Module 9 PP - Oxygenation and Hypoxemia

• Respiratory & Pulmonary Vascular Pharmacology relates to advanced pharmacology in anesthesiology practice in Spring semester

Oxygenation & Hypoxemia

• Arterial O2 saturation (SaO2) and pulse oximetry (SpO2) measures oxygenation, with a goal of >94%, or 88-92% for COPD patients
• Arterial O2 tension (PaO2) has a goal of > 80 mmHg
• Arterial O2 content (CaO2) can be calculated using the formula: CaO2 = (1.34 x Hb x SaO2) + (0.0031 x PaO2)
• Alveolar-arterial (A-a) oxygen gradient is the difference between O2 in alveoli (PAO2) and O2 dissolved in plasma (PaO2), with a goal gradient of 2.5 + 0.21 x Age
• The gradient increases with increasing FiO2
• PaO2/FiO2 ratio is typically used for ventilated patients, with a goal of 400-500
• Other oxygenation measures includes a-A oxygen ratio and oxygenation index

Shifts in Oxyhemoglobin Dissociation Curve

• Left-shifted curve:
  • Results in increased oxygen affinity (R state), but reduced oxygen delivery to tissues
  • Caused by high pH (more basic), low temperature, low 2,3-BPG, presence of fetal Hb (HbF), methemoglobinemia, and high O2 affinity Hb variants
• Right-shifted curve:
  • Results in reduced oxygen affinity (T state), but increased oxygen delivery to tissues
  • Caused by low pH (more acidic), increased CO₂, high temperature, high 2,3-BPG, and low O2 affinity Hb variants

Hypoxemia

• Hypoxemia refers to abnormally low O2 in blood.
• Hypoxia is general whole body low O2 supply
• Tissue hypoxia refers to regional low O2 supply
• Hypoventilation causes: PaCO2 and PACO2 increase and PAO2 decreases
• Decreased O2 diffusion is often readily corrected with a small increase in FiO2
• Right-to-left shunt occurs due to anatomic vs physiologic shunting
• Diffusion limitations occur due to interstitial lung disease, inflammation, or fibrosis
• Reduced inspired O2 tension can also cause hypoxemia

Prescribing Oxygen in Anesthesia

• Oxygen is prescribed in anesthesia to prevent or treat oxygen desaturation and reduced O2 delivery to tissues
• It also helps prevent cellular injury and inflammatory reactions.
• Oxygen is a drug and should be titrated to a goal O2 saturation, assessing the full clinical picture.

Supplemental O2 Delivery Systems

• Low-Flow Systems:
  • Provide a variable FiO2 depending on the stability of the patient's respiratory pattern and rate
  • The actual FiO2 can vary considerably from breath to breath
  • Examples: nasal cannula, simple face mask, face tent, and non-rebreather mask
• High-Flow Systems:
  • Preferable in variable respiratory patterns and rates
  • Indicated for patients with high O2 and respiratory demand
  • Examples: high flow nasal cannula, venturi mask, nebulizer, and non-invasive and invasive mechanical ventilation

Device FiO2 and LPM

• Nasal cannula (Low flow) has FiO2 of 0.24-0.4 with 1-6 LPM with FiO2 increases ~4% per liter O2
• Simple face mask (Low flow) has FiO2 of 0.35-0.55 with 5-10 LPM and is useful for mouth breathers, moderate O2 needs
• Non-rebreather mask (Low flow) has FiO2 of 0.80-0.95 with 10-15 LPM with Reservoir delivers high O2 conc; valve prevents rebreathing; good for severely hypoxic, ventilating well
• Venturi mask (High flow) has FiO2 of 0.24-0.6 with 2-15 LPM with precise O2 titration; good for COPD
• Trach collar (High flow) has similar FiO2/LPM to venturi providing Oxygenation +/- humidification to trach

Pre-Oxygenation

• Pre-oxygenation uses 100% inspired oxygen to prevent hypoxemic events by replacing nitrogen (de-nitrogenation)
• It increases O2 reserves by ~1.5-4L with a minimal effect on CaO2
• Target end-tidal ETO2 should be 90%
• Apneic diffusion oxygenation maintains SaO2
• Absorption atelectasis poses a risk.

Risks of Delivering High O2 Fraction

• Hyperoxia can cause pulmonary, CNS, and ocular toxicity, as well as pro-inflammatory, cytotoxic effects
• It can increase mortality in critically ill patients.
• Intraoperatively, it can cause hemorrhage, hypotension, cardiac ischemia, and cerebral ischemia

Airway Control

• Airway caliber is regulated by NS
• Glandular activity is regulated by NS
• Microvasculature is regulated by NS
• Sympathetic NS has no direct control with Abundance of beta receptors in airway smooth muscle
• Nonadrenergic, noncholinergic (NANC) has direct influence on smooth muscle tone, Role in inflammatory response

Parasympathetic Influence

• Vagus preganglionic → postganglionic, cholinergic nerves
• Release of ACh
• Activation of muscarinic M3 receptor
• Activation of Gq protein
• Activation of phospholipase C (PLC)
• Increased inositol triphosphate (IP3) → SR release of calcium
• Bronchial smooth muscle contracts

Bronchoconstricting Mediators

• Mediators include mast cells and pro-inflammatory cells.
• Specific constricting substances: histamine, prostaglandins, leukotrienes, platelet activating factor, bradykinin, substance P, neurokinin A, calcitonin gene-related peptide

Sympathetic Influence

• Sympathetic innervation leads to vasoconstriction
• B-Receptors cause vasodilation

Bronchodilation

• Bronchodilation is the Beta-2 receptor on postganglionic cholinergic nerve leading to Hyperpolarization
• Beta-2 receptor on airway smooth muscle cell stimulates adenyl cyclase increasing CAMP
• Hyperpolarization leads to Smooth muscle relaxation

NANC Influence

• NANC has direct innervation of airway smooth muscle leady to Hyperpolarization
• NANC is also known as postganglionic, non-cholinergic, parasympathetic nerves by releasing Nitric oxide and vasoactive intestinal peptide to inhibitory
• The substances used are Substance P and neurokinin A for excitatory

Airway Pathology - Asthma

• Asthma incidence ~25 million (US) and ~6 million children
• Airway pathology includes airway inflammation, hyperirritability, bronchoconstriction, airway remodeling, fibrosis, mucous hypersecretion, smooth muscle hypertrophy & Angiogenesis

Asthma Pathogenesis

• Asthma is characterized by increased resistance and decreased air flow that Decreases airway diameter
• Downstream effects include Goblet cell metaplasia & Inflammation

Airway Pathology - COPD

• COPD incidence ~5% adults (US) and 3rd leading cause of death
• COPD is an expiratory airflow limitation that is not fully reversible due to Emphysema with Parenchymal destruction and loss of elastic recoil and Chronic bronchitis with Small airway narrowing and increased mucous production

COPD Pathogenesis

• COPD includes Bronchiolar inflammation, fibrosis and narrowing of airways, Goblet cell metaplasia, Epithelial cells, Mucus hypersecretion, Alveolar destruction(emphysema), Reduced elastic reoil, Increased resistance, Decreased airflow

Intraoperative Bronchospasm

• Bronchospasm is caused by IgE-mediated anaphylaxis, mechanical factors (eg, airway manipulation), Pharmacologic-induced (eg, histamine-releasing drugs), Hyperreactive airway

Intraoperative Bronchospasm Assessment

• The assessment involves increased peak airway pressures, reduction in tidal volumes, Difficulty with bag-mask ventilation, Capnographic waveform changes ("shark-fin"), Changes in SaO2 and PaCO2 and Wheezing on auscultation

Causes of Wheezing During General Anesthesia

• Partial obstruction of tracheal tube (including ETT abutting the carina or endobronchial intubation)
• Bronchospasm causes Wheezing
• Pulmonary oedema and aspiration of gastric contents causes Wheezing
• Pulmonary embolism and Tension pneumothorax causes Wheezing
• Foreign body in the tracheobronchial tree causes Wheezing

Causes of Increased Peak Airway Pressure During IPPV

• Excessive tidal volume causes increased peak airway pressure

• High inspiratory flow rates cause increased peak airway pressure

• Obesity and Head down position causes increased peak airway pressure

• Pneumoperitoneum and Tension pneumothorax causes increased peak airway pressure

• Bronchospasm and Small diameter tracheal tube causes increased peak airway pressure

• Endobronchial intubation and Tube kinked or blocked causes increased peak airway pressure

• Figure Legend: Pathophysiologic mechanisms involved during perioperative immediate hypersensitivity reaction according to the onset of bronchospasm when compared with endotracheal tube insertion

Indications for Bronchodilating Drugs

• Bronchodilating Drugs are used for Acute Bronchospasm, Allergic Rhinitis and Sinusitis and Asthma, COPD and Bronchitis

Preanesthetic Assessment relating to Medications

• Review patients medications and usage pattern if they are taking it daily seasonally or as needed
• Last use of medication to understand if Best as rescue, acute attack

Beta-2 Adrenergic Agonists

• Beta-2 Adrenergic Agonists are used for Bronchodilation
• Vasodilation occurs from Beta-2 Adrenergic Agonists
• Decrease diastolic pressure occurs from Beta-2 Adrenergic Agonists
• Hepatic glycogenolysis occurs from Beta-2 Adrenergic Agonists
• Pancreatic release of glucagon occurs from Beta-2 Adrenergic Agonists
• Uterine relaxation occurs from Beta-2 Adrenergic Agonists
• Stimulation of Na+/K+ ATPase from Beta-2 Adrenergic Agonists

Systemic Side Effects of Beta Agonists

• Tachycardia and hyperglycemia are side effects
• Hypokalemia and hypomagnesemia side effects
• Reduced PaO2 and Tolerance, withdrawal are also side effects

Albuterol (Proventil) MDI Pharmacology

• Beta-2 agonist (with some Beta-1 activity)
• Relaxes bronchial smooth muscle with little effect on heart rate
• Aerosol, airway inhalation has an onset of 5 - 10 min
• PO inhalation has an onset of 15 - 30 min
• Duration of action is average 4 – 6 hrs
• 4-8 puffs (every 20 min) for acute, severe bronchospasm
• Only 16-30% of dose may reach target sites with 30 - 35% reaching the trachea
• Hepatic metabolism in the Albuterol (Proventil) MDI

Racemic Epinephrine (Nebulized)

• Dose should be: 0.5 mL of 2.25% in 4 mL NS, administered via nebulizer
• Relieves airway obstruction
• Vasoconstriction in tracheal mucosa
• Improvement within 20 - 30 min
• Monitor vital signs

Muscarinic Antagonists (Anticholinergics)

• Anticholinergics includes drugs like Ipratropium, Tiotropium, Atropine and Glycopyrrolate and is used to help with Tachycardia
• Tachycardia is a Muscarinic Antagonists (Anticholinergics)
• Side effects include Blurred vision, mydriasis, G upset, nausea, Urinary retention and Tremors

Methylxanthines - Theophylline

• Methylxanthines - Theophylline Phosphodiesterase inhibitors
• PDE normally breaks down cAMP
• Increased cAMP in ASM leading to Relaxation
• Decrease eosinophils, neutrophils
• Receptor Adenosine has influence NANC and Inflammatory cells

Methylxanthines Side Effects

• Gl upset, GERD, nausea, vomiting is side effect
• Headache and Restlessness is side effect
• The toxicity of Drug can cause Arrhythmias and Death if *Toxic plasma levels are > 20 mcg/mL

Corticosteroids Process

• Glucocorticoid forms complex with glucocorticoid receptor alpha
• Changes genetic expression of proinflammatory mediators
• Alters genetic expression of inflammatory gene products

Glucocorticoid actions

• Glucocorticoid affects cell numbers of Eosinophils, T-lymphocyte, Mast Cells and Macrophages
• Reduction of Cytokine, Mediator and Leak

Corticosteroids (Drugs and Side effects)

• Fluticasone, Mometasone, Methylprednisolone and Prednisone
• SIDE EFFECTS: Infection (eg, oral fungal, pneumonia), Hyperglycemia, Hypertension, Adrenal suppression and Psychosis

Leukotriene Modifiers

• Montelukast is Leukotriene Modifiers used to Block conversion of arachidonic acid to leukotrienes
• Zileuton is Leukotriene Modifiers used to conversion of arachidonic acid to leukotrienes and it Block leukotriene receptors

Mast Cell Stabilizers

• Cromolyn sodium is an example of Mast Cell Stabilizers
• Nedocromil is also an example of Mast Cell Stabilizers
• It Stabilizes mast cells and Block mast cell degranulation which blocks the release of histamine & bronchoconstriction, mucosal edema and mucus secretion

Anesthetics

• Volatile anesthetics
• Decrease bronchomotor tone
• Except: nitrous oxide
• Increase cAMP, decrease calcium??

Adjuncts with Antihistamines

• May have role in reducing histamine release from mast cells, basophils
• Beneficial in allergic reaction-induced bronchoconstriction intraop

Adjuncts with Magnesium sulfate

• Improves bronchodilation when given with standard therapy
• Given nebulized or IV

Perioperative Management with Bronchodilators

• Use lowest effective dose and assess vital signs with cough, wheeze, decreased breath sounds, sputum and secretions
• Monitor for cardiac arrhythmias
• If awake, monitor for restlessness, confusion, tremor, palpitations, or other adverse reaction

Review of COPD Medications:

• Beta-2 Agonists helps with bronchodilation
• Anti-cholinergics help with ↓acetylcholine

Management of patient with suspected bronchospasm during general anaesthesia

• On suspecting bronchospasm the Switch to 100% oxygen and the Ventilat by hand is the thing to do or Stop stimulation/surgery
• Stop administration of suspected drugs/colloid/blood products and CALL FOR HELP if there is Difficulty with ventilation/falling SpO2

IV Vasodilators for pulmonary hypertension

• Milrinone uses a 25-50 µg.kg¹ bolus, followed by 0.5-0.75 µg.kg-1.min¹ continuous infusion
• Prostacyclin uses a 4-10 ng.kg-1.min¹ continuous infusion
• Iloprost and Sildenafil uses a bolus three times a day

Intraoperative Monitoring Recommendation for patients with PH:

• Basic monitoring should include a ECG,SaO2, End-expiratory CO2 and/or Invasive blood pressure
• Extended monitoring should include a Pulmonary arterial catheter and/or Transesophageal echocardiography (TEE) and/or ScvO2

Intraoperative "basic treatment" to avoid an increase of pulmonary arterial pressure:

• oxygenation with inspiratory FiO2 0,6-1,0
• Moderate hyperventilation (goal: PaCO2 30-35 mmHg)
• Avoidance of metabolic acidosis (pH > 7,4) and Ventilation to avoid overinflation (goal: 6-8 mL/kg ideal body weight)

Table 11: Specific interventions for therapy of intra- and/or postoperative increase of pulmonary arterial pressure:

• Reduction of right-ventricular afterload: through Intravenous vasodilation and through Pulmonary-selective inhalative vasodilatation

Table 1. Drug doses for use in bronchospasm

• MDI for Salbutamol is 6-8 puffs
• Nebulised is-1ml 0.5% (5mg) and IV-250mcg slow IV then 5mcg.min for for Salbutamol
• Epinephrine for IV-10mcg-100mcg (0.1-1.0 ml 1:10,000) titrated to response with Nebulised 5ml 1:1000.

Stimulating Adrenergic Receptors

• Stimulation of beta adrenergic receptor promotes bronchodilation
• The cellular mechanism includes Increased cAMP which Activates Protein Kinase A to relax smooth muscle

Administration of Albuterol

• Only 16-30% of the albuterol reaches the trachea during ETT and MDI
• Ipratropium (Atrovent) is a Anticholinergic that is administered topically

Cromolyn Sodium

• How it works is stabilizes mast cells which prevents histamine release and used for asthmatics not intraop What 2nd messenger concentration is increased by Albuterol cAMP? cAMP
• Leukotrienes constrict pulmonary SM and enhance mucus by inflammation Corticosteroids inhibit phosphilpase A to block arachadonic pathway of inflammation

Definition of pulmonary hypertension (PH)

• Mean pulmonary artery pressure > 20 - 25 mmHg
• Increased pulmonary vascular resistance (> 2 Woods units)
• PH Pathogenesis includes Decreased NOS, prostacyclin and Increased thromboxane and Increased endothelin-1

gs-Proteins

• Beta-2 and IP receptors are bound to Gs proteins which helps with Vasodilation
• Alpha-2 receptors are bound to Gi proteins

Endothelial cells

• Pre-pro-ET pro-ET

CGMP Influence

• NOS leads to CGMP activation
• L Arginine produces this

Treatment of pulmonary hypertensive crisis

• Table 9. Treatment of pulmonary hypertensive crisis needs to Avoid hypoxic pulmonary vasoconstriction
• Avoid hypercarbia, acidosis and hypothermia with that Avoid high airway pressures

IV Vasodilators

• Intravenous vasodilators (caution if low systolic blood pressure)
• Milrinone (25-50 µg.kg¹ bolus, followed by 0.5-0.75 µg.kg-1.min¹ continuous infusion)
• Prostacyclin and Iloprost infusion
• Sildenafil (10 mg bolus three times a day)

Intravenous "basic treatment" to avoid an increase of pulmonary arterial pressure include"

• "luxury" oxygenation with inspiratory FiO2 0,6-1,0 and hyperventilation
• Recruit patient not to give metabolic crisis to the patient

Specific interventions for therapy of intra-and/or postoperative increase of pulmonary arterial pressure

• Reduction of the heart
• With medicine