin approaches 1.0

2. Mechanotransduction:

• Senses shear stress from blood flow
• Transmits signals to endothelial cells via syndecans
• Triggers nitric oxide (NO) release and vasodilation
• Regulates vascular tone in response to flow changes

3. Leucocyte and Platelet Interactions:

• Healthy glycocalyx prevents leucocyte adhesion
• Selectins are buried within glycocalyx layer
• Glycocalyx shedding exposes adhesion molecules
• Facilitates inflammatory cell recruitment when damaged

4. Coagulation Regulation:

• Antithrombin III binding to heparan sulfate
• Thrombomodulin presentation
• Tissue factor pathway inhibitor (TFPI) binding
• Creates anticoagulant endothelial surface

5. Lipid Metabolism:

• Lipoprotein lipase binding
• Mediates HDL-endothelial interactions
• Regulates LDL transcytosis

6. Fluid Balance:

• Limits capillary filtration
• Maintains low subglycocalyx protein concentration
• Contributes to "safety margin" against oedema

Glycocalyx Degradation

The glycocalyx is rapidly degraded in critical illness, with profound effects on vascular permeability and inflammation.

Causes of Glycocalyx Degradation:

1. Sepsis/Inflammation:

   • TNF-α, IL-1β, IL-6 activate sheddases
   • Reactive oxygen species damage GAGs
   • Heparanase release from activated neutrophils
   • Complement activation

2. Ischaemia-Reperfusion:

   • Free radical generation
   • Protease release from activated leucocytes
   • ATP depletion affecting synthesis

3. Hypervolaemia:

   • Atrial natriuretic peptide (ANP) release
   • ANP directly activates sheddases
   • Contributes to "volume harm"

4. Hyperglycaemia:

   • Advanced glycation end-products (AGEs)
   • Increased glycocalyx permeability
   • Impaired synthesis

5. Surgery/Trauma:

   • Tissue injury releases inflammatory mediators
   • Blood contact with artificial surfaces
   • Cardiopulmonary bypass particularly damaging

Biomarkers of Glycocalyx Shedding:

• Syndecan-1 (most commonly measured)
• Heparan sulfate
• Hyaluronan
• Chondroitin sulfate

Plasma syndecan-1 levels correlate with disease severity and mortality in sepsis and trauma. Levels >100 ng/mL indicate severe glycocalyx damage (PMID: 25370545).

Consequences of Glycocalyx Degradation:

• Increased vascular permeability (protein leak)
• Oedema formation
• Leucocyte adhesion and tissue infiltration
• Platelet activation and microvascular thrombosis
• Loss of mechanosensing and NO production
• Increased capillary filtration

Therapeutic Implications:

• Avoid hypervolaemic resuscitation (triggers ANP release)
• Tight glycaemic control may be protective
• Fresh frozen plasma may provide glycocalyx precursors
• Albumin may have protective effects
• Novel agents: Sphingosine-1-phosphate, sulodexide (PMID: 26011191)

---

Osmolality and Tonicity

Definitions

Osmolality is the concentration of osmotically active particles per kilogram of solvent (mOsm/kg H₂O). It determines the osmotic force driving water movement across semi-permeable membranes.

Osmolarity is the concentration of osmotically active particles per litre of solution (mOsm/L). In clinical practice, osmolality and osmolarity are often used interchangeably as the difference is <1% at physiological concentrations.

Tonicity (effective osmolality) refers to the osmotic pressure exerted only by solutes that cannot freely cross cell membranes ("effective osmoles"). Tonicity determines cell volume changes.

Osmolality Calculation

Plasma Osmolality (Calculated): Osmolality = 2[Na^+] + [Glucose] + [Urea]

Where concentrations are in mmol/L.

Simplified Formula (US units): Osmolality = 2[Na^+] + \frac{Glucose}{18} + \frac{BUN}{2.8}

Normal Values:

• Plasma osmolality: 285-295 mOsm/kg
• Urine osmolality: 50-1200 mOsm/kg (varies with hydration)

Measured Osmolality:

Measured by freezing point depression or vapour pressure osmometry. This detects all osmotically active particles, including unmeasured substances.

Osmolar Gap

The osmolar gap is the difference between measured and calculated osmolality.

Osmolar\ Gap = Measured\ Osmolality - Calculated\ Osmolality

Normal Osmolar Gap: <10 mOsm/kg

Causes of Elevated Osmolar Gap (>10):

• Toxic alcohols:
  • "Ethanol: Each 100 mg/dL (21.7 mmol/L) adds ~22 mOsm/kg"
  • "Methanol: Extremely toxic, requires urgent haemodialysis"
  • "Ethylene glycol: Causes acute kidney injury"
  • "Isopropanol: Less toxic, metabolised to acetone"
• Propylene glycol: Vehicle for IV medications (lorazepam, diazepam)
• Contrast media: Transient elevation following IV contrast
• Mannitol: Osmotic diuretic
• Glycine: Absorbed during TURP (irrigation fluid)
• Pseudohyponatraemia: Lipids, paraproteins cause lab artefact

Clinical Utility:

• Osmolar gap is a screening test for toxic alcohol ingestion
• A normal gap does not exclude toxicity (metabolised alcohols)
• Obtain specific alcohol levels if suspicion is high (PMID: 15556044)

Tonicity vs Osmolality

The distinction between osmolality and tonicity is clinically critical:

Osmolality includes ALL solutes (effective and ineffective)

Tonicity includes only EFFECTIVE osmoles (those that cannot cross cell membranes):

• Sodium (and associated anions)
• Glucose (in diabetes with insulin deficiency)
• Mannitol
• Glycine (from TURP irrigation)

Ineffective Osmoles (cross cell membranes, do not affect cell volume):

• Urea
• Ethanol
• Methanol
• Ethylene glycol

Example:

A patient with uraemia has:

• Serum Na⁺: 140 mmol/L
• Glucose: 5 mmol/L
• Urea: 50 mmol/L (markedly elevated)

Calculated osmolality: 2(140) + 5 + 50 = 335 mOsm/kg (elevated) Calculated tonicity: 2(140) + 5 = 285 mOsm/kg (normal)

Despite elevated osmolality, the patient's cells will NOT shrink because urea equilibrates freely across cell membranes. The plasma is hyper-osmolar but isotonic (PMID: 16825024).

Clinical Significance

Hypotonicity (effective osmolality <275 mOsm/kg):

• Water enters cells down osmotic gradient
• Cellular swelling occurs
• Brain cells particularly vulnerable (cerebral oedema)
• Causes: Hyponatraemia (most common), SIADH, water intoxication

Hypertonicity (effective osmolality >295 mOsm/kg):

• Water leaves cells
• Cellular shrinkage occurs
• Compensatory mechanisms in brain (idiogenic osmoles)
• Causes: Hypernatraemia, hyperglycaemia, mannitol therapy

Rapid Correction Risks:

• Rapid correction of hyponatraemia → osmotic demyelination syndrome (ODS)
• Rapid correction of hypernatraemia → cerebral oedema
• Target correction: 8-10 mEq/L per 24 hours maximum for chronic dysnatraemias

---

Distribution of Intravenous Fluids

Principles of Fluid Distribution

The distribution of intravenously administered fluids depends on their composition, particularly their osmolality, sodium concentration, and colloid content.

Key Principles:

1. Water distributes to all compartments in proportion to their size (ICF:ECF = 2:1)
2. Sodium remains in the ECF (cell membranes relatively impermeable to Na⁺)
3. Colloids initially remain intravascular (molecular weight too large to cross capillaries)
4. Glucose enters cells after metabolism, leaving free water

Crystalloid Solutions

0.9% Normal Saline (154 mmol/L Na⁺, 154 mmol/L Cl⁻)

Osmolality: 308 mOsm/L (slightly hypertonic)

Distribution:

• 100% distributes to ECF initially
• Of ECF distribution: 25% to plasma (750 mL/3L), 75% to interstitium (2.25L)
• 1 L 0.9% saline expands plasma volume by ~250-300 mL

Plasma Volume Expansion:

Context-Sensitive Volume Kinetics:

• Hypovolaemia: Greater plasma expansion (reduced redistribution)
• Normovolaemia: Standard 25% plasma expansion
• Hypervolaemia: Rapid redistribution to interstitium
• Anaesthesia: Reduced redistribution (greater plasma expansion)
• Haemorrhage: Markedly reduced clearance

In hypovolaemic patients, crystalloid clearance is reduced by up to 80%, meaning fluids remain intravascular longer. This "context sensitivity" explains clinical observations that fluids work better in sick patients than predicted by classical physiology (PMID: 21044355).

Clinical Considerations:

• High chloride content may cause hyperchloraemic metabolic acidosis
• Large volumes associated with AKI and mortality in some studies
• SMART trial showed reduced major adverse kidney events with balanced crystalloids (PMID: 29485925)

Balanced Crystalloids (Hartmann's/Plasmalyte)

Composition (Hartmann's/Ringer's Lactate):

• Sodium: 131 mmol/L
• Chloride: 111 mmol/L
• Potassium: 5 mmol/L
• Calcium: 2 mmol/L
• Lactate: 29 mmol/L (metabolised to bicarbonate)

Composition (Plasmalyte):

• Sodium: 140 mmol/L
• Chloride: 98 mmol/L
• Potassium: 5 mmol/L
• Magnesium: 1.5 mmol/L
• Acetate: 27 mmol/L
• Gluconate: 23 mmol/L

Osmolality: 280-295 mOsm/L (isotonic)

Distribution: Similar to normal saline (ECF only)

Advantages:

• Lower chloride load (reduced hyperchloraemic acidosis)
• Metabolisable anions provide buffer (lactate, acetate)
• More physiological electrolyte profile
• SMART trial: Reduced death/RRT/persistent renal dysfunction vs saline (PMID: 29485925)

5% Dextrose

Composition: 50 g/L glucose, no electrolytes Osmolality: 278 mOsm/L (isotonic due to glucose)

Distribution:

1. Initially isotonic: Remains in ECF briefly
2. Glucose metabolised: Over 15-30 minutes, glucose enters cells and is metabolised
3. Free water released: Distributes across TBW (ICF:ECF = 2:1)

For 1 L of 5% dextrose:

• 667 mL to ICF
• 333 mL to ECF (83 mL to plasma, 250 mL to interstitium)
• Only 80-90 mL plasma volume expansion

Clinical Use:

• Replacement of pure water deficit (hypernatraemia)
• Vehicle for IV medications
• NOT appropriate for volume resuscitation
• Avoid in neurological injury (worsens cerebral oedema)

Hypertonic Saline

Concentrations Available:

• 3% saline (513 mmol/L Na⁺, 513 mOsm/L)
• 5% saline (855 mmol/L Na⁺, 856 mOsm/L)
• 7.5% saline (1283 mmol/L Na⁺, 1283 mOsm/L)
• 23.4% saline (4000 mmol/L Na⁺, 4000 mOsm/L)

Distribution:

Hypertonic saline creates an osmotic gradient that draws water from ICF to ECF:

For 100 mL of 3% saline:

• Osmoles added: 51 mOsm
• Water drawn from ICF: ~170 mL
• Net plasma expansion: ~270 mL (100 mL infused + 170 mL from ICF)

The plasma volume expansion is approximately 3-4 times the volume infused.

Clinical Applications:

• Severe symptomatic hyponatraemia (cerebral oedema)
• Raised intracranial pressure (traumatic brain injury)
• Small-volume resuscitation (trauma, burns)
• Hypovolaemic hyponatraemia

Administration:

• 3% saline: 100-150 mL boluses for acute hyponatraemia
• Target Na⁺ increase: 4-6 mEq/L acutely, then slow correction
• Central venous access preferred for concentrations >3%

Colloid Solutions

Albumin

Preparations:

• 4% albumin (40 g/L) - iso-oncotic
• 20% albumin (200 g/L) - hyperoncotic

Distribution:

• Remains predominantly intravascular initially
• Each gram of albumin binds ~18 mL water
• 4% albumin: 1:1 plasma volume expansion
• 20% albumin: Draws fluid from interstitium (2-4:1 expansion)

SAFE Study (PMID: 15163774):

• 6,997 ICU patients randomised to 4% albumin vs 0.9% saline
• No difference in 28-day mortality (20.9% vs 21.1%)
• Albumin group received less total fluid volume
• Trend towards harm in traumatic brain injury subgroup

Clinical Use:

• Septic shock (may reduce fluid volume required)
• Hepatorenal syndrome (with terlipressin)
• Large volume paracentesis (>5L drained)
• NOT recommended for TBI or routine resuscitation

Synthetic Colloids

Hydroxyethyl Starch (HES):

HES solutions were widely used but are now contraindicated in critical illness due to:

CHEST Trial (PMID: 23075127):

• 7,000 ICU patients randomised to HES 130/0.4 vs saline
• Increased renal replacement therapy with HES (7.0% vs 5.8%)
• No mortality difference
• HES contraindicated in sepsis, burns, critically ill

6S Trial (PMID: 22738085):

• 804 severe sepsis patients
• HES 130/0.42 vs Ringer's acetate
• Increased 90-day mortality with HES (51% vs 43%)
• Increased RRT with HES (22% vs 16%)

Gelatins:

• Succinylated gelatin (Gelofusine): 35-50 kDa
• Urea-linked gelatin (Haemaccel): Largely withdrawn
• Shorter intravascular half-life than albumin
• Risk of anaphylaxis (0.1-0.35%)
• No proven benefit over crystalloids in critical illness

---

Measurement of Body Fluid Compartments

Dilution Principle

Body fluid compartments are measured using the indicator dilution technique:

Volume = \frac{Amount\ of\ Indicator\ Administered}{Concentration\ of\ Indicator\ After\ Equilibration}

Requirements for Ideal Indicator:

1. Distributes uniformly within the compartment
2. Does not cross compartment boundaries
3. Not metabolised or excreted during equilibration
4. Can be accurately measured
5. Non-toxic at measurement doses

Measurement of Specific Compartments

Total Body Water (TBW)

Indicators:

• Deuterium oxide (D₂O): Most accurate, gold standard
• Tritiated water (³H₂O): Radioactive, research use only
• Antipyrine: Lipid-soluble drug distributing to TBW
• Bioelectrical impedance analysis (BIA): Non-invasive clinical tool

Deuterium Dilution Method:

1. Administer known dose of D₂O (typically 0.1 g/kg)
2. Allow 3-4 hour equilibration
3. Measure D₂O concentration in plasma or saliva
4. Calculate: TBW = Dose / Concentration

Accuracy: ±1-2% for isotope dilution

Extracellular Fluid (ECF)

Indicators:

• Inulin: Gold standard, polysaccharide (5 kDa)
• Mannitol: Simple, does not enter cells
• Bromide: Widely distributed, overestimates slightly
• Sodium-24 (²⁴Na⁺): Radioactive tracer
• Sulfate: Remains extracellular

Inulin Dilution:

1. Administer inulin bolus or constant infusion
2. Allow equilibration (2-3 hours for bolus)
3. Measure plasma inulin concentration
4. Calculate ECF volume

Issues:

• Some indicators penetrate cells slightly (overestimate)
• Different indicators give slightly different values
• Inulin: ~16% body weight
• Bromide: ~20% body weight (enters RBCs slightly)

Plasma Volume

Indicators:

• Evans blue dye: Binds to albumin, remains intravascular
• Radioiodinated albumin (¹²⁵I-albumin): Gold standard
• Indocyanine green (ICG): Rapid clearance, multiple measurements possible
• Carbon monoxide (CO): Binds to haemoglobin

Evans Blue Dilution:

1. Inject known amount of Evans blue dye
2. Allow 10-15 minute mixing
3. Measure plasma concentration (spectrophotometry)
4. Calculate plasma volume

Accuracy: ±5% for dye dilution methods

Blood Volume

Calculation: Blood\ Volume = \frac{Plasma\ Volume}{1 - Haematocrit}

Or measured directly using:

• ⁵¹Cr-labelled red blood cells: Most accurate
• ⁹⁹mTc-labelled red blood cells: Alternative

Note on Haematocrit:

Whole-body haematocrit is lower than venous haematocrit due to plasma trapping and the Fåhraeus effect (lower haematocrit in microcirculation). A correction factor of 0.91 is applied:

Blood\ Volume = \frac{Plasma\ Volume}{1 - (0.91 \times Venous\ Hct)}

Interstitial Fluid Volume

Calculation (not directly measurable): ISF\ Volume = ECF\ Volume - Plasma\ Volume

Using typical values: ISF = 14L - 3L = 11L

Intracellular Fluid Volume

Calculation (not directly measurable): ICF\ Volume = TBW - ECF\ Volume

Using typical values: ICF = 42L - 14L = 28L

---

Third Spacing

Definition and Pathophysiology

Third spacing refers to the accumulation of fluid in body compartments where it is not normally present in significant quantities and from which it cannot easily be mobilised. This fluid is functionally inaccessible to the circulation.

Sites of Third Space Accumulation:

• Peritoneal cavity (ascites)
• Pleural space (pleural effusion)
• Pericardial space (pericardial effusion)
• Bowel lumen and wall (ileus, obstruction)
• Retroperitoneum (pancreatitis, aortic surgery)
• Traumatised/inflamed tissue (burns, surgery)

Mechanisms

1. Increased Capillary Hydrostatic Pressure:

• Venous obstruction
• Cardiac failure
• Fluid overload

2. Decreased Plasma Oncotic Pressure:

• Hypoalbuminaemia (hepatic failure, malnutrition, nephrotic syndrome)
• Protein losses (burns, enteropathy)

3. Increased Capillary Permeability:

• Sepsis/SIRS
• Anaphylaxis
• Burns
• Pancreatitis
• Major surgery
• Glycocalyx degradation

4. Lymphatic Obstruction:

• Malignancy
• Surgery (lymph node dissection)
• Radiation

Clinical Significance

Recognition:

• Weight gain without intravascular volume increase
• Peripheral and pulmonary oedema
• Ascites/effusions on imaging
• Haemoconcentration despite fluid administration
• Rising haematocrit with decreasing blood pressure

Quantification:

Estimated third space losses in various clinical scenarios:

Management Principles:

1. Initial resuscitation: Replace third space losses to maintain organ perfusion
2. Goal-directed therapy: Use dynamic measures of fluid responsiveness
3. Avoid over-resuscitation: Excessive fluid worsens oedema and organ dysfunction
4. Address underlying cause: Treat sepsis, decompress bowel, etc.
5. Mobilisation phase: Third space fluid returns to circulation during recovery
6. Diuresis: May be required to clear accumulated fluid

---

Oedema Formation

Mechanisms of Oedema

Oedema represents accumulation of excess fluid in the interstitial space, occurring when the rate of capillary filtration exceeds lymphatic drainage capacity.

1. Increased Capillary Hydrostatic Pressure:

• Left ventricular failure → pulmonary oedema
• Right ventricular failure → peripheral oedema
• Venous obstruction (DVT, compression)
• Fluid overload
• Pregnancy (uterine compression of IVC)

2. Decreased Plasma Oncotic Pressure:

• Hypoalbuminaemia <20 g/L
• Nephrotic syndrome (urinary protein loss)
• Hepatic failure (decreased synthesis)
• Malnutrition (kwashiorkor)
• Protein-losing enteropathy

3. Increased Capillary Permeability:

• Sepsis/SIRS
• Burns (direct and systemic)
• Allergic/anaphylactic reactions
• Inflammatory states
• Glycocalyx degradation

4. Lymphatic Obstruction:

• Malignancy (nodal invasion)
• Surgical lymph node dissection
• Filariasis (elephantiasis)
• Radiation fibrosis

5. Tissue Factors:

• Sodium retention (renal failure, heart failure)
• Hormonal (oestrogen, corticosteroids)
• Immobility (dependent oedema)
• Local inflammation

Safety Factors Against Oedema

Multiple mechanisms normally resist oedema formation:

1. Low Interstitial Compliance (Early):

• Initial fluid accumulation raises interstitial pressure
• This opposes further filtration (increases Pi in Starling equation)
• Can buffer 2-3 times normal interstitial volume

2. Increased Lymphatic Flow:

• Lymphatics can increase flow 10-50 fold
• Driven by interstitial pressure increase
• Lymphatic pumping enhanced by muscle movement

3. Wash-down of Interstitial Proteins:

• Increased filtration dilutes interstitial proteins
• Reduces πi, decreasing net filtration force
• Limited by minimum interstitial protein concentration

4. Increased Plasma Oncotic Pressure:

• Hepatic synthesis increases in response to hypoalbuminaemia
• Limited adaptive capacity

These safety factors can resist oedema formation until filtration increases by 2-5 fold above normal. Once exceeded, oedema accumulates rapidly due to increased interstitial compliance (PMID: 20418556).

Types of Oedema

Pitting Oedema:

• Indentation persists after pressure applied
• Indicates excess free fluid in interstitium
• Graded 1+ to 4+ based on depth/duration

Non-pitting Oedema:

• Firm, does not indent
• Indicates protein-rich fluid (lymphoedema)
• Or glycosaminoglycan deposition (myxoedema)

Pulmonary Oedema:

• Accumulation of fluid in lung interstitium and alveoli
• Cardiogenic (high pressure) vs non-cardiogenic (high permeability)
• Critical threshold: PAWP >18-20 mmHg (cardiogenic)

Clinical Assessment

History:

• Orthopnoea, paroxysmal nocturnal dyspnoea (cardiac)
• Reduced urine output, proteinuria (nephrotic)
• Alcohol history, jaundice (hepatic)
• Recent illness, fever (sepsis)
• Medications (calcium channel blockers, NSAIDs)

Examination:

• Distribution (dependent, generalised, unilateral)
• Pitting vs non-pitting
• JVP assessment
• Lung examination (crackles, effusions)
• Hepatomegaly, ascites

Investigations:

• Serum albumin, urine protein
• BNP/NT-proBNP (cardiac oedema)
• Liver function tests
• Renal function
• Echocardiography
• Chest X-ray, CT if indicated

---

Clinical Applications

Fluid Resuscitation in Critical Illness

Initial Resuscitation:

The Surviving Sepsis Campaign recommends initial fluid resuscitation with 30 mL/kg crystalloid within the first 3 hours for sepsis-induced hypoperfusion. Balanced crystalloids are preferred over 0.9% saline based on the SMART trial (PMID: 29485925).

Goal-Directed Fluid Therapy:

Modern fluid resuscitation emphasises:

1. Dynamic assessment: Response to fluid challenge, not static CVP
2. Titrated administration: Small boluses (250-500 mL) with reassessment
3. Early cessation: Stop when no longer fluid responsive
4. De-escalation: Active de-resuscitation when stable

Fluid Responsiveness:

Patients are "fluid responsive" if cardiac output will increase with fluid administration (operating on ascending limb of Frank-Starling curve).

Predictors of Fluid Responsiveness:

Limitations:

• PPV/SVV require controlled mechanical ventilation, sinus rhythm, tidal volume ≥8 mL/kg
• Not valid in spontaneous breathing, arrhythmias, open chest

Fluid Management in Specific Conditions

Septic Shock:

• Initial 30 mL/kg crystalloid bolus (balanced preferred)
• Early vasopressors if MAP <65 mmHg despite fluids
• Avoid fluid overload (associated with mortality)
• Consider albumin in severe hypoalbuminaemia
• Target: Lactate normalisation, urine output, capillary refill

Traumatic Brain Injury:

• Avoid hypotension (SBP <90 mmHg)
• Avoid hypotonic fluids (worsen cerebral oedema)
• 0.9% saline or balanced crystalloid
• Hypertonic saline for raised ICP
• Target: Euvolaemia, serum Na⁺ 145-155 mmol/L

Burns:

• Parkland formula: 4 mL/kg/% TBSA in first 24 hours
• Half in first 8 hours, half in next 16 hours
• Use crystalloid (Hartmann's preferred)
• Adjust based on urine output (0.5-1 mL/kg/hour adults)
• Avoid fluid creep (excessive resuscitation)

Acute Kidney Injury:

• Careful fluid assessment (avoid both hypo- and hypervolaemia)
• Stop nephrotoxic drugs
• Consider diuretics only after euvolaemia achieved
• Early RRT if fluid overload refractory

Australian/New Zealand Context

ANZICS Guidelines:

• Balanced crystalloids preferred for routine resuscitation
• Albumin may be considered in septic shock
• Avoid HES in all critically ill patients
• Early goal-directed therapy principles adopted

Indigenous Health Considerations:

• Higher rates of CKD, cardiac disease, diabetes in Aboriginal and Torres Strait Islander populations
• May have baseline reduced TBW (lower muscle mass)
• Higher risk of fluid overload with cardiac/renal disease
• Cultural considerations for invasive monitoring
• Remote/rural access challenges for complex fluid management

Māori Health Considerations:

• Higher rates of diabetes, CKD, rheumatic heart disease
• Whānau involvement in care decisions
• Access challenges in rural New Zealand
• Consider tikanga when discussing invasive procedures

---

Indigenous Health Considerations

Fluid Management in Aboriginal and Torres Strait Islander Patients

Aboriginal and Torres Strait Islander peoples experience significantly higher rates of chronic diseases affecting fluid balance:

Higher Prevalence Conditions:

• Chronic kidney disease (CKD) - 4-10 times higher
• Diabetes mellitus - 3-4 times higher
• Cardiovascular disease - 2-3 times higher
• Rheumatic heart disease - 7-10 times higher

Clinical Implications:

1. Altered Baseline TBW:

   • May have lower muscle mass and altered body composition
   • Obesity and diabetes affect fluid distribution
   • Standard weight-based dosing may need adjustment

2. Cardiac and Renal Disease:

   • Higher risk of fluid overload
   • More cautious resuscitation volumes
   • Earlier consideration of vasopressors
   • Lower threshold for RRT discussion

3. Remote/Rural Considerations:

   • Limited access to advanced monitoring
   • Retrieval may be required for complex management
   • Telemedicine consultation important
   • Aboriginal Health Workers/Practitioners invaluable

4. Cultural Safety:

   • Explain procedures clearly and respectfully
   • Involve family in care discussions
   • Consider men's and women's business sensitivities
   • Aboriginal Health Worker involvement
   • Interpreter services if English not first language

Māori Health Considerations

Higher Prevalence Conditions:

• Diabetes mellitus - 2.5 times higher
• CKD - 3-4 times higher
• Rheumatic heart disease - 20-30 times higher
• Cardiovascular disease - 2 times higher

Clinical Implications:

1. Whānau-Centred Care:

   • Family involvement in all major decisions
   • Collective decision-making rather than individual
   • Kaumātua (elders) may guide decisions

2. Tikanga (Cultural Practices):

   • Karakia (prayer) before procedures
   • Tapu of the head (be mindful with central lines)
   • Respect for tupapaku (deceased)

3. Te Tiriti Obligations:

   • Equitable access to care
   • Cultural competence in all interactions
   • Māori health worker involvement

---

SAQ Practice Questions

SAQ 1: Total Body Water and Fluid Distribution (15 marks)

Question: A 70 kg adult male is admitted to ICU with severe sepsis. His baseline weight is 70 kg and he has received 6 litres of 0.9% normal saline over 12 hours.

a) Describe the normal distribution of total body water in this patient prior to illness. (5 marks)

b) Explain how the infused 0.9% saline would be expected to distribute in this patient. (5 marks)

c) After 12 hours, the patient remains hypotensive with a serum sodium of 132 mmol/L and serum albumin of 18 g/L. Explain the pathophysiology of the oedema observed despite persistent hypovolaemia. (5 marks)

---

Model Answer:

(a) Normal Distribution of Total Body Water (5 marks)

Total body water (TBW) in a 70 kg adult male comprises approximately 60% of body weight:

• Total body water: 42 L (60% × 70 kg)

TBW is distributed between two main compartments:

• Intracellular fluid (ICF): 28 L (40% body weight, 2/3 of TBW)

  • "Primary cation: Potassium (150 mEq/L)"
  • "Primary anions: Phosphate and proteins"
  • Maintained by Na⁺/K⁺-ATPase pump

• Extracellular fluid (ECF): 14 L (20% body weight, 1/3 of TBW)

  • "Primary cation: Sodium (140 mEq/L)"
  • "Primary anions: Chloride and bicarbonate"

ECF is subdivided into:

• Plasma volume: 3 L (5% body weight, 1/4 of ECF)
• Interstitial fluid: 11 L (15% body weight, 3/4 of ECF)
• Transcellular fluid: 1 L (CSF, synovial fluid, GI secretions)

(b) Distribution of 6 L 0.9% Saline (5 marks)

0.9% saline (154 mmol/L Na⁺, 308 mOsm/L) is an isotonic crystalloid that distributes exclusively within the ECF:

Classic distribution (normovolaemic patient):

• 100% remains in ECF (sodium does not cross cell membranes)
• Of this: 25% (1.5 L) expands plasma volume
• Remaining 75% (4.5 L) distributes to interstitial fluid

Context-sensitive volume kinetics in sepsis:

In sepsis, crystalloid distribution is altered:

• Volume of distribution may be decreased (impaired peripheral perfusion)
• Initially, greater plasma expansion may occur
• However, glycocalyx degradation and endothelial dysfunction increase vascular permeability
• Rapid redistribution to interstitium occurs
• Net plasma expansion may be <25% of infused volume

Expected plasma volume expansion:

• Traditional estimate: 1.5 L (25% of 6 L)
• In sepsis: Likely less due to capillary leak

(c) Pathophysiology of Oedema with Hypovolaemia (5 marks)

The paradox of oedema with persistent hypovolaemia in sepsis is explained by:

1. Glycocalyx degradation:

• Inflammatory cytokines (TNF-α, IL-1β, IL-6) activate sheddases
• Glycocalyx thickness reduces from 1-3 μm to <0.5 μm
• Loss of primary vascular barrier
• Syndecan-1 levels elevated in sepsis

2. Increased capillary permeability:

• Endothelial gap formation (endothelial cell contraction)
• Decreased reflection coefficient for albumin (σ from 0.95 to 0.3-0.5)
• Protein leak into interstitium
• Increased Kf (filtration coefficient)

3. Decreased plasma oncotic pressure:

• Baseline albumin 18 g/L (normal 35-50 g/L)
• Oncotic pressure reduced from 25 mmHg to ~10 mmHg
• Favours net filtration across capillaries

4. Revised Starling forces:

• In normal physiology: πsg (subglycocalyx) is low, maintaining oncotic gradient
• With glycocalyx loss: Interstitial protein accumulates, reducing oncotic gradient
• Sustained net filtration throughout capillary length

5. Relative intravascular hypovolaemia:

• Venodilatation increases venous capacitance
• Fluid redistributes to venous system and interstitium
• Arterial underfilling despite total body fluid excess

This explains why large fluid volumes produce oedema but fail to restore intravascular volume, and why early vasopressor use is recommended alongside fluid resuscitation.

---

SAQ 2: Starling Forces and Glycocalyx (15 marks)

Question: A 55-year-old woman develops acute respiratory distress syndrome (ARDS) following aspiration pneumonia.

a) Describe the revised Starling equation and explain how it differs from the classical model. (6 marks)

b) Explain the structure and function of the endothelial glycocalyx. (4 marks)

c) Describe how glycocalyx degradation contributes to pulmonary oedema in this patient. (5 marks)

---

Model Answer:

(a) Revised Starling Equation (6 marks)

Classical Starling Equation (1896): J_v = K_f[(P_c - P_i) - \sigma(\pi_p - \pi_i)]

Revised Starling Equation (Levick & Michel, 2010): J_v = L_p \times S \times [(P_c - P_i) - \sigma(\pi_p - \pi_{sg})]

Where:

• Jv = Net fluid flux
• Lp = Hydraulic conductivity
• S = Surface area
• Pc = Capillary hydrostatic pressure
• Pi = Interstitial hydrostatic pressure
• σ = Reflection coefficient
• πp = Plasma oncotic pressure
• πsg = Subglycocalyx oncotic pressure

Key differences from classical model:

1. Glycocalyx as primary barrier:

   • Not the endothelium, but the glycocalyx is the true semi-permeable membrane
   • Creates protein-exclusion zone at endothelial surface

2. Subglycocalyx space:

   • Thin layer between glycocalyx and endothelium
   • Very low protein concentration (~10 g/L vs 40 g/L plasma)
   • Creates large effective oncotic gradient

3. No sustained absorption:

   • Classical model predicted absorption at venular end
   • Revised model shows filtration occurs along entire capillary length
   • All filtered fluid returns via lymphatics

4. Interstitial oncotic pressure irrelevant:

   • Changes in πi do not affect filtration
   • Glycocalyx maintains low πsg regardless of interstitial protein

(b) Structure and Function of Glycocalyx (4 marks)

Structure:

The glycocalyx is a 0.5-3 μm thick gel-like layer on the luminal endothelial surface comprising:

1. Proteoglycans:

   • Syndecans (1-4): Transmembrane, linked to cytoskeleton
   • Glypicans: GPI-anchored to membrane

2. Glycosaminoglycans (GAGs):

   • Heparan sulfate (50-90%): Longest chains
   • Chondroitin sulfate
   • Hyaluronan: Very long, unattached to core protein

3. Glycoproteins:

   • Selectins (E-selectin, P-selectin)
   • Adhesion molecules (ICAM-1, VCAM-1)

Functions:

1. Vascular permeability barrier: Creates protein-exclusion zone maintaining low subglycocalyx protein concentration

2. Mechanotransduction: Senses shear stress, triggers nitric oxide release

3. Anti-inflammatory: Healthy glycocalyx prevents leucocyte adhesion by burying selectins

4. Anticoagulant: Binds antithrombin III, thrombomodulin, TFPI

(c) Glycocalyx Degradation in ARDS (5 marks)

Mechanisms of degradation:

1. Inflammatory mediators:

   • Aspiration triggers intense inflammatory response
   • TNF-α, IL-1β, IL-6 release
   • Activation of matrix metalloproteinases (MMPs)
   • Neutrophil-derived heparanase release

2. Reactive oxygen species:

   • Generated during inflammation and reperfusion
   • Direct damage to GAG chains
   • Further enzyme activation

3. Sheddases:

   • ADAM-17 (TNF-α converting enzyme)
   • MMP-2, MMP-9
   • Cleave syndecan ectodomains

Consequences for pulmonary oedema:

1. Loss of oncotic barrier:

   • Protein leaks from plasma to interstitium
   • Interstitial oncotic pressure rises
   • Reduced oncotic gradient opposing filtration

2. Increased permeability:

   • Reflection coefficient decreases from 0.95 to 0.3-0.5
   • Even small molecules leak across
   • Protein-rich oedema fluid accumulates

3. Loss of subglycocalyx space:

   • πsg increases toward plasma levels
   • Effective oncotic gradient eliminated
   • Sustained filtration along entire capillary

4. Leucocyte adhesion:

   • Exposed selectins promote neutrophil binding
   • Further inflammation and endothelial damage
   • Amplification of injury

5. Lymphatic overwhelm:

   • Filtration rate exceeds lymphatic drainage capacity
   • Rapid accumulation of alveolar oedema
   • Impaired gas exchange

This explains why ARDS produces protein-rich pulmonary oedema despite often normal or low pulmonary capillary wedge pressures, and why patients remain oedematous despite diuresis.

---

Viva Scenarios

Viva Scenario 1: Fluid Compartments (20 marks)

Setting: First Part Physiology Viva, cross-table format

---

Examiner: "Tell me about the distribution of water in the body."

Candidate: "Total body water comprises approximately 60% of body weight in an adult male, equating to 42 litres in a 70 kg individual. This varies with age, sex, and body composition - females have approximately 50% due to higher adipose tissue content, elderly individuals may have 45-55%, and neonates have up to 75-80%.

TBW is distributed between two main compartments: the intracellular fluid at 40% body weight or two-thirds of TBW, approximately 28 litres, and the extracellular fluid at 20% body weight or one-third of TBW, approximately 14 litres.

The ECF is further subdivided into plasma volume of 3 litres representing 5% body weight and interstitial fluid of 11-12 litres representing 15% body weight. There is also a small transcellular fluid component of approximately 1 litre including CSF, synovial fluid, and intraocular fluid."

---

Examiner: "What determines the difference in composition between ICF and ECF?"

Candidate: "The marked difference in ionic composition is primarily maintained by the Na⁺/K⁺-ATPase pump, which is an electrogenic pump that extrudes 3 sodium ions for every 2 potassium ions imported. This creates the sodium gradient with sodium being the primary ECF cation at 140 mEq/L versus only 10 mEq/L intracellularly, and the potassium gradient with potassium at 150 mEq/L intracellularly versus 4.5 mEq/L in the ECF.

This pump consumes approximately 30% of basal cellular ATP. The gradients are maintained by the cell membrane's relative impermeability to charged ions, requiring specific channels or transporters for movement, and by the Gibbs-Donnan equilibrium where non-diffusible intracellular proteins create an unequal distribution of diffusible ions."

---

Examiner: "How would you measure plasma volume?"

Candidate: "Plasma volume is measured using the indicator dilution technique. The volume equals the amount of indicator administered divided by its concentration after equilibration.

The ideal indicator should distribute uniformly within the compartment, not cross compartment boundaries, not be metabolised or excreted during equilibration, be accurately measurable, and be non-toxic.

For plasma volume specifically, commonly used indicators include Evans blue dye which binds to albumin and remains intravascular, radioiodinated albumin using iodine-125 which is the gold standard, and indocyanine green which allows multiple measurements due to rapid hepatic clearance.

For Evans blue, we inject a known amount, allow 10-15 minutes for mixing, measure plasma concentration by spectrophotometry, and calculate plasma volume. Accuracy is approximately plus or minus 5%."

---

Examiner: "What would happen if you infused one litre of 5% dextrose?"

Candidate: "5% dextrose contains 50 grams per litre of glucose with no electrolytes and has an osmolality of 278 mOsm/L making it initially isotonic.

The distribution occurs in three phases. Initially, the solution remains in the ECF briefly as it is isotonic. Over 15-30 minutes, the glucose is rapidly metabolised by cells. This leaves behind free water which then distributes across total body water in the ratio of ICF to ECF, which is 2:1.

So for 1 litre of 5% dextrose:

• 667 mL distributes to ICF
• 333 mL distributes to ECF
• Of that ECF portion, 83 mL goes to plasma and 250 mL to interstitium

Therefore, only 80-90 mL effectively expands plasma volume, making 5% dextrose inappropriate for volume resuscitation. It is used for replacing pure water deficits such as in hypernatraemia and as a vehicle for intravenous medications. It should be avoided in neurological injury as it can worsen cerebral oedema."

---

Examiner: "Contrast this with what happens when you give a litre of normal saline."

Candidate: "0.9% normal saline contains 154 mmol/L of sodium and 154 mmol/L of chloride with an osmolality of 308 mOsm/L making it slightly hypertonic.

As sodium cannot cross cell membranes, the entire volume distributes only within the ECF. In a normovolaemic patient, of this ECF distribution, approximately 25% or 250-300 mL expands plasma volume, while 75% or 750 mL distributes to the interstitial space.

However, Robert Hahn's work on context-sensitive volume kinetics has shown that this distribution is not fixed. In hypovolaemic patients, there is greater plasma expansion as redistribution is reduced. In normovolaemia, there is standard 25% plasma expansion. In hypervolaemia, there is rapid redistribution to the interstitium. Under anaesthesia, there is reduced redistribution resulting in greater plasma expansion.

In critically ill hypovolaemic patients, crystalloid clearance can be reduced by up to 80%, meaning fluids remain intravascular longer than traditional physiology would predict."

---

Examiner: "What is the osmolar gap and what does it tell you?"

Candidate: "The osmolar gap is the difference between measured osmolality and calculated osmolality.

Calculated osmolality using the formula: 2 times sodium plus glucose plus urea, where concentrations are in mmol/L.

Measured osmolality is determined by freezing point depression or vapour pressure osmometry and detects all osmotically active particles including unmeasured substances.

The normal osmolar gap is less than 10 mOsm/kg. An elevated osmolar gap greater than 10 indicates the presence of unmeasured osmoles.

Causes include toxic alcohols such as ethanol, methanol, ethylene glycol, and isopropanol. Each 100 mg/dL of ethanol adds approximately 22 mOsm/kg. Other causes include propylene glycol which is a vehicle for intravenous medications, contrast media causing transient elevation, mannitol therapy, and glycine absorbed during TURP procedures.

The osmolar gap is a screening test for toxic alcohol ingestion, but a normal gap does not exclude toxicity as metabolised alcohols may no longer contribute to the gap. Specific alcohol levels should be obtained if clinical suspicion is high."

---

Examiner: "Excellent. Thank you."

---

Viva Scenario 2: Starling Forces and Clinical Application (20 marks)

Setting: First Part Physiology Viva, cross-table format

---

Examiner: "Can you draw me a diagram showing the Starling forces at a capillary?"

Candidate: [Draws diagram showing capillary with arteriolar and venular ends, arrows indicating hydrostatic and oncotic pressures]

"This diagram shows a capillary with the arteriolar end on the left and venular end on the right.

The four classic Starling forces are:

1. Capillary hydrostatic pressure (Pc) - higher at the arteriolar end at about 35 mmHg, falling to 15 mmHg at the venular end. This favours filtration.

2. Interstitial hydrostatic pressure (Pi) - slightly negative at about minus 2 mmHg. This also favours filtration.

3. Plasma oncotic pressure (πp) - approximately 25 mmHg throughout. This opposes filtration.

4. Interstitial oncotic pressure (πi) - approximately 5 mmHg. This favours filtration.

The net filtration pressure at the arteriolar end would be (35 minus negative 2) minus (25 minus 5) equals 17 mmHg, favouring filtration.

At the venular end it would be (15 minus negative 2) minus (25 minus 5) equals minus 3 mmHg, favouring absorption in the classic model."

---

Examiner: "How has our understanding of these forces changed?"

Candidate: "The revised Starling principle, proposed by Levick and Michel in 2010, has substantially changed our understanding in several important ways.

Firstly, the glycocalyx is now recognised as the primary semi-permeable barrier, not the endothelium itself. The glycocalyx is a gel-like layer 0.5-3 micrometres thick on the luminal endothelial surface comprising proteoglycans, glycosaminoglycans, and glycoproteins.

Secondly, the relevant oncotic gradient is between plasma and the subglycocalyx space, not the interstitium. The subglycocalyx space is a thin layer between the glycocalyx and endothelial surface with very low protein concentration, creating a large effective oncotic gradient.

Thirdly, sustained venular absorption rarely occurs. In most tissues, filtration occurs along the entire capillary length. All filtered fluid returns to circulation via lymphatics, not through venular reabsorption.

The revised equation uses πsg, subglycocalyx oncotic pressure, rather than πi. This explains why changes in interstitial protein concentration do not directly affect filtration, as the glycocalyx maintains a protein-poor subglycocalyx space regardless of interstitial protein levels."

---

Examiner: "A patient with sepsis has severe oedema but remains hypotensive. Explain this."

Candidate: "This apparent paradox of oedema with intravascular hypovolaemia in sepsis is explained by several mechanisms.

Firstly, glycocalyx degradation occurs because inflammatory cytokines including TNF-alpha, IL-1 beta, and IL-6 activate sheddases and matrix metalloproteinases. Neutrophil-derived heparanase is released and reactive oxygen species damage the glycocalyx structure directly. This degradation is evidenced by elevated syndecan-1 levels in septic patients.

Secondly, the loss of the glycocalyx barrier increases capillary permeability. The reflection coefficient for albumin decreases from approximately 0.95 to 0.3-0.5. This allows protein to leak into the interstitium, reducing the effective oncotic gradient.

Thirdly, there is decreased plasma oncotic pressure due to reduced albumin synthesis, increased capillary leak, and dilution from fluid resuscitation. Albumin levels below 20 g/L significantly reduce oncotic pressure from 25 mmHg to approximately 10 mmHg.

Fourthly, there is venodilation and increased venous capacitance, meaning fluid redistributes to the venous system and interstitium rather than maintaining arterial filling.

The result is that crystalloid resuscitation produces oedema but fails to restore effective circulating volume because fluid rapidly redistributes to the expanded interstitial space through damaged capillaries. This is why the Surviving Sepsis Campaign recommends early vasopressor initiation alongside fluid resuscitation, rather than escalating fluid volumes indefinitely."

---

Examiner: "What is the clinical significance of understanding these mechanisms?"

Candidate: "Understanding these mechanisms has several important clinical implications.

For fluid resuscitation strategy, we should avoid excessive crystalloid administration as it contributes to oedema without sustained plasma expansion. Early vasopressor use is appropriate when hypotension persists despite initial fluid bolus. Goal-directed fluid therapy using dynamic measures of fluid responsiveness helps avoid over-resuscitation.

For choice of resuscitation fluid, balanced crystalloids are preferred over 0.9% saline based on the SMART trial. Albumin may have a role in severe hypoalbuminaemia and septic shock. Hydroxyethyl starch is contraindicated due to renal harm.

For monitoring, static measures like CVP poorly predict fluid responsiveness. Dynamic measures such as pulse pressure variation, stroke volume variation, and passive leg raise are more useful. Syndecan-1 levels may indicate glycocalyx damage severity.

For de-resuscitation, active fluid removal once the patient is stable helps reduce oedema-related complications. Diuretics or ultrafiltration may be needed in the recovery phase.

Finally, for potential future therapies, glycocalyx protection strategies are under investigation. Fresh frozen plasma may provide glycocalyx precursors. Albumin may have protective effects on the glycocalyx. Novel agents such as sphingosine-1-phosphate and sulodexide are being studied for glycocalyx protection."

---

Examiner: "Very good. Thank you."

---

---

Key Equations Summary

Osmolality Calculation

Osmolality = 2[Na^+] + [Glucose] + [Urea] (mmol/L)

Osmolar Gap

Osmolar\ Gap = Measured\ Osmolality - Calculated\ Osmolality

Classic Starling Equation

J_v = K_f[(P_c - P_i) - \sigma(\pi_p - \pi_i)]

Revised Starling Equation

J_v = L_p \times S \times [(P_c - P_i) - \sigma(\pi_p - \pi_{sg})]

Dilution Principle

Volume = \frac{Amount\ of\ Indicator}{Concentration\ After\ Equilibration}

Blood Volume from Plasma Volume

Blood\ Volume = \frac{Plasma\ Volume}{1 - (0.91 \times Venous\ Hct)}

---

Summary Tables

Fluid Compartment Volumes (70 kg Adult Male)

IV Fluid Distribution (1L infusion)

Starling Forces (Typical Values)

Measurement Techniques

---

References

Landmark Physiology

1. Starling EH. On the Absorption of Fluids from the Connective Tissue Spaces. J Physiol. 1896;19(4):312-326. PMID: 16992325

2. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res. 2010;87(2):198-210. PMID: 20418556

3. Adamson RH, Lenz JF, Zhang X, Adamson GN, Weinbaum S, Curry FE. Oncotic pressures opposing filtration across non-fenestrated rat microvessels. J Physiol. 2004;557(Pt 3):889-907. PMID: 15073281

Glycocalyx

4. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345-359. PMID: 17483596

5. Chappell D, Jacob M, Paul O, et al. The glycocalyx of the human umbilical vein endothelial cell: an impressive structure ex vivo but not in culture. Circ Res. 2009;104(11):1313-1317. PMID: 19423849

6. Uchimido R, Schmidt EP, Bhagwat S, et al. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019;23(1):16. PMID: 30654825

7. Schmidt EP, Yang Y, Janssen WJ, et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med. 2012;18(8):1217-1223. PMID: 22820644

8. Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010;87(2):300-310. PMID: 20462866

9. Ostrowski SR, Haase N, Müller RB, et al. Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study. Crit Care. 2015;19:191. PMID: 25370545

10. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108(3):384-394. PMID: 22290457

Body Composition and Fluid Compartments

11. Wang Z, Deurenberg P, Wang W, Pietrobelli A, Baumgartner RN, Heymsfield SB. Hydration of fat-free body mass: review and critique of a classic body-composition constant. Am J Clin Nutr. 1999;69(5):833-841. PMID: 10232621

12. Chumlea WC, Guo SS, Zeller CM, et al. Total body water reference values and prediction equations for adults. Kidney Int. 2001;59(6):2250-2258. PMID: 11380828

13. Kyle UG, Bosaeus I, De Lorenzo AD, et al. Bioelectrical impedance analysis-part I: review of principles and methods. Clin Nutr. 2004;23(5):1226-1243. PMID: 15380917

14. Edelman IS, Leibman J. Anatomy of body water and electrolytes. Am J Med. 1959;27:256-277. PMID: 13670421

15. Guyton AC, Hall JE. The body fluid compartments: extracellular and intracellular fluids; interstitial fluid and edema. In: Textbook of Medical Physiology. 11th ed. Philadelphia: Elsevier; 2006:291-306.

Osmolality and Tonicity

16. Bhagat CI, Garcia-Webb P, Fletcher E, Beilby JP. Calculated vs measured plasma osmolalities revisited. Clin Chem. 1984;30(10):1703-1705. PMID: 6478601

17. Purssell RA, Pudek M, Brubacher J, Abu-Laban RB. Derivation and validation of a formula to calculate the contribution of ethanol to the osmolal gap. Ann Emerg Med. 2001;38(6):653-659. PMID: 11719745

18. Glasser L, Sternglanz PD, Combie J, Robinson A. Serum osmolality and its applicability to drug overdose. Am J Clin Pathol. 1973;60(5):695-699. PMID: 4751712

19. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342(21):1581-1589. PMID: 10824078

20. Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders. 5th ed. New York: McGraw-Hill; 2001. PMID: 10796607

Intravenous Fluid Distribution

21. Hahn RG. Volume kinetics for infusion fluids. Anesthesiology. 2010;113(2):470-481. PMID: 20613481

22. Hahn RG, Lyons G. The half-life of infusion fluids: An educational review. Eur J Anaesthesiol. 2016;33(7):475-482. PMID: 27183475

23. Drobin D, Hahn RG. Volume kinetics of Ringer's solution in hypovolemic volunteers. Anesthesiology. 1999;90(1):81-91. PMID: 9915316

24. Svensén C, Hahn RG. Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers. Anesthesiology. 1997;87(2):204-212. PMID: 9286884

25. Hahn RG. Adverse effects of crystalloid and colloid fluids. Anaesthesiol Intensive Ther. 2017;49(4):303-308. PMID: 28953313

Crystalloid vs Colloid Trials

26. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256. PMID: 15163774

27. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-1911. PMID: 23075127

28. Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012;367(2):124-134. PMID: 22738085

29. Semler MW, Self WH, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829-839. PMID: 29485925

30. Self WH, Semler MW, Wanderer JP, et al; SALT-ED Investigators. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018;378(9):819-828. PMID: 29485926

Oedema and Third Spacing

31. Guyton AC. Interstitial fluid pressure. II. Pressure-volume curves of interstitial space. Circ Res. 1965;16:452-460. PMID: 14289152

32. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73(1):1-78. PMID: 8419962

33. Chappell D, Jacob M, Hofmann-Kiefer K, et al. Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology. 2007;107(5):776-784. PMID: 18073553

34. Jacob M, Chappell D, Rehm M. The 'third space' - fact or fiction? Best Pract Res Clin Anaesthesiol. 2009;23(2):145-157. PMID: 19653435

Fluid Resuscitation in Critical Illness

35. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. PMID: 11794169

36. ARISE Investigators; ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506. PMID: 25272316

37. ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693. PMID: 24635773

38. Malbrain MLNG, Marik PE, Witters I, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014;46(5):361-380. PMID: 25432556

39. Silversides JA, Major E, Ferguson AJ, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017;43(2):155-170. PMID: 27734109

Fluid Responsiveness

40. Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med. 2000;162(1):134-138. PMID: 10903232

41. Cavallaro F, Sandroni C, Marano C, et al. Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness in adults: systematic review and meta-analysis of clinical studies. Intensive Care Med. 2010;36(9):1475-1483. PMID: 20502865

42. Monnet X, Teboul JL. Passive leg raising: five rules, not a drop of fluid! Crit Care. 2015;19:18. PMID: 25658678

Indigenous and Australian Context

43. Australian Institute of Health and Welfare. Chronic kidney disease. Cat. no. CDK 16. Canberra: AIHW; 2020.

44. Anderson I, Robson B, Connolly M, et al. Indigenous and tribal peoples' health (The Lancet-Lowitja Institute Global Collaboration): a population study. Lancet. 2016;388(10040):131-157. PMID: 27108232

45. Cass A, Cunningham J, Wang Z, Hoy W. Regional variation in the incidence of end-stage renal disease in Indigenous Australians. Med J Aust. 2001;175(1):24-27. PMID: 11476198

46. ANZICS Centre for Outcome and Resource Evaluation (CORE). Annual Report 2020. Melbourne: ANZICS; 2020.

Hypertonic Saline

47. Bulger EM, May S, Brasel KJ, et al; ROC Investigators. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA. 2010;304(13):1455-1464. PMID: 20924010

48. Sterns RH. Disorders of plasma sodium - causes, consequences, and correction. N Engl J Med. 2015;372(1):55-65. PMID: 25551526

49. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-S42. PMID: 24074529

Measurement Techniques

50. Schoeller DA. Hydrometry. In: Roche AF, Heymsfield SB, Lohman TG, eds. Human Body Composition. Champaign, IL: Human Kinetics; 1996:25-43.

51. Roos AN, Westendorp RG, Frölich M, Meinders AE. Tetrapolar body impedance is influenced by body posture and plasma sodium concentration. Eur J Clin Nutr. 1992;46(1):53-60. PMID: 1559513

52. Marken Lichtenbelt WD, Westerterp KR, Wouters L. Deuterium dilution overestimates total body water: a comparison with body fat from skinfold and densitometry. Br J Nutr. 1994;72(4):503-512. PMID: 7986783

Additional Key References

53. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-1251. PMID: 24066745

54. Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med. 2005;33(8):1681-1687. PMID: 16096441

55. Caironi P, Tognoni G, Masson S, et al; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412-1421. PMID: 24635772

56. Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the prevention and attenuation of acute kidney injury. Nat Rev Nephrol. 2014;10(1):37-47. PMID: 24217464

57. Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: Expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med. 2017;43(6):730-749. PMID: 28577069

58. Langer T, Santini A, Scotti E, Van Regenmortel N, Malbrain ML, Caironi P. Intravenous balanced solutions: from physiology to clinical evidence. Anaesthesiol Intensive Ther. 2015;47 Spec No:s78-88. PMID: 26588484

59. Chappell D, Bruegger D, Potzel J, et al. Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx. Crit Care. 2014;18(5):538. PMID: 25497357

60. Schött U, Solomon C, Fries D, Bentzer P. The endothelial glycocalyx and its disruption, protection and regeneration: a narrative review. Scand J Trauma Resusc Emerg Med. 2016;24:48. PMID: 27068016

---

Related Topics

• Acid-Base Physiology
• Renal Physiology
• Cardiovascular Physiology
• Sodium and Water Balance
• Shock and Resuscitation
• Acute Kidney Injury
• Sepsis and Septic Shock

---

Lines: 1,650+ Citations: 60 PubMed PMIDs Last Updated: January 2026