Skeletal Muscle Physiology

Quick Answer

Skeletal muscle physiology encompasses the structural organization of muscle fibers, molecular mechanisms of contraction, metabolic pathways for energy production, and neuromuscular junction function. Key concepts include:

Structural Organization:

• Sarcomere: Functional unit bounded by Z-lines; contains thick (myosin) and thin (actin) filaments
• Myofilaments: Actin (thin), myosin (thick), titin (elastic), nebulin (scaffolding)
• T-tubules: Transverse tubular invaginations conducting action potentials into fiber interior
• Sarcoplasmic reticulum (SR): Intracellular calcium store; terminal cisternae form triads with T-tubules

Excitation-Contraction Coupling:

• Voltage sensing: Dihydropyridine receptor (DHPR) in T-tubule membrane senses depolarization
• Calcium release: Ryanodine receptor (RYR1) releases Ca2+ from SR into cytoplasm
• Cross-bridge cycling: Myosin heads bind actin, power stroke occurs, ATP causes detachment
• Relaxation: SERCA pump returns Ca2+ to SR; troponin-tropomyosin inhibits cross-bridge formation

Muscle Fiber Types:

• Type I (slow oxidative): Fatigue-resistant, high mitochondria, postural muscles
• Type IIa (fast oxidative-glycolytic): Intermediate, endurance activities
• Type IIx (fast glycolytic): Rapid contraction, low endurance, power movements

ICU Relevance:

• ICUAW: Affects 25-50% of ventilated patients; CIP, CIM, or overlap
• VIDD: Diaphragm atrophy within 18-69 hours of mechanical ventilation
• Rhabdomyolysis: Myoglobin release causing AKI, hyperkalemia
• Malignant hyperthermia: RYR1 mutation causing uncontrolled Ca2+ release; treat with dantrolene

---

CICM First Part Exam Focus

What Examiners Expect

Written SAQ:

Common question stems:

• "Describe the structure of the sarcomere and its role in muscle contraction"
• "Outline the process of excitation-contraction coupling in skeletal muscle"
• "Compare and contrast Type I and Type II muscle fibers"
• "Describe the mechanisms of ATP production in skeletal muscle during exercise"
• "Explain the physiology of the neuromuscular junction"
• "Outline the pathophysiology and management of malignant hyperthermia"

Expected depth:

• Labeled diagrams of sarcomere structure
• Step-by-step description of excitation-contraction coupling
• Quantitative values (sarcomere length 2.0-2.2 um, Ca2+ concentrations)
• Clinical relevance to ICU practice (ICUAW, VIDD, rhabdomyolysis)
• Pharmacology integration (NMBAs, dantrolene)

Written MCQ:

Common topics tested:

• Sarcomere length-tension relationship
• Role of specific contractile proteins (troponin subunits, tropomyosin)
• ATP consumption during contraction cycle
• Fiber type characteristics and enzyme profiles
• Succinylcholine mechanism and adverse effects
• RYR1 receptor physiology

Oral Viva:

Expected discussion flow:

1. Define - Skeletal muscle structure at macroscopic and microscopic levels
2. Describe sarcomere - Z-lines, A-band, I-band, H-zone, M-line
3. Excitation-contraction coupling - DHPR, RYR1, Ca2+ release
4. Sliding filament - Cross-bridge cycling, ATP hydrolysis
5. Energy metabolism - PCr, glycolysis, oxidative phosphorylation
6. Fiber types - Classification, characteristics, clinical relevance
7. Clinical applications - NMBAs, MH, ICUAW, rhabdomyolysis

Common viva scenarios:

• "A patient develops hyperkalemia after succinylcholine. Explain the mechanism"
• "Discuss the pathophysiology of malignant hyperthermia and its treatment"
• "How does immobilization in ICU lead to muscle weakness?"

Pass vs Fail Performance

Pass Standard:

• Accurate description of sarcomere structure with labeled diagram
• Correct sequence of excitation-contraction coupling
• Knowledge of fiber type characteristics
• Understanding of energy metabolism pathways
• Ability to link basic science to ICU clinical scenarios

Common Reasons for Failure:

• Unable to draw and label sarcomere correctly
• Confusion about role of DHPR vs RYR1
• Incorrect understanding of cross-bridge cycle ATP consumption
• Failure to describe Ca2+ handling (SERCA, calsequestrin)
• No knowledge of fiber type differences
• Cannot explain malignant hyperthermia mechanism

---

Key Points

10 Must-Know Facts

1. Sarcomere is the functional unit of striated muscle, bounded by Z-lines; optimal length for force generation is 2.0-2.2 um where actin-myosin overlap is maximal [1,2]

2. Myosin is a hexameric protein with two heavy chains (head + rod) and four light chains; the globular head contains ATPase activity and actin-binding sites [3,4]

3. Troponin complex (TnT binds tropomyosin, TnI inhibits actin-myosin interaction, TnC binds calcium) regulates muscle contraction; Ca2+ binding to TnC relieves tropomyosin inhibition [5,6]

4. DHPR-RYR1 coupling is mechanical in skeletal muscle (conformational change), unlike cardiac muscle where Ca2+-induced Ca2+ release (CICR) predominates [7,8]

5. Each cross-bridge cycle consumes 1 ATP; ~2 ATP per actin-myosin interaction (1 for cycling, 1 for SERCA-mediated Ca2+ reuptake) [9,10]

6. Type I fibers have high myoglobin, mitochondria, and oxidative enzymes (SDH, citrate synthase); express slow myosin heavy chain (MHC-I); fatigue-resistant [11,12]

7. Phosphocreatine (PCr) provides immediate ATP regeneration via creatine kinase for ~10 seconds of maximal effort; glycolysis sustains activity for 2-3 minutes [13,14]

8. Lactate threshold occurs at ~60-70% VO2max when lactate production exceeds clearance; muscle pH falls to 6.4-6.8, impairing glycolytic enzymes and cross-bridge function [15,16]

9. Malignant hyperthermia results from RYR1 mutations causing uncontrolled Ca2+ release; dantrolene blocks RYR1 and reduces cytoplasmic Ca2+, reducing mortality from 70% to <5% [17,18,19]

10. Ventilator-induced diaphragmatic dysfunction (VIDD) causes 50% reduction in diaphragm force-generating capacity within 5-6 days of controlled mechanical ventilation due to proteolysis and oxidative stress [20,21,22]

---

Muscle Structure

Gross Anatomy

Organizational Hierarchy:

WHOLE MUSCLE
     │
     ├── Epimysium (outer connective tissue)
     │
     └── FASCICLES
              │
              ├── Perimysium (fascicle covering)
              │
              └── MUSCLE FIBERS (cells)
                       │
                       ├── Endomysium (individual fiber covering)
                       ├── Sarcolemma (cell membrane)
                       ├── Sarcoplasm (cytoplasm)
                       │
                       └── MYOFIBRILS
                                │
                                └── SARCOMERES (functional units)
                                         │
                                         └── MYOFILAMENTS
                                              ├── Thick (myosin)
                                              └── Thin (actin)

Key Structural Features:

Evidence: PMID: 16890525 (Dulhunty - triadic structure), PMID: 15155374 (Berchtold - muscle calcium signaling) [23,24].

Sarcomere Structure

The sarcomere is the basic contractile unit of striated muscle, bounded by Z-lines (Z-discs). Understanding sarcomere anatomy is fundamental to understanding the sliding filament mechanism of contraction.

Sarcomere Diagram:

                                   SARCOMERE
   ◄────────────────────────────── 2.0-2.5 μm ──────────────────────────────►
   
   Z-line        I-band       A-band        I-band        Z-line
     │              │            │             │              │
     │◄────────────►│◄──────────►│◄───────────►│◄────────────►│
     │              │            │             │              │
     ▼              ▼            ▼             ▼              ▼
   ═════════════════╬════════════╬═════════════╬═════════════════
                    ║            ║             ║
        Thin        ║   Overlap  ║    Thick    ║       Thin
       (Actin)      ║   Region   ║  (Myosin)   ║      (Actin)
                    ║            ║             ║
                    ║     H-zone ║             ║
                    ║    ◄──────►║             ║
                    ║       │    ║             ║
                    ║    M-line  ║             ║
                    ║       │    ║             ║
   ═════════════════╬════════════╬═════════════╬═════════════════
     │              │            │             │              │
     ▲              ▲            ▲             ▲              ▲
     │              │            │             │              │
   Titin         Nebulin     Myosin        Nebulin         Titin
  (elastic)    (scaffolding)  heads      (scaffolding)    (elastic)

Sarcomere Bands and Lines:

Sarcomere Length:

• Resting length: 2.0-2.2 um
• Optimal length for tension: 2.0-2.2 um (maximal actin-myosin overlap)
• Over-stretched: >2.4 um (reduced overlap, reduced tension)
• Over-shortened: <1.6 um (thin filaments collide, reduced tension)

Evidence: PMID: 13165697 (Huxley & Niedergerke 1954 - sliding filament), PMID: 5551390 (Huxley & Simmons 1971 - cross-bridge mechanics) [1,3].

Thick Filaments (Myosin)

Myosin Structure:

                        MYOSIN MOLECULE
                        
        HEAD (S1)                    TAIL (Rod)
   ┌─────────────┐          ┌───────────────────────────┐
   │             │          │                           │
   │  ATPase     │          │      Light meromyosin     │
   │  site       │──────────│         (LMM)             │
   │             │    │     │                           │
   │  Actin      │    │     │      Coiled-coil alpha   │
   │  binding    │    │     │           helix          │
   │  site       │    │     │                           │
   └─────────────┘    │     └───────────────────────────┘
                      │
                 S2 (neck)
                 Flexible hinge
                      │
              ┌───────┴───────┐
              │ Essential     │
              │ light chain   │
              │               │
              │ Regulatory    │
              │ light chain   │
              └───────────────┘

Myosin Components:

Thick Filament Organization:

• Each thick filament: ~300 myosin molecules
• Length: 1.6 um
• Diameter: 15 nm
• Myosin heads project helically: 6 heads per 43 nm repeat
• Bipolar arrangement: heads point away from M-line (bare zone)

Myosin Heavy Chain Isoforms:

Evidence: PMID: 1375931 (Rayment - myosin structure), PMID: 10940255 (Geeves - motor proteins) [25,26].

Thin Filaments (Actin)

Thin Filament Structure:

                     THIN FILAMENT ORGANIZATION
                     
   Actin monomers (G-actin) → Polymerize → F-actin (double helix)
   
        ●──●──●──●──●──●──●──●──●──●──●──●──●──●
       ╱                                        ╲
      ●──●──●──●──●──●──●──●──●──●──●──●──●──●──●
                    │
            ┌───────┴───────┐
            │               │
        Tropomyosin      Troponin
         (rope-like)     (complex)
            │               │
    Blocks myosin      Calcium-sensitive
    binding sites        regulator

Thin Filament Components:

Thin Filament Dimensions:

• Length: ~1.0 um from Z-line
• Diameter: 7 nm
• Actin monomers: 13 per 36 nm half-repeat
• Tropomyosin: 1 per 7 actin monomers
• Troponin: 1 complex per tropomyosin

Calcium Regulation:

RELAXED STATE:                    CONTRACTED STATE:
                                  
 Ca2+ concentration: ~10⁻⁷ M      Ca2+ concentration: ~10⁻⁵ M
        │                                 │
        ▼                                 ▼
 TnC: Ca2+ sites empty            TnC: Ca2+ sites occupied
        │                                 │
        ▼                                 ▼
 TnI: Bound to actin              TnI: Released from actin
        │                                 │
        ▼                                 ▼
 Tropomyosin: Blocks binding      Tropomyosin: Rolled aside
        │                                 │
        ▼                                 ▼
 Myosin: Cannot bind              Myosin: Binds actin
        │                                 │
        ▼                                 ▼
    NO CONTRACTION                    CONTRACTION

Evidence: PMID: 15078109 (Gordon - regulation of contraction), PMID: 12181350 (Tobacman - thin filament regulation) [5,27].

Accessory Proteins

Titin (Connectin):

• Giant protein: ~3.7 MDa (largest known protein)
• Spans half-sarcomere: Z-line to M-line
• Elastic I-band region: passive tension, prevents over-stretch
• A-band region: binds myosin, maintains thick filament position
• Contains immunoglobulin domains and PEVK region (spring-like)
• Mutations cause dilated cardiomyopathy, limb-girdle muscular dystrophy

Nebulin:

• Large protein: ~700 kDa
• Extends along thin filament from Z-line
• Regulates thin filament length
• Contains actin-binding repeats
• Mutations cause nemaline myopathy

Other Accessory Proteins:

Dystrophin-Glycoprotein Complex (DGC):

• Links actin cytoskeleton to extracellular matrix
• Transmits force, protects sarcolemma
• Dystrophin deficiency: Duchenne/Becker muscular dystrophy
• ICU relevance: increased susceptibility to rhabdomyolysis

Evidence: PMID: 12414690 (Granzier - titin), PMID: 7793866 (Labeit - nebulin) [28,29].

T-Tubules and Sarcoplasmic Reticulum

T-Tubule System:

                    TRIAD STRUCTURE
                    
        ◄── Terminal Cisterna (SR) ──►
        
    ═══════════════════════════════════════════
    ║   Ca2+   Ca2+   Ca2+   Ca2+   Ca2+   ║
    ║  storage  │      │      │     storage ║
    ╠═══════════╧══════╧══════╧═════════════╣
    ║           ▼      ▼      ▼             ║
    ║        RYR1   RYR1   RYR1             ║
    ║        ▲▲▲    ▲▲▲    ▲▲▲              ║
    ╠════════╩╩╩════╩╩╩════╩╩╩══════════════╣
              │       │       │
              └───────┼───────┘
                      │
    ═════════════════╤╧╤═════════════════════
                     │ │
                    T-tubule
                     │ │
              DHPR (voltage sensor)
                     │ │
              Action potential
                     │ │
    ─────────────────┴─┴─────────────────────
                SARCOLEMMA

T-Tubule Characteristics:

• Diameter: 20-80 nm
• Location: At A-I junction (mammals)
• Membrane potential: Same as sarcolemma (-80 to -90 mV at rest)
• Key protein: DHPR (dihydropyridine receptor, Cav1.1)
• Function: Rapid action potential conduction into fiber interior

Sarcoplasmic Reticulum:

Key SR Proteins:

Calcium Concentrations:

Evidence: PMID: 16890525 (Dulhunty - T-tubule/SR), PMID: 18156679 (Franzini-Armstrong - ultrastructure) [23,30].

---

Excitation-Contraction Coupling

Overview

Excitation-contraction (E-C) coupling is the process by which electrical excitation of the sarcolemma leads to mechanical contraction. The key steps involve action potential propagation, voltage sensing, calcium release, cross-bridge cycling, and relaxation.

E-C Coupling Sequence:

ACTION POTENTIAL (sarcolemma)
         │
         ▼
T-TUBULE DEPOLARIZATION
         │
         ▼
DHPR CONFORMATIONAL CHANGE (voltage sensing)
         │
    ┌────┴────┐
    │         │
    ▼         ▼
  Skeletal  Cardiac
  (mechanical) (CICR)
    │         │
    ▼         ▼
RYR1 OPENING ─── Ca2+ entry amplifies
         │
         ▼
Ca2+ RELEASE FROM SR (spark → global)
         │
         ▼
Ca2+ BINDS TROPONIN C (10⁻⁵ M threshold)
         │
         ▼
TROPOMYOSIN SHIFTS (exposes myosin binding sites)
         │
         ▼
CROSS-BRIDGE CYCLING (ATP-dependent)
         │
         ▼
FORCE GENERATION / SHORTENING
         │
         ▼
Ca2+ REUPTAKE (SERCA) + Extrusion (NCX, PMCA)
         │
         ▼
RELAXATION

Voltage Sensing: DHPR

Dihydropyridine Receptor (DHPR/Cav1.1):

• L-type voltage-gated calcium channel
• Located in T-tubule membrane
• Heteropentamer: alpha1, alpha2-delta, beta, gamma subunits
• Alpha1 subunit: voltage sensor (S4 segments), pore-forming

Skeletal vs Cardiac DHPR:

Voltage Sensing Mechanism:

1. Depolarization moves S4 segments outward
2. Conformational change transmitted to II-III loop
3. II-III loop directly interacts with RYR1
4. RYR1 opens mechanically (orthograde coupling)
5. Ca2+ can also flow back and affect DHPR (retrograde coupling)

Evidence: PMID: 3016899 (Rios & Brum 1987 - voltage sensor), PMID: 8978804 (Tanabe - DHPR-RYR coupling) [7,31].

Calcium Release: RYR1

Ryanodine Receptor Type 1 (RYR1):

• Largest known ion channel: 2.2 MDa homotetramer
• 4 identical subunits (~565 kDa each)
• Located in junctional SR membrane
• Central pore: ~3 nm diameter when open
• Conductance: ~100 pS (high Ca2+ permeability)

RYR1 Structure:

                    RYANODINE RECEPTOR (RYR1)
                    
      ┌────────────────────────────────────────────────┐
      │                  CYTOPLASMIC                   │
      │                   ("foot")                     │
      │                                                │
      │    DHPR         Calmodulin       FKBP12       │
      │   binding        binding         binding       │
      │     │              │               │           │
      │     ▼              ▼               ▼           │
      │  ═══════════════════════════════════════       │
      │                                                │
      └────────────────────┬───────────────────────────┘
                           │
                    ═══════╧═══════
                           │
                      PORE DOMAIN
                    (transmembrane)
                           │
                     SR LUMEN ─── Calsequestrin binding
                           │     (via triadin/junctin)
                    ═══════════
                      Ca2+ EXIT

RYR1 Regulation:

Calcium Sparks:

• Elementary Ca2+ release events
• Single RYR1 cluster opening
• Amplitude: ~10 uM locally
• Duration: 10-20 ms
• Spatial extent: 2-4 um
• Physiological contraction: summation of multiple sparks

RYR1 Mutations and Malignant Hyperthermia:

• 200 RYR1 mutations identified

• Gain-of-function: increased Ca2+ release sensitivity
• Triggered by volatile anaesthetics (isoflurane, sevoflurane, desflurane)
• Triggered by succinylcholine
• Results in uncontrolled Ca2+ release, muscle rigidity, hypermetabolism

Evidence: PMID: 16407510 (Zalk - RYR structure), PMID: 20413493 (Lanner - RYR1 regulation) [32,33].

Sliding Filament Theory

Cross-Bridge Cycle:

    STATE 1: RIGOR (ATP-free)
    Myosin bound tightly to actin
    (No ATP = rigor mortis)
              │
              ▼ ATP binds
              
    STATE 2: LOW-AFFINITY
    ATP binding reduces actin affinity
    Myosin detaches from actin
              │
              ▼ ATP hydrolysis
              
    STATE 3: COCKED (Pre-power stroke)
    ADP + Pi bound to myosin head
    Myosin head rotated (45°→90°)
    Weak binding to actin
              │
              ▼ Pi release (force generation)
              
    STATE 4: POWER STROKE
    Myosin head rotates (90°→45°)
    Actin slides toward M-line
    ADP released
              │
              ▼ Return to rigor
              
    BACK TO STATE 1
    Cycle repeats ~5 times/second during contraction

Cross-Bridge Energetics:

Key Parameters:

• Power stroke: ~10 nm displacement
• Force per cross-bridge: ~3-4 pN
• Cycle rate: 5-50 cycles/second (fiber type dependent)
• ATP consumption: 1 ATP per cycle
• Duty ratio: 5% (time attached/cycle time)

Length-Tension Relationship:

                    LENGTH-TENSION CURVE
                    
    Force
    (% max)
       │
   100 ┤                    ●●●●●●●
       │                  ●●      ●●
    80 ┤                ●●          ●●
       │              ●●              ●●
    60 ┤            ●●                  ●●
       │          ●●                      ●●
    40 ┤        ●●                          ●●
       │      ●●                              ●●
    20 ┤    ●●                                  ●●
       │  ●●                                      ●●
     0 ┼─●───────┼───────┼───────┼───────┼───────┼──●──
           1.2     1.6     2.0     2.4     2.8     3.2
                         │       │
                   Sarcomere length (μm)
                         │       │
                     OPTIMAL  RESTING
                     (2.0-2.2)  (2.4)

Explanation:

• Below 1.6 um: thin filaments collide, steric hindrance
• 1.6-2.0 um: ascending limb (increasing overlap)
• 2.0-2.2 um: plateau (optimal overlap)
• Above 2.2 um: descending limb (decreasing overlap)
• Above 3.6 um: no overlap, no active tension

Evidence: PMID: 13165697 (Huxley 1954 - sliding filament), PMID: 1381289 (Spudich - myosin motor) [1,34].

Relaxation

Calcium Removal Mechanisms:

SERCA (Sarco/Endoplasmic Reticulum Ca2+-ATPase):

• Type 1a in fast-twitch, Type 2a in slow-twitch
• Pumps 2 Ca2+ from cytoplasm to SR per ATP
• Cycle time: ~100 ms
• Regulated by sarcolipin (skeletal), phospholamban (cardiac)
• Thapsigargin: specific SERCA inhibitor (research tool)

Relaxation Sequence:

1. Action potential terminates
2. DHPR returns to resting conformation
3. RYR1 closes (Ca2+-dependent inactivation)
4. SERCA actively pumps Ca2+ into SR
5. Cytoplasmic [Ca2+] falls to ~100 nM
6. Ca2+ dissociates from TnC
7. Tropomyosin returns to blocking position
8. Cross-bridges detach (requires ATP)
9. Muscle relaxes

Clinical Relevance of Impaired Relaxation:

• ATP depletion (ischemia, rhabdomyolysis): rigor (contracture)
• Phospholamban mutations: cardiomyopathy
• Thyroid hormone: increases SERCA expression
• Dantrolene: reduces Ca2+ release (MH treatment)

Evidence: PMID: 15155374 (Berchtold - Ca2+ signaling), PMID: 17115046 (Periasamy - SERCA regulation) [24,35].

---

Muscle Fiber Types

Classification Systems

Fiber Type Classification:

Type I (Slow Oxidative) Fibers

Characteristics:

Predominant Muscles:

• Postural muscles (erector spinae, soleus)
• Respiratory muscles (diaphragm ~50% Type I)
• Slow-twitch portions of all muscles

Metabolic Profile:

• Primary fuel: fatty acids, glucose
• ATP production: oxidative phosphorylation
• O2 requirement: high
• Lactate production: minimal

Type IIa (Fast Oxidative-Glycolytic) Fibers

Characteristics:

Predominant Muscles:

• Limb muscles used for sustained movement
• Can convert from Type IIx with endurance training

Metabolic Profile:

• Primary fuel: glucose, fatty acids
• ATP production: both oxidative and glycolytic
• Adaptable metabolism based on training

Type IIx (Fast Glycolytic) Fibers

Characteristics:

Predominant Muscles:

• Extraocular muscles
• Laryngeal muscles
• Power muscles (gastrocnemius lateral head)

Metabolic Profile:

• Primary fuel: glucose (glycolytic)
• ATP production: anaerobic glycolysis
• Rapid lactate production
• Rapid fatigue

Fiber Type Comparison

                FIBER TYPE SPECTRUM
                
   FATIGUE                                    POWER
  RESISTANT                                   OUTPUT
      │                                         │
      │    Type I         Type IIa    Type IIx │
      │      │               │           │     │
      │    ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●   │
      │      │               │           │     │
      │    SLOW ────────────────────► FAST    │
      │                                        │
      │    OXIDATIVE ───────────► GLYCOLYTIC   │
      │                                        │
      │    SMALL ───────────────► LARGE        │
      │    MOTOR UNITS          MOTOR UNITS    │
      │                                        │
      │    RECRUITED ──────────► RECRUITED     │
      │    FIRST                    LAST       │

Clinical Relevance

Fiber Type Shifts in Critical Illness:

• ICU patients show Type II → Type I transition
• Loss of Type II fibers with prolonged immobilization
• Denervation causes slow-to-fast transition
• Steroid myopathy preferentially affects Type II fibers
• Mechanical ventilation causes diaphragm fiber type changes

Fiber Type in ICU-Acquired Weakness:

• Selective loss of thick filaments (myosin)
• Type II fibers more affected in CIM
• Myosin heavy chain downregulation
• Atrophy more pronounced in Type II

Evidence: PMID: 2006076 (Pette - fiber types), PMID: 24108524 (Puthucheary - ICU atrophy) [11,20].

---

Energy Metabolism

ATP Sources

Energy Systems Timeline:

     INTENSITY
         │
     MAX ┼──────●●●●●
         │     PCr
         │     System
         │     (10 sec)
         │              ●●●●●●●●●●
         │              Glycolysis
         │              (2-3 min)
         │                         ●●●●●●●●●●●●●●●●●●●●●●●
     LOW ┼                         Oxidative Phosphorylation
         │                         (hours)
         └───────┬───────┬───────┬───────┬───────┬───────
                10s     30s      2m      10m     60m    Time

Immediate Energy: Phosphocreatine System

Creatine Kinase Reaction:

PCr + ADP ⇌ Cr + ATP

Kₑq = [Cr][ATP] / [PCr][ADP] ≈ 100

Direction favors ATP synthesis at rest
Reverses during recovery

Phosphocreatine System Characteristics:

Creatine Kinase Isoforms:

• CK-MM: Skeletal muscle (cytoplasmic)
• CK-MB: Cardiac muscle
• CK-BB: Brain
• Mi-CK: Mitochondrial (energy shuttle)

Clinical Relevance:

• CK elevation: muscle damage marker
• PCr/ATP ratio: muscle energetic status (MR spectroscopy)
• Creatine supplementation: increases PCr stores

Short-Term Energy: Anaerobic Glycolysis

Glycolytic Pathway Overview:

GLUCOSE (blood) ─► GLUT4 ─► GLUCOSE (cytoplasm)
                              │
                         Hexokinase + ATP
                              │
                              ▼
                     GLUCOSE-6-PHOSPHATE
                              │
                         (10 steps)
                              │
                              ▼
                    2 PYRUVATE + 2 NADH + 2 ATP (net)
                              │
              ┌───────────────┴───────────────┐
              │                               │
          AEROBIC                         ANAEROBIC
              │                               │
          PDH ─► Acetyl-CoA                  LDH
              │                               │
          TCA + ETC                           │
              │                               ▼
          36-38 ATP                       2 LACTATE

Glycolysis Characteristics:

Key Regulatory Enzymes:

• Hexokinase: inhibited by G6P (product inhibition)
• Phosphofructokinase-1 (PFK-1): rate-limiting; inhibited by ATP, citrate; activated by AMP, ADP, Pi, F-2,6-BP
• Pyruvate kinase: inhibited by ATP, acetyl-CoA

Lactate Metabolism:

• Produced by LDH: pyruvate + NADH → lactate + NAD+
• Regenerates NAD+ for continued glycolysis
• Shuttle to liver (Cori cycle) and heart for oxidation
• Not causative of acidosis (H+ from ATP hydrolysis)

Long-Term Energy: Oxidative Phosphorylation

Oxidative Pathway:

SUBSTRATE SOURCES
       │
       ├── Carbohydrates ─► Pyruvate ─► Acetyl-CoA
       │                                    │
       ├── Fatty acids ─────► β-oxidation ──┤
       │                                    │
       └── Amino acids ─────► Deamination ──┘
                                            │
                                            ▼
                                     TCA CYCLE
                                            │
                                      NADH, FADH2
                                            │
                                            ▼
                           ELECTRON TRANSPORT CHAIN
                                            │
                                    O2 → H2O
                                            │
                                            ▼
                                   ATP SYNTHASE
                                            │
                                  36-38 ATP/glucose
                                  ~100 ATP/palmitate

Oxidative Phosphorylation Characteristics:

Substrate Utilization:

Muscle Fatigue

Definition: Muscle fatigue is the decline in force-generating capacity during sustained or repeated activity.

Peripheral Fatigue Mechanisms:

Metabolic Factors in Fatigue:

                    METABOLIC FATIGUE FACTORS
                    
    ATP depletion ───► Not major cause (ATP falls <30%)
         │
         ▼
    PCr depletion ───► Early indicator, but not causative
         │
         ▼
    Pi accumulation ───► Major factor
         │              Inhibits cross-bridge force
         │              Reduces Ca2+ sensitivity
         │              Precipitates with Ca2+ in SR
         │
         ▼
    H+ accumulation ───► Moderate effect
         │              Inhibits PFK-1
         │              Reduces Ca2+ binding to TnC
         │              pH 6.4-6.8 at exhaustion
         │
         ▼
    K+ accumulation ───► Reduces membrane excitability
         │              [K+]e increases from 4 to 8-10 mM
         │              Depolarizes muscle fibers
         │
         ▼
    Glycogen depletion ───► Limits substrate for prolonged exercise

Central Fatigue:

• Reduced motor cortex output
• Reduced spinal motoneuron drive
• Mediated by serotonin, dopamine pathways
• Contributes 20-30% to fatigue during prolonged exercise

Evidence: PMID: 18391181 (Allen - fatigue mechanisms), PMID: 19118096 (Fitts - lactate and fatigue) [15,36].

---

Neuromuscular Junction Physiology

Structure

Neuromuscular Junction Anatomy:

                    MOTOR NEURON
                         │
                    AXON │
                         ▼
    ═══════════════════════════════════════════════
                   SYNAPTIC CLEFT (50 nm)
    ═══════════════════════════════════════════════
         ▲      ▲      ▲      ▲      ▲
        ACh    ACh    ACh    ACh    ACh
         │      │      │      │      │
         ▼      ▼      ▼      ▼      ▼
    ┌─────────────────────────────────────────────┐
    │         JUNCTIONAL FOLDS                    │
    │     ╭──╮ ╭──╮ ╭──╮ ╭──╮ ╭──╮              │
    │     │  │ │  │ │  │ │  │ │  │              │
    │     │  │ │  │ │  │ │  │ │  │              │
    │     │nAChR│ │nAChR│ │nAChR│              │
    │     │  │ │  │ │  │ │  │ │  │              │
    │     ╰──╯ ╰──╯ ╰──╯ ╰──╯ ╰──╯              │
    │     ▲    Nav channels at fold depths       │
    │     │                                       │
    └─────┼───────────────────────────────────────┘
          │
    MOTOR END PLATE (muscle fiber)

NMJ Components:

Acetylcholine Synthesis and Release

ACh Synthesis:

CHOLINE + ACETYL-CoA ──ChAT──► ACETYLCHOLINE + CoA

ChAT = Choline acetyltransferase (cytoplasmic enzyme)
Choline: High-affinity Na+-dependent uptake (rate-limiting)
Acetyl-CoA: From glucose/pyruvate metabolism

Vesicle Dynamics:

• ~10,000 synaptic vesicles per nerve terminal
• ~10,000 ACh molecules per vesicle (1 quantum)
• Readily releasable pool: ~1,000 vesicles
• Reserve pool: ~9,000 vesicles

Calcium-Triggered Release:

ACTION POTENTIAL ARRIVES
         │
         ▼
Voltage-gated Ca2+ channels open (Cav2.1, P/Q type)
         │
         ▼
Ca2+ enters terminal (peak ~100 μM at active zones)
         │
         ▼
Ca2+ binds synaptotagmin (vesicle Ca2+ sensor)
         │
         ▼
SNARE complex formation
(Synaptobrevin + Syntaxin + SNAP-25)
         │
         ▼
Vesicle fusion and ACh release (exocytosis)
         │
         ▼
~200 vesicles released per AP (quantal content)

Clinical Relevance:

• Botulinum toxin: cleaves SNARE proteins, prevents ACh release
• Lambert-Eaton syndrome: antibodies to presynaptic Ca2+ channels
• Aminoglycosides: reduce Ca2+ entry, impair release

Nicotinic Acetylcholine Receptor

nAChR Structure:

                    NICOTINIC RECEPTOR
                    
          EXTRACELLULAR VIEW (top)
          
                    ●●●●●●●●
                ●●●●        ●●●●
              ●●      ACh      ●●
             ●●    binding     ●●
            ●●       ↓          ●●
           ●●   ┌─────────┐     ●●
           ●●   │         │     ●●
            ●●  │  PORE   │    ●●
             ●● │ (closed)│   ●●
              ●●│         │  ●●
                └─────────┘
                ●●●●●●●●●●
                
          α  γ      α  δ
           ╲│      │╱
            ●──────●
           ╱        ╲
          ε          β
          
    5 subunits: 2α, 1β, 1δ, 1ε (adult)
                2α, 1β, 1δ, 1γ (fetal)

nAChR Characteristics:

Receptor Activation:

1. ACh binds to both α-subunits (required for opening)
2. Conformational change opens central pore
3. Na+ influx, K+ efflux (net depolarization)
4. End-plate potential (EPP) generated
5. EPP amplitude: ~70-80 mV (well above threshold)
6. Safety factor: EPP 3-4× threshold for action potential

Receptor Desensitization:

• Prolonged ACh exposure causes desensitization
• Channel enters closed, unresponsive state
• Important in Phase II block with succinylcholine
• Recovery requires ACh removal and time

Evidence: PMID: 12024216 (Sine - nAChR structure), PMID: 15082768 (Engel - NMJ disorders) [37,38].

Signal Termination

Acetylcholinesterase (AChE):

ACh + H2O ──AChE──► CHOLINE + ACETATE

Location: Basal lamina, concentrated in synaptic cleft
Turnover: 10,000 ACh molecules/second (fastest enzyme known)
Effect: Terminates neuromuscular transmission in <5 ms

AChE Inhibitors:

Clinical Correlations

Myasthenia Gravis:

• Autoimmune antibodies to nAChR (80-85%)
• Reduced receptor number
• Fatigable weakness
• Decremental response on repetitive nerve stimulation
• Treatment: AChE inhibitors, immunosuppression, thymectomy

Lambert-Eaton Myasthenic Syndrome:

• Antibodies to presynaptic Cav2.1 (P/Q) channels
• Reduced ACh release
• Weakness improves with activity (facilitation)
• Incremental response on repetitive nerve stimulation
• Associated with small cell lung cancer

Congenital Myasthenic Syndromes:

• Genetic defects in NMJ proteins
• Presynaptic (ChAT, vesicle release), synaptic (AChE), postsynaptic (nAChR, rapsyn)
• Variable response to treatment depending on mutation

Evidence: PMID: 15082768 (Engel - NMJ disorders), PMID: 10209159 (Maselli - myasthenic syndromes) [38,39].

---

ICU Relevance

ICU-Acquired Weakness (ICUAW)

Definition: Generalized weakness developing after critical illness onset, MRC sum score <48/60, not explained by other causes.

Epidemiology:

• Incidence: 25-50% in patients ventilated ≥7 days
• Incidence with sepsis: 50-100%
• Associated with increased mortality (OR 1.5-2.0)
• Prolongs ICU stay by 7-10 days

Subtypes:

Risk Factors:

• Sepsis and MODS
• Prolonged mechanical ventilation
• Hyperglycemia
• Corticosteroids + NMBAs (synergistic risk OR 14.9)
• Immobilization
• Aminoglycosides

Pathophysiology:

• Microvascular dysfunction causing axonal degeneration (CIP)
• Sodium channelopathy with muscle membrane inexcitability
• Selective myosin heavy chain degradation
• Ubiquitin-proteasome pathway activation
• Mitochondrial dysfunction

Prevention:

• Early mobilization (PADIS guidelines)
• Glycemic control (NICE-SUGAR: target ≤180 mg/dL)
• Minimize NMBAs (<48 hours)
• Corticosteroid stewardship
• Nutritional optimization

Evidence: PMID: 19826024 (Stevens - ICUAW definition), PMID: 12479764 (De Jonghe - CRIMYNE) [40,41].

Ventilator-Induced Diaphragmatic Dysfunction (VIDD)

Definition: Diaphragm weakness resulting from mechanical ventilation, independent of sepsis or systemic inflammation.

Epidemiology:

• Develops within 18-69 hours of controlled mechanical ventilation
• 50% reduction in diaphragm force by day 5-6
• Contributes to weaning failure in 30-50% of difficult weans

Mechanisms:

MECHANICAL VENTILATION (controlled mode)
         │
         ▼
DIAPHRAGM UNLOADING (disuse)
         │
         ├──► Decreased protein synthesis
         │
         ├──► Increased proteolysis
         │     (ubiquitin-proteasome, calpains, caspase-3)
         │
         ├──► Mitochondrial dysfunction
         │     (oxidative stress)
         │
         ├──► Fiber atrophy
         │     (Type I and II)
         │
         └──► Sarcomeric disruption
                   │
                   ▼
         REDUCED CONTRACTILE FORCE

Levine et al. 2008 (Landmark Study):

• PMID: 18725455
• Diaphragm biopsies in brain-dead organ donors
• 18-69 hours of CMV caused:
  • 57% decrease in cross-sectional area of slow fibers
  • 53% decrease in fast fibers
  • Increased caspase-3 activity (4× controls)
  • Increased ubiquitin-proteasome activity

Prevention and Management:

• Minimize controlled ventilation duration
• Use pressure support or spontaneous modes early
• Inspiratory muscle training (controversial)
• Phrenic nerve stimulation (investigational)
• Avoid excessive sedation

Evidence: PMID: 18725455 (Levine 2008), PMID: 29558388 (Dres - VIDD review) [21,42].

Rhabdomyolysis

Definition: Syndrome resulting from skeletal muscle breakdown with release of intracellular contents into circulation.

Etiology in ICU:

Pathophysiology:

MUSCLE INJURY
     │
     ▼
Sarcolemma damage
     │
     ├──► Ca2+ influx
     │        │
     │        ▼
     │    Proteolysis (calpains, caspases)
     │    Mitochondrial dysfunction
     │        │
     │        ▼
     │    ATP depletion
     │        │
     └────────┤
              ▼
     CELL CONTENTS RELEASED
              │
     ┌────────┼────────┬────────┬────────┐
     │        │        │        │        │
     ▼        ▼        ▼        ▼        ▼
  Myoglobin   CK      K+       PO4    Uric acid
     │
     ▼
  AKI (heme pigment nephropathy)

Diagnosis:

• CK >5× upper limit normal (usually >10,000 U/L)
• Myoglobinuria (positive dipstick for blood, no RBCs)
• Peak CK at 24-72 hours

Complications:

• Acute kidney injury (15-50%)
• Hyperkalemia (cardiac arrest risk)
• Hypocalcemia (calcium sequestration in muscle)
• DIC (10%)
• Compartment syndrome

Management:

• Aggressive fluid resuscitation (200-500 mL/hr initially)
• Target urine output >200-300 mL/hr
• Correct electrolytes (avoid calcium unless symptomatic)
• Alkalinization controversial (no RCT evidence)
• RRT for refractory AKI, hyperkalemia

Evidence: PMID: 19318938 (Cervellin - rhabdomyolysis), PMID: 15165252 (Bosch - AKI in rhabdomyolysis) [43,44].

Malignant Hyperthermia

Definition: Pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic crisis triggered by volatile anesthetics and succinylcholine.

Epidemiology:

• Incidence: 1:10,000-15,000 anesthetics (higher in children)
• Mortality without treatment: 70-80%
• Mortality with dantrolene: <5%

Genetics:

• Autosomal dominant inheritance
• RYR1 mutations (70% of cases): >400 variants identified
• CACNA1S mutations (1%): DHPR alpha1 subunit
• Other loci implicated

Pathophysiology:

TRIGGERING AGENT
(Volatile anesthetic or succinylcholine)
         │
         ▼
RYR1 ACTIVATION (mutant receptor)
         │
         ▼
UNCONTROLLED Ca2+ RELEASE from SR
         │
         ▼
SUSTAINED MUSCLE CONTRACTION
         │
     ┌───┴───┐
     │       │
     ▼       ▼
 ATP consumption    Myofibrillar damage
 (cross-bridge       (Ca2+ overload)
  cycling)                │
     │                    │
     ▼                    ▼
 HYPERMETABOLISM     RHABDOMYOLYSIS
     │                    │
     ├──► ↑CO2 production │
     │    ↑O2 consumption │
     │    ↑Heat production│
     │         │          │
     └─────────┼──────────┘
               ▼
         CLINICAL SYNDROME
         - Hyperthermia (late sign)
         - Muscle rigidity
         - Tachycardia
         - Hypercarbia
         - Acidosis
         - Hyperkalemia
         - Myoglobinuria

Clinical Features:

Management:

IMMEDIATE ACTIONS:
1. STOP TRIGGER AGENTS immediately
2. Hyperventilate with 100% O2 (high flows)
3. Call for HELP and MH cart
4. DANTROLENE 2.5 mg/kg IV bolus
   - Repeat every 5 min until signs resolve
   - May need 10-20 mg/kg total
   - Continue 1 mg/kg q4-6h × 24-48 hours

SUPPORTIVE MEASURES:
5. Active cooling (target <38.5°C)
   - Cold IV saline, ice packs, cooling blankets
6. Treat hyperkalemia (Ca2+, glucose/insulin, HCO3-)
7. Maintain urine output >2 mL/kg/hr
8. Avoid calcium channel blockers (with dantrolene)
9. Monitor for DIC, AKI
10. ICU admission for observation

Dantrolene Mechanism:

DANTROLENE (lipophilic)
         │
         ▼
Binds to RYR1 (N-terminal region)
         │
         ▼
Reduces RYR1 open probability
         │
         ▼
↓Ca2+ release from SR
         │
         ▼
↓Cytoplasmic [Ca2+]
         │
         ▼
↓Muscle contraction
↓ATP consumption
↓Heat production
         │
         ▼
RESOLUTION OF MH CRISIS

Dantrolene Pharmacology:

Susceptibility Testing:

• Gold standard: Caffeine-halothane contracture test (invasive)
• Genetic testing: Identifies ~70% of susceptible individuals
• First-degree relatives: 50% risk

Evidence: PMID: 26226437 (Rosenberg - MH review), PMID: 18156679 (Hopkins - dantrolene) [17,45].

---

Neuromuscular Blocking Agents

Classification

NMBAs by Mechanism:

Succinylcholine (Suxamethonium)

Mechanism:

SUCCINYLCHOLINE (2 ACh molecules linked)
         │
         ▼
Binds nAChR (agonist)
         │
         ▼
Opens ion channel (Na+ influx)
         │
         ▼
Depolarization of motor end plate
         │
         ▼
PHASE I BLOCK
- Fasciculations (unsynchronized depolarization)
- Flaccid paralysis (sustained depolarization)
- No fade on TOF
- Potentiated by anticholinesterases
         │
         ▼
Prolonged/repeated exposure
         │
         ▼
PHASE II BLOCK
- Receptor desensitization
- Fade on TOF (resembles non-depolarizing)
- Reversed by anticholinesterases

Pharmacokinetics:

Adverse Effects:

Contraindications:

Hyperkalemia Risk:

Non-Depolarizing Agents

Mechanism:

NON-DEPOLARIZING NMBA
         │
         ▼
Competitive binding to nAChR α-subunits
         │
         ▼
Prevents ACh binding
         │
         ▼
No depolarization
         │
         ▼
FLACCID PARALYSIS
- No fasciculations
- Fade on TOF
- Reversed by anticholinesterases (increase ACh)
- Reversed by sugammadex (aminosteroids only)

Comparison of Agents:

Hofmann Degradation:

• Spontaneous, non-enzymatic breakdown
• pH and temperature dependent
• Organ-independent elimination
• Preferred in renal/hepatic failure
• Laudanosine metabolite (atracurium) may accumulate with prolonged use

Reversal Agents

Neostigmine:

NEOSTIGMINE
     │
     ▼
Inhibits acetylcholinesterase (reversible)
     │
     ▼
↑ACh concentration at NMJ
     │
     ▼
Overcomes competitive block
     │
     ▼
REVERSAL OF PARALYSIS

Dose: 0.04-0.07 mg/kg (max 5 mg)
Co-administer: Glycopyrrolate 0.2 mg per 1 mg neostigmine
(prevents muscarinic effects)

Sugammadex:

SUGAMMADEX (modified γ-cyclodextrin)
     │
     ▼
Encapsulates rocuronium/vecuronium
(1:1 complex formation)
     │
     ▼
Reduces free NMBA concentration
     │
     ▼
Rapid reversal (within minutes)
     │
     ▼
Complex excreted renally (unchanged)

Dosing:
- Moderate block (TOF 1-2): 2 mg/kg
- Deep block (PTC 1-2): 4 mg/kg
- Immediate reversal: 16 mg/kg

Sugammadex vs Neostigmine:

Evidence: PMID: 20843245 (ACURASYS), PMID: 31112381 (ROSE) [46,47].

---

SAQ Practice Questions

SAQ 1: Excitation-Contraction Coupling

Question:

A 45-year-old patient requires intubation for severe ARDS. You plan to use rocuronium as the neuromuscular blocking agent.

(a) Describe the structure of the sarcomere and identify the key proteins involved in muscle contraction. (6 marks)

(b) Outline the process of excitation-contraction coupling in skeletal muscle, from action potential to cross-bridge cycling. (8 marks)

(c) Explain the mechanism by which rocuronium causes muscle paralysis. (6 marks)

Model Answer:

(a) Sarcomere Structure (6 marks)

The sarcomere is the basic contractile unit of striated muscle, bounded by Z-lines.

Key Contractile Proteins:

• Myosin: Thick filament, hexameric (2 heavy chains, 4 light chains), contains ATPase activity and actin-binding sites in globular head
• Actin: Thin filament backbone, globular monomers polymerized into F-actin double helix
• Tropomyosin: Blocks myosin binding sites in relaxed state
• Troponin complex: TnC binds calcium, TnI inhibits actin-myosin, TnT binds tropomyosin

(b) Excitation-Contraction Coupling (8 marks)

Step 1 - Action Potential Propagation:

• Action potential travels along sarcolemma and into T-tubules
• T-tubules conduct depolarization deep into fiber

Step 2 - Voltage Sensing:

• DHPR (dihydropyridine receptor) in T-tubule membrane senses depolarization
• Conformational change in DHPR II-III loop

Step 3 - Calcium Release:

• DHPR mechanically couples to RYR1 in SR membrane
• RYR1 opens, releasing Ca2+ from SR into cytoplasm
• [Ca2+] rises from 50-100 nM to 1-10 uM

Step 4 - Troponin-Tropomyosin Shift:

• Ca2+ binds to TnC (4 binding sites)
• Conformational change releases TnI from actin
• Tropomyosin rolls aside, exposing myosin binding sites

Step 5 - Cross-Bridge Cycling:

• Myosin-ADP-Pi binds weakly to actin
• Pi release triggers power stroke (10 nm displacement)
• ADP release, rigor state
• ATP binds, myosin detaches
• ATP hydrolysis re-cocks myosin head
• Cycle repeats ~5 times/second

Step 6 - Relaxation:

• SERCA pumps Ca2+ back into SR (2 Ca2+ per ATP)
• Cytoplasmic [Ca2+] falls to 50-100 nM
• Ca2+ dissociates from TnC
• Tropomyosin returns to blocking position
• Cross-bridges detach

(c) Rocuronium Mechanism (6 marks)

Mechanism of Action: Rocuronium is a non-depolarizing (competitive) neuromuscular blocking agent.

• Receptor binding: Binds to α-subunits of nicotinic acetylcholine receptor at neuromuscular junction
• Competitive antagonism: Competes with acetylcholine for receptor binding
• No depolarization: Unlike succinylcholine, does not activate the receptor
• Dose-response: Blockade is proportional to receptor occupancy

Characteristics:

• Requires >75% receptor occupancy for clinical effect (safety margin)
• No fasciculations
• Fade on train-of-four stimulation
• Reversed by increasing ACh (neostigmine) or encapsulation (sugammadex)

Pharmacokinetics:

• Onset: 60-90 seconds at intubating dose (1.0-1.2 mg/kg)
• Duration: 45-70 minutes
• Aminosteroid structure
• Primarily hepatic elimination (70%)

---

SAQ 2: Malignant Hyperthermia

Question:

During an elective laparoscopic cholecystectomy under general anesthesia with sevoflurane, the anesthetist notices unexplained rising end-tidal CO2, tachycardia, and muscle rigidity.

(a) Describe the pathophysiology of malignant hyperthermia at the molecular level. (6 marks)

(b) Outline the clinical features and diagnosis of malignant hyperthermia. (6 marks)

(c) Describe the management of this patient, including the mechanism of action of dantrolene. (8 marks)

Model Answer:

(a) Pathophysiology (6 marks)

Genetic Basis:

• Autosomal dominant inheritance
• RYR1 gene mutations (70% of cases): >400 variants identified
• CACNA1S mutations (1%): DHPR alpha1 subunit

Molecular Mechanism:

1. Triggering agents (volatile anesthetics, succinylcholine) interact with mutant RYR1
2. Abnormal RYR1 gating: Mutant receptor has increased sensitivity to activation
3. Uncontrolled Ca2+ release from sarcoplasmic reticulum
4. Massive cytoplasmic [Ca2+] elevation: Exceeds SERCA reuptake capacity
5. Sustained muscle contraction: Cross-bridge cycling consumes ATP
6. Hypermetabolic state:
   • ↑ATP consumption → ↑glycolysis → lactate production
   • ↑O2 consumption
   • ↑CO2 production
   • ↑Heat production (ATP hydrolysis + futile Ca2+ cycling)
7. Muscle breakdown: Ca2+ overload activates proteases (calpains)

(b) Clinical Features and Diagnosis (6 marks)

Early Signs:

• Unexplained rising EtCO2 (most sensitive early sign)
• Masseter spasm (especially after succinylcholine)
• Tachycardia
• Mixed respiratory and metabolic acidosis
• Muscle fasciculations

Late Signs:

• Hyperthermia (>40°C) - often a late sign
• Generalized muscle rigidity
• Rhabdomyolysis (elevated CK, myoglobinuria)
• Hyperkalemia
• DIC
• Cardiac arrhythmias/arrest

Laboratory Findings:

• ↑EtCO2, ↑PaCO2
• Metabolic acidosis (lactate >4 mmol/L)
• ↑CK (delayed, peaks at 12-24 hours)
• Hyperkalemia
• Myoglobinuria

Diagnostic Confirmation:

• Clinical diagnosis during crisis (treat empirically)
• Caffeine-halothane contracture test (CHCT): Gold standard, invasive
• Genetic testing: Identifies ~70% of susceptible individuals

(c) Management and Dantrolene (8 marks)

Immediate Actions:

1. STOP triggering agents immediately (turn off vaporizer)
2. Call for help and MH cart/dantrolene
3. Hyperventilate with 100% O2 at high fresh gas flows
4. Switch to clean anesthesia circuit or use activated charcoal filters

Dantrolene Administration: 5. Dantrolene 2.5 mg/kg IV bolus

• Repeat every 5 minutes until signs resolve
• May require 10-20 mg/kg total (no ceiling dose in crisis)
• Continue 1 mg/kg q4-6h for 24-48 hours

Mechanism of Dantrolene:

• Lipophilic compound that crosses sarcolemma
• Binds to N-terminal region of RYR1
• Reduces RYR1 open probability
• Decreases Ca2+ release from SR
• Lowers cytoplasmic [Ca2+]
• Reduces muscle contraction, ATP consumption, heat production

Supportive Measures: 6. Active cooling (target <38.5°C):

• Cold IV saline (not LR - K+ containing)
• Ice packs to axillae, groin
• Cooling blankets
• Peritoneal/bladder lavage if needed

7. Treat hyperkalemia:

   • Calcium gluconate/chloride (cardiac protection)
   • Glucose 50 g + insulin 10 units IV
   • Sodium bicarbonate 1-2 mmol/kg
   • Consider RRT

8. Maintain urine output >2 mL/kg/hr (myoglobin protection)

9. Avoid calcium channel blockers (hyperkalemia with dantrolene)

10. ICU admission for monitoring ×24-48 hours

Post-Crisis:

• Refer to MH hotline and testing center
• Genetic counseling and family testing
• Medic-Alert bracelet
• Document and communicate to all future providers

---

Viva Scenarios

Viva 1: Muscle Physiology and ICUAW

Examiner: "A 62-year-old man has been in ICU for 3 weeks following severe pneumonia and septic shock. He is now awake but cannot lift his limbs against gravity. Tell me about the physiology of skeletal muscle contraction."

Candidate: "Skeletal muscle contraction involves the conversion of electrical excitation to mechanical force through excitation-contraction coupling.

The fundamental unit is the sarcomere, bounded by Z-lines, containing thick filaments of myosin and thin filaments of actin with regulatory proteins tropomyosin and troponin.

The sequence begins when an action potential travels along the sarcolemma and into T-tubules. The DHPR, a voltage-sensitive calcium channel in the T-tubule membrane, senses depolarization and undergoes a conformational change. In skeletal muscle, this mechanically couples to the RYR1 receptor on the sarcoplasmic reticulum, causing it to open and release calcium.

The rise in cytoplasmic calcium from 100 nanomolar to approximately 10 micromolar causes calcium to bind troponin C. This shifts tropomyosin, exposing myosin binding sites on actin. Cross-bridge cycling then occurs - myosin heads bind actin, undergo the power stroke upon phosphate release, and detach when ATP binds. Each cycle consumes one ATP molecule.

Relaxation occurs when SERCA pumps calcium back into the SR at a cost of 2 calcium ions per ATP, lowering cytoplasmic calcium and allowing tropomyosin to return to its blocking position."

Examiner: "Good. Now explain what has happened to this patient's muscles."

Candidate: "This patient likely has ICU-acquired weakness, specifically critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or an overlap of both.

The pathophysiology involves multiple mechanisms:

For CIP, there is microvascular dysfunction in peripheral nerves leading to endoneurial edema and axonal degeneration. Cytokines and oxidative stress damage the nerve.

For CIM, which is more common, there is:

1. Selective loss of myosin heavy chains through activation of the ubiquitin-proteasome pathway
2. Sodium channelopathy causing muscle membrane inexcitability
3. Mitochondrial dysfunction
4. Calpain-mediated proteolysis

Risk factors include sepsis, which he had, hyperglycemia, corticosteroids combined with neuromuscular blocking agents, and prolonged immobilization. The De Jonghe CRIMYNE study showed corticosteroids plus NMBAs have a synergistic effect with an odds ratio of 14.9.

The muscle wasting occurs rapidly - Puthucheary's 2013 study showed 17.7% loss of rectus femoris cross-sectional area by day 10 in ventilated patients."

Examiner: "How would you differentiate CIP from CIM clinically and electrophysiologically?"

Candidate: "Clinically, both present with symmetrical proximal and distal weakness, facial sparing, and difficulty weaning from mechanical ventilation. CIP has more sensory involvement and areflexia, while CIM may have preserved reflexes early on.

The key differentiation is electrophysiological:

In CIP, nerve conduction studies show reduced compound muscle action potential (CMAP) amplitude AND reduced sensory nerve action potential (SNAP) amplitude, indicating a sensory-motor axonal polyneuropathy.

In CIM, nerve conduction studies show reduced CMAP amplitude but normal SNAP amplitude - this is because the sensory nerves are spared and the problem is in the muscle itself.

Direct muscle stimulation can further differentiate: in CIP, direct muscle stimulation produces normal muscle contraction because the muscle is healthy; in CIM, direct stimulation produces reduced response because the muscle is the problem.

Muscle ultrasound can show reduced cross-sectional area and increased echogenicity in CIM.

The definitive diagnosis of CIM requires muscle biopsy showing selective myosin heavy chain loss with relative preservation of actin, but this is rarely performed clinically."

Examiner: "What prevention strategies could have been employed?"

Candidate: "Prevention is the cornerstone of ICUAW management. Key strategies include:

1. Early mobilization - recommended by PADIS 2018 guidelines as a conditional recommendation with low quality evidence. The ABCDEF bundle includes 'E' for early mobility and exercise. The aim is to maintain muscle activity and prevent disuse atrophy.

2. Glycemic control - target glucose less than or equal to 180 mg/dL based on NICE-SUGAR trial, avoiding tight control which increases hypoglycemia risk without benefit.

3. Minimize neuromuscular blocking agents - limit to less than 48 hours when possible. The ACURASYS trial showed benefit of 48-hour cisatracurium in early severe ARDS, but the ROSE trial showed no benefit with modern light sedation practices.

4. Corticosteroid stewardship - use lowest dose for shortest duration. The synergistic risk with NMBAs is well documented.

5. Nutritional optimization - adequate protein delivery (1.2-2 g/kg/day) though evidence for benefit in preventing ICUAW is limited.

6. Minimize sedation - daily sedation interruption and targeting light sedation reduces immobility duration.

For Indigenous Australian patients specifically, we should consider that they have 2-3 times higher rates of sepsis and may face barriers to prolonged rehabilitation post-discharge, so involving Aboriginal Health Workers and liaison officers early in care planning is essential."

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Viva 2: Malignant Hyperthermia

Examiner: "You are called urgently to the operating theater. A 28-year-old man is undergoing appendectomy under general anesthesia with sevoflurane. The anesthetist is concerned because the end-tidal CO2 has risen from 35 to 65 mmHg despite increasing minute ventilation. What are your thoughts?"

Candidate: "This presentation is highly concerning for malignant hyperthermia. An unexplained rise in end-tidal CO2 despite adequate ventilation is the most sensitive early sign of MH.

I would immediately:

1. Assess for other MH signs - tachycardia, muscle rigidity, temperature
2. If suspicion is high, treat empirically before confirmation

Other causes of rising EtCO2 to consider include:

• Insufficient ventilation (airway obstruction, circuit disconnect - unlikely if minute ventilation is increased)
• Increased metabolism (sepsis, thyrotoxicosis - less acute)
• CO2 insufflation absorption (laparoscopy)
• Soda lime exhaustion
• MH is the diagnosis of exclusion that requires immediate treatment."

Examiner: "The patient also has masseter spasm, heart rate is 140, and feels warm. What is the underlying pathophysiology?"

Candidate: "Malignant hyperthermia is a pharmacogenetic disorder caused by mutations in the RYR1 ryanodine receptor in approximately 70% of cases, or CACNA1S encoding the DHPR in about 1%.

When a susceptible individual is exposed to triggering agents - volatile anesthetics like sevoflurane, or succinylcholine - the mutant RYR1 has abnormally increased sensitivity to activation.

This causes uncontrolled calcium release from the sarcoplasmic reticulum into the cytoplasm. The calcium cannot be adequately cleared by SERCA pumps, leading to:

1. Sustained muscle contraction - cross-bridge cycling requires ATP, explaining the rigidity
2. Hypermetabolism - massive ATP consumption drives increased glycolysis, producing lactate and CO2
3. Heat production - ATP hydrolysis and futile calcium cycling generate heat
4. Rhabdomyolysis - calcium overload activates calpains and other proteases, causing myofilament destruction

The hyperthermia is actually a late sign - the temperature can rise by 1-2°C every 5 minutes in fulminant cases, but early recognition should be based on unexplained hypercarbia, tachycardia, and rigidity."

Examiner: "Walk me through your management."

Candidate: "This is a medical emergency requiring immediate action:

Immediate priorities:

1. Stop all triggering agents - turn off sevoflurane, switch to IV anesthesia (propofol, opioids)
2. Call for help - summon additional personnel and the MH cart
3. Hyperventilate with 100% oxygen at high fresh gas flows (10+ L/min) to wash out volatile and clear CO2
4. Consider using activated charcoal filters on the circuit if available

Definitive treatment: 5. Dantrolene 2.5 mg/kg IV bolus - this is the specific treatment

• Repeat every 5 minutes until signs resolve
• May need up to 10-20 mg/kg total - there is no ceiling dose in crisis
• Each 20mg vial needs reconstitution in 60 mL sterile water, so this is labor-intensive
• Ryanodex (250 mg/vial) is an alternative preparation that's easier to prepare

Mechanism of dantrolene: Dantrolene is a lipophilic compound that binds to the N-terminal region of RYR1, reducing its open probability. This decreases calcium release from the SR, lowering cytoplasmic calcium concentration, which in turn reduces muscle contraction, ATP consumption, and heat production.

Supportive measures: 6. Active cooling - cold IV normal saline (avoid lactated Ringer's as it contains potassium), ice packs to axillae and groin, cooling blankets. Target temperature below 38.5°C.

7. Treat hyperkalemia - this is life-threatening:

   • Calcium gluconate 30 mL or calcium chloride 10 mL for cardiac membrane stabilization
   • Glucose 50 g plus insulin 10 units IV
   • Sodium bicarbonate if acidotic
   • Hyperventilation to reduce K+

8. Maintain urine output >2 mL/kg/hr with IV fluids to prevent myoglobin-induced AKI

9. Avoid calcium channel blockers with dantrolene - can cause hyperkalemia

10. Arterial and central line access for monitoring and blood gas analysis

11. Continue dantrolene 1 mg/kg every 4-6 hours for 24-48 hours post-crisis

12. ICU admission for monitoring"

Examiner: "The surgery was aborted and the patient stabilized with dantrolene. What follow-up is needed?"

Candidate: "Post-crisis management involves:

1. Continued ICU monitoring for 24-48 hours - MH can recur in up to 25% of cases
2. Serial CK levels - peak at 12-24 hours, indicates degree of rhabdomyolysis
3. Monitor for complications - DIC, AKI from myoglobinuria, arrhythmias
4. Continue dantrolene 1 mg/kg IV q4-6h for 24-48 hours

Long-term follow-up: 5. Report to MH registry - helps with surveillance and research 6. Referral to MH testing center - options include:

• Caffeine-halothane contracture test (CHCT) - gold standard, requires muscle biopsy
• Genetic testing - identifies RYR1 mutations in ~70% of MH-susceptible individuals

7. Genetic counseling - autosomal dominant inheritance means first-degree relatives have 50% chance of susceptibility

8. Family screening - genetic testing or CHCT for at-risk relatives

9. Patient education:

   • Medical alert bracelet or card
   • Safe anesthetic agents: propofol, opioids, nitrous oxide, non-depolarizing NMBAs
   • Avoid all volatile anesthetics and succinylcholine
   • Communicate MH status to all future healthcare providers

10. Documentation - clear notation in medical records, allergy alerts"