Respiratory Failure

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RESPIRATORY FAILURE: Early or Selective

Causes
Adult onset
Infantile onset
Evaluation & Management
Exacerbating factors
Home ventilation
Spirometric abnormalities

Elevated right
hemidiaphragm

Respiratory involvement: Adult onset ⁷

Muscle
- Hereditary
  - Congenital disorders
    - Myopathy: Rod; Centronuclear; Cap
    - Diaphragm defects
  - Cytoplasmic body myopathy
  - Glycogen storage
    - Acid Maltase
    - Debrancher
  - LGMD
    - 2A: Calpain-3
    - 2I: FKRP
    - R29: SNUPN
  - MADD
  - Mitochondrial: PEO; Myopathy; Leigh's
  - Multicore-Minicore: MEGF10; SEPN1
  - Myofibrillar myopathy
    - Desmin ;
    - αB-crystallin
    - Distal myopathy with early respiratory failure (HMERF): Titin
    - Respiratory failure & Rigid spine: DNAJB4
  - Myotonic dystrophy: Central component (Pickwickian syndrome; Hypoventilation)
  - Oculopharyngodistal MD
  - Nemaline rod
  - Congenital fiber type size disproportion: TPM3 mutations
  - Fibrosing Poikiloderma with Contractures, Myopathy & Pulmonary Fibrosis
  - Ullrich scleroatonic muscular dystrophy
- Acquired
  - Acute Quadriplegic Myopathies (Myosin loss)
  - Amyloid myopathy
  - Hydroxychloroquine: Myopathy & Neuropathy
  - Inflammatory Myopathy: Especially Interstitial lung disease
  - SLONM
Neuromuscular junction
Nerve
- ALS
- Amiodarone toxicity
- Brachial plexopathy, especially bilateral
- Churg-Strauss: Asthma & Pulmonary infiltrates
- CIDP: Multifocal
- CMT
  - 1A (Sleep apnea)
  - 1B (Cough)
  - 2C
  - 4A
  - 4B1
- Diphtheria
- Guillain-Barré syndrome
- Hopkins' syndrome (with acute asthma)
- Krabbe
- Moebius syndrome
- HMN: SMARD1 (HMN 6)
- HNA1
- HSAN 3
- Lower motor neuron syndrome: MAPT
- Phrenic nerve lesions ¹¹
  - Direct damage
    - Trauma
    - Post cardiac surgery
    - Neoplasm
    - Pneumonia: Covid-19 ¹⁰
    - Radiation
  - Systemic
    - Polio
    - Toxic: n-Hexane (Glue sniffing)
    - Immune checkpoint inhibitors (ICI)
    - Brachial neuritis
  - Idiopathic (25%)
- Vocal cord disorders
Spinal
- Arnold-Chiari Malformation
  - Reduced respiratory drive, or vocal cord paralysis
  - Isolated respiratory failure in adult onset, sporadic type
- Cervical spondylitic myelopathy
- Giant cell arteritis of cervical radicular vessels ¹
CNS
- Congenital central hypoventilation syndrome (CCHS)
- Depression of ventilatory response to hypoxia and hypercapnia
- Familial lethal sleep apnea
- HSAN9

Respiratory insufficiency: Infantile & Childhood

Myopathic

Congenital myopathies
- X-linked myotubular (Centronuclear) (MTM1)
- Nemaline rod: ACTA1; NEB
- Central core (RYR1)
- CACNA1S
Myotonic dystrophy 1, Congenital
Reduced Muscle carnitine uptake (Infantile)
Diaphragm defects
SEPN1

Neuromuscular Junction
- Myasthenia Gravis, Congenital
Neuropathic

Arthrogryposis: Distal arthrogryposis 5E
Rule out: CNS disorders
- Congenital central hypoventilation syndrome (CCHS)

Respiratory failure: Evaluation & Management

Testing
- Forced vital capacity (FVC): Reliable; May miss some respiratory problems
- P_Emax/P_Imax ratios ⁵
  - Normal: 1.31
  - Myasthenia gravis: 1.94
  - ALS: 1.33
  - Myotonic dystrophy: 0.93
- Other testing
  - FVC while supine
  - Formal pulmonary function testis
  - Nocturnal disorders of breathing
Management
- Early: Non-invasive nocturnal ventilation, preferably NIPPV
- Assist cough when needed
- Avoid early tracheostomy
- Maintain ideal body weight.
- Control oral secretions
- Aggressively treat URI’s.
- Give Influenza vaccine & Pneumovax.
- Avoid supplemental O₂ unless addressing hypoventilation fails
Outcomes in patients with chronic neuromuscular disease,
- Prolongs life
- Reduces symptoms
- Improves quality of life
- Prevents acute respiratory failure & delays tracheostomy
End of life
- Prevent dyspnea and discomfort with O₂
- Use of narcotics & benzodiazepines
- Terminal weaning: Not sudden withdrawal of support

Respiratory failure: Exacerbating factors

Reduced central drive
- Primary: Myotonic dystrophy
- Drugs: Sedatives hypnotics
- Supplemental oxygen
Physical impediments
- Obesity: Increased work of chest wall movement
- Constipation
- Supine position: Inhibition of diaphragmatic movement
- Kyphoscoliosis: Reduced chest wall compliance
Primary lung disease: Obstructive disease
- FEV₁/FVC ratio reduced
- Increased airway resistance slows expiration

PATTERNS OF SPIROMETRIC ABNORMALITIES
	Obstructive Diseases	Restrictive Diseases
FVC	Normal or ↓	↓ to ↓↓↓
FEV₁	↓ to ↓↓↓	↓ to ↓↓↓
FEV₁ /FVC	↓ to ↓↓↓	Normal or ↑
FEF_25%-75%	↓ to ↓↓↓	↓ to ↓↓↓

Restrictive ventilatory defects are characterized by proportional decreases in FVC and FEV₁, leaving the FEV₁/FVC normal or even slightly elevated. Any lesion affecting the lung, chest wall, or respiratory muscles that reduces the ability to take in a normal amount of air but does not affect the conducting airways is classified as a restrictive lung disease.

Obstructive defects are characterized by their involvement of the airways and the resultant reduction in expiratory flow. Spirometric studies of obstructive lung disease generally show a reduced FEV₁, FEV₁/FVC and flow rates with a relatively normal FVC. In severe obstructive lung disease, the FVC may also be reduced.

Home ventilation: Types

Pressure-limited: BiPAP

Mechanisms
- Patient initiates breath
- Machine senses negative pressure
- Air delivered until set pressure is reached
- End inspiration pressure drops to set (positive) level
- Typical settings
  - IPAP: 12 to 20 cm H₂O
  - EPAP: 3 to 4 cm H₂O
Advantages
- 1st step: When hypoventilation in only nocturnal
- Can deliver breaths without patient triggering: For sleep apnea
- Simple to operate
- Inexpensive
- Semi-portable
Disadvantages
- Can't deliver large volumes: No cough assist
- Most unit have no battery

Volume-limited

Mechanisms
- Patient initiates breath
- Machine senses negative pressure
- Air delivered until set volume is reached
- No compenstaion for air leakage: Set for large volumes (10 to 15 cc/kg)
Advantages
- Battery back-up
- Back-up alarms
- Better for full time respiratory support
- Adjustable flow rates
- Can increase voice volume & cough
Disadvantages
- Expensive
- Units may be heavy: But can be place on power wheelchair

MYOSIN-LOSS (Acute Quadriplegic; Critical Illness) MYOPATHIES ²

General Syndrome
- Rapidly Evolving Myopathy with Myosin-Deficient Fibers
- Diagnostic muscle biopsy stain: ATPase pH 9.4
  - Diagnostic feature: Muscle fibers, non-necrotic, with staining intensity less than type I
Epidemiology
- Age: Mean 6th decade
- Sex: Males & Females involved
Clinical features
- History
  - Weakness
    - Onset: Progressive or Subacute, Over days to weeks
    - Distribution: Proximal > Distal
  - Persistent weakness after
    - Respiratory support
    - Neuromuscular paralysis or NMJ block
    - Corticosteroid treatment
  - Early: Some with mild to moderate rhabdomyolysis
- Weakness
  - Diffuse: Proximal > Distal; Neck flexors
  - Symmetric
  - Respiratory failure (80%)
  - Severe cases: Face & occasional EOM
  - Mild cases: Monophasic; May have Proximal arm weakness
- Sensory: Normal, or Mild distal loss
- Tendon reflexes: Reduced
- Prognosis
  - Slow improvement in weakness (months) when steroids tapered
  - High mortality (30% to 50%) from associated disorders
Associated factors
- Corticosteroids (80%): Especially higher doses
- Transplant: Lung; Liver
- Systemic disease
  - Sepsis
  - Myasthenia gravis
  - Renal disease & Dialysis
  - Severe "critical" illness
  - Multiple organ failure
- Post-Paralysis Paralysis
  - History
    - Paralytic treatment for Status asthmaticus or other disorders
    - Treatment with NMJ blocking agents
      - Non-depolarizing agents; e.g. Vecuronium; ?Corticosteroids
      - Treatment > 1 week
  - Inability to wean from respirator
  - Persistent weakness
Laboratory
- Serum CK: Elevated or Normal
  - High in 1st 2 weeks in status asthmaticus patients
  - Normal or Low: After 2 weeks
- Glucose variability, Serum: Increased ⁹
- Electrodiagnostic
  - NCV
    
    From: M. Al-Lozi
    CMAPs: Slow & Prolonged Repolarization
    - Compound motor action potential (CMAP)
      - Amplitude
        
        Small
        
        Often < 50% of lower limit of normal
      - Duration: Increased
        
        Onset: Slow
        
        Late repolarization: Delayed
        
        Quantitative
        
        > 8 msec for most motor nerves
        
        > 15 msec for fibular nerve
    - Sensory: SNAP amplitudes normal or mildly small
    - Normal: Nerve conduction velocities; Distal Latencies
  - EMG
    - Often normal, or mild non-specific changes
    - Irritative changes
      - Occur early in course: Some patients
      - Fibrillations
      - Positive sharp waves
    - Myopathic changes
      - Occur in some patients: Later in course
      - Action potentials
        
        Amplitude: Low
        
        Duration: Short
  - Repetitive nerve stimulation
    - Decrement: Occasional
      - Early in disease course
      - 1st week after discontinuation of paralytic agent
    - Normal: Late
  - Muscle fibers may be electrically inexcitable
- Muscle Pathology
  - Myosin loss in muscle fibers on ATPase stain (ATPase, pH 9.4 & 4.3)
    - ATPase
      - pH 9.4: Fibers with staining intensity less than type 1
      - pH 4.3: Pale staining in fibers with reduced staining intensity at pH 9.4
    - Patterns of myosin loss
      - Most have diffuse loss within muscle fibers
      - sopme with focal regions of myosin loss within fibers
      - Myosin loss distribution in muscle
        
        Scattered muscle fibers
        
        Not focal or diffuse regions
    - Quantitation of myosin loss ³
      - Normal myosin/actin ratio in muscle: 1.31 to 1.57
      - Myosin-loss (Critical illness) myopathy myosin/actin ratio
        
        Low: Mean 0.37
        
        Mild cases may have normal myosin/actin ratios
    - Differential diagnosis: Reduced ATPase 9.4 staining in muscle fibers
      - Muscle fiber necrosis
      - Dermatomyositis: In focal regions of muscle fiber damage
      - HIV: With nemaline rods
  - Atrophic muscle fibers
    - Basophilic, atrophic type II muscle fibers (60%)
    - Shape: Small fibers polygonal or angular
    - All fibers atrophic (30%)
    - Enlarged nuclei in atrophic muscle fibers
      - Common with myosin loss
      - Unusual with other causes of muscle fiber atrophy
  - Degeneration & Regeneration of muscle fibers: Occasional; Early
  - Sarcolemma: Reduced NOS1 (nNOS) staining
    - NOS1 staining also lost after denervation
    - NOS1 activity, but not amount, increased with Caveolin-3 mutations
  - Active disease phase
    - Muscle fibers: LC3 aggregates
    - Endomysial capillaries: Associated with acid phosphatase+ histiocytes
Weakness: Pathophysiology
- Muscle membrane inexcitability
  - Animal (rat) model
    - Denervate hindlimb + High dose dexamethasone
    - Loss of myosin with preservation of actin
  - Muscle membrane changes
    - Depolarization
    - Reduced Membrane impedance 2° to: Increased Cl^- conductance
    - Reduced Na⁺ current amplitudes
      - Reduced number of Na⁺ channels
      - Reduced Na⁺ channel conductance or voltage-dependent gating
    - Slow repolarization: ? Abnormal K⁺ currents
    - Increased glucocorticoid receptors
- Myosin loss
  - ? via Calpain pathway
  - ? Related to Increased general muscle catabolism
  - Protein degradation pathways possibly involved ⁴
    - TGF-β/MAPK
    - Atrogin-1/proteasome
Also see: Critical illness polyneuropathy

Cough & Neuromuscular Disorders ⁶

Cough: General
- Stimuli: Mechanical or Chemical
- Afferent pathway: Vagus nerve
- CNS: ? N-methyl-D-aspartate (NMDA) receptors on brainstem neurons
- Treatment
  - Anti-tussives
  - Amitriptyline
  - Gabapentin
Neuropathies with Cough
- Hereditary
  - HSN + Cough & GE reflux (HSAN1B)
  - HSAN9
  - CMT 1B
  - CANVAS
  - Ataxia + Sensory neuropathy
  - SCA4
- Autonomic disorders
- Other neuropathy
  - Vitamin B12 deficiency
- Focal
  - Vagal mononeuropathy: Sarcoid; Neurofibromatosis
  - Laryngeal sensory neuropathy: Chronic cough
  - Cough hypersensitivity syndrome: Neuropathic cough
    - Symptoms: Tickling, Irritating of rawness sensation in pharynx or laryngeal area
    - Cough reflex: Increased response to citric acid or capsaicin inhalation
Cough: Other
- CNS
  - SCA 20
  - SPG49
- Myopathy
  - Interstitial lung disease with Immune myopathies: IMPP
- Reduced Cough
  - Respiratory muscle weakness
  - Diabetic autonomic neuropathy

Hoarse voice & Neuromuscular Disorders

Phrenic Neuropathy

Phrenic nerve

Formed from
- Roots: 4th > 3rd & 5th cervical ventral spinal rami
- At upper part of scalenus anterior muscle

Phrenic Nerve Disorders

Neuralgic amyotrophy
Phrenic nerve lesions
- Epidemiology
  - Males > Females
  - Triggered by: Infections; Surgery
- Diagnosis
  - Phrenic NCS
  - Diaphragm EMG
  - Chest imaging
- Unilateral
  - FVC: Mean 68%
  - Often asymptomatic
- Bilateral
  - More often: Arterial hypertension; Severe respiratory symptoms
  - Less: Pain
  - FVC: Mean 49%

Chronic Obstructive Pulmonary Diseasae (COPD) ⁸

Associations
- Sarcopenia
- Peripheral Neuropathy
  - Clinical pattern: Sensory loss, distal
  - Symptomatic: 30%
  - Subclinical: 30% to 50%
  - Associated COPD feature: Base excess
  - NCV: Axon loss
  - CNS: VEP prolonged latency
- Autonomic neuropathy, Cardiac
  - Elderly males
  - Correlates with: Hypercapnia
- Diaphragm weakness

Return to Neuropathy Index
Return to Myopathy & NMJ Index

References
1. J Neurol Neurosurg Psychiatry 1999;67:223-226
2. Muscle Nerve 2000;23:1785-1788, Neurology 2024;103:e209496
3. Intensive Care Medicine 2003;Online August
4. Ann Neurol 2004;55:195-206
5. Respir Care 2015 Jan 13
6. Pulm Pharmacol Ther 2015 Oct 19
7. Muscle Nerve 2017;56:881-886
8. Respir Res 2020;21:28
9. J Crit Care 2021;63:32-39
10. Thorax 2022 Apr 22
11. Muscle Nerve 2024;70:980-987

12/20/2024