1. In the name of GOD Respiratory Failure Dr. Hassan Ghobadi Assistant professor of Internal Medicine Ardabil University of Medical Science

2. Definition : Defined as inadequate gas exchange due to pulmonary or non-pulmonary causes leading to : hypoxemia, hypercarbia or both. Documented by PaCO2 > 50 mm of Hg or PaO2 < 50-60 mm of Hg.

3. Respiratory Failure 1- Hypoxemic Respiratory Failure Arterial Po2 of less than 60 mm Hg. 2- Hypercapnic Respiratory Failure Arterial Pco2 more than 50 mm Hg & PH < 7.3, Two conditions may coexist. ABG analysis: Single most important lab test for evaluation of respiratory failure.

4. Hypoxemic Respiratory Failure This definition of hypoxemic respiratory failure (based on the arterial Po2) does not fully address the importance of oxygenation at the level of the tissues. Oxygen delivery to the tissues is the product of cardiac output and oxygen content. ( DO 2 = Q × O 2 content ) Oxygen content is critically dependent on the hemoglobin concentration and its saturation with oxygen. O 2 content = 1.34 × [Hb.] × Sat. + 0.003 × PO 2 Oxygen saturation depends on the arterial Po 2 (as described by the oxyhemoglobin dissociation curve). In the anemic patient or in patients with very low cardiac output, tissue hypoxia may occur despite a seemingly adequate arterial Po 2.

5. CLASSIFICATION ( Structural-anatomic ) 1-Air spaces (alveoli): Pulmonary edema (cardiogenic) Acute lung injury (ALI), ARDS, Pulmonary hemorrhage, Pneumonia. 2- Interstitium: Pulmonary fibrosis, Extrinsic allergic alveolitis ( HP ), Viral or "atypical" pneumonia. 3- Pulmonary vasculature: PTE, Intrapulmonary shunt, Congestive heart failure. 4- Airways: Asthma, COPD, Mucous plug, Right main bronchus intubation, Upper airways obstruction. 5- Pleura: Pneumothorax, Pleural effusion.

6. CLASSIFICATION ( Pathophysiologic mechanisms ) 1- Decreased inspired Po2, 2- Hypoventilation, 3- Impaired diffusion, 4- Ventilation-perfusion (V/Q) mismatch, 5- Right-to-left shunt.

7. Etiology In a hospital setting, a decreased inspired Po2 can essentially be excluded. Impaired diffusion by itself is not an important cause of acute hypoxemia. Hypoventilation can rapidly be excluded if the patient is not hypercapnic or acidemic. Hypoxemia from V/Q mismatch is responsive to supplemental oxygen. Hypoxemia from a right-to-left shunt is not responsive to supplemental oxygen.

8. CLINICAL FEATURES A basic history should be obtained. A focused physical examination of the cardiac and respiratory systems. The clinical features of acute hypoxemic respiratory failure will vary on the underlying cause. The hypoxemic patient will be tachypneic and tachycardic. Cyanosis of the lips or tongue (deoxygenated hemoglobin is greater than 5 g/100 mL) may be seen.

9. Clinical manifestations Tachypnea Exaggerated use of accessory muscles. Intercostal, supraclavicular and subcostal retractions. In neuromuscular disease, the signs of respiratory distress may not be obvious. In CNS disease, an abnormally low respiratory rate, and shallow breathing are clues to impending respiratory failure.

10. DIAGNOSTIC APPROACH Implementation of therapy is simultaneous with the diagnostic workup. Continuous cardiac monitoring and pulse oximetry should be available. All patients should have a chest radiograph, an electrocardiogram, and routine blood work. An arterial blood gas should be obtained and the alveolar-arterial Po2 gradient should be calculated.

11. DIAGNOSTIC APPROACH A completely normal CXR in the setting of hypoxemic respiratory failure narrows the differential diagnosis substantially (PTE and right-to-left shunts ). A more common scenario is that the chest radiograph of a patient with pneumonia can appear surprisingly normal (or may show only a "small" infiltrate) due to concomitant intravascular volume depletion. The need for further investigations, including bronchoscopy, CT angiography of the chest, and echocardiography, will depend on the results of the initial assessment.

12. Evaluation of Respiratory failure The following parameters are important in evaluation of respiratory failure: 1- PaO 2 2- PaCO 2 3- Alveolar-Arterial PO 2 Gradient 4- Hyperoxia Test PaO2 (Upright) = 104.2 - 0.27 x age (Yrs)

13. Measurement of Gas Exchange The actual content of O 2 in blood therefore depends both on the hemoglobin concentration and on the PaO 2. The PaO 2 determines what percentage of hemoglobin is saturated with O 2, based on the position on the oxyhemoglobin dissociation curve. O2 content = 1.34 x [hemoglobin] x Sat. + 0.0031 x PO2

14. Alveolar – arterial O2 gradient This calculation takes into account the fact that alveolar and arterial PO2 can be expected to change depending on the level of alveolar ventilation (reflected by the arterial PCO2). PAO2 = FIO2 x (PB – PH2O) – PaCO2/R PAO2 = 150 – 1.25 x PaCO2 A-a gradient = 2.5 + 0.21 x age in years In a healthy young person, the PAO2 – PaO2 is normally <15 mmHg; this value increases with age and may be 30 mmHg in elderly patients.

15. A – a O2 gradient A sensitive indicator of disturbance of gas exchange. Useful in differentiating extrapulmonary and pulmonary causes of respiratory failure. For any age, an A-a gradient > 20 - 30 mm of Hg is always abnormal.

16. CAUSES  Most common causes of acute respiratory failure: o 1- Postoperative respiratory failure, o 2- COPD, and asthma o 3- Pneumonia, o 4- Congestive heart failure, o 5- Sepsis, o 6- Trauma, o 7- Acute respiratory distress syndrome (ARDS), o 8- Mucous plugging

17. Approach to the Patient 1- Decreased inspired Po2, At high altitude 2- Hypoventilation, Normal A-a gradient 3- Impaired diffusion, 4- Ventilation-perfusion (V/Q) mismatch, High A-a gradient 5- Right-to-left shunt, High A-a gradient Determining the underlying mechanism for hypoxemia depends on measurement of the PaCO2, calculation of PAO2 – PaO2, and knowledge of the response to supplemental O2.

18. Treatment 1- Supportive therapy 2- Specific therapy

19. Supportive therapy Secure the airway Pulse oximetry Oxygen: by mask, nasal cannula, head box Proper positioning Nebulization if indicated Blood sampling: Routine, electrolytes, ABG Secure IV line CXR: upright AP & lateral views

20. Hypoxemic / Non - Hypercapnic respiratory failure The major problem is low PaO2. If due to low V/Q mismatch; oxygen therapy. If due to pulmonary intra-parenchymal shunts (ARDS), assisted ventilation with PEEP may be needed. If due to intracardiac R-L shunt: O2 therapy is of limited benefit & Surgery is needed.

21. Mechanical Ventilation: Indications Loss of ventilatory reserve Respiratory rate > 35 breaths/min Tidal volume < 5 mL/kg Vital capacity < 10 mL/kg Negative inspiratory force Weaker than - 25 cmH 2 0 Minute ventilation < 10 L/min Rise in PCO2 >10 mmHg Refractory hypoxemia Alveolar-arterial gradient (FiO2 = 1.0) > 450 PaO2/PAO2 < 0.15 PaO2 with supplemental O2 <55 mmHg

22. Hypercapnic Respiratory failure Key decision is whether mechanical ventilation is required or not. In Acute respiratory acidosis: Mechanical ventilation must be strongly considered. Chronic Resp acidosis: patient should be followed closely, mech. ventilation is rarely required. In acute-on-chronic respiratory failure, the trend of acidosis over time is a crucial factor.

23. Hypercapnic Respiratory Failure ( PAO2 - PaO2 ) Alveolar Hypoventilation V/Q abnormality  Pi max Increased Normal NL VCO2 PaCO2 >46mmHg Not compensation for metabolic alkalosis Central Hypoventilation Neuromuscular Problem  VCO2 V/Q Abnormality Hyper metabolism Overfeeding

24. ARDS ACUTE RESPIRATORY DISTRESS SYNDROME

25. Introduction ARDS is characterized by noncardiogenic pulmonary edema, lung inflammation, hypoxemia, and decreased lung compliance. The pathogenesis of ARDS remains elusive and there is no gold standard diagnostic test. The heterogeneity of the clinical conditions associated with ARDS. ARDS is in fact a collection of different diseases that have not yet been separately identified.

26. Incidence Incidence of ARDS has ranged from 75 per 100,000 population to as low as 1.5 per 100,000. The incidence of ALI is higher (20 to 50 cases per 100,000)

27. Diagnosis ARDS was defined as a syndrome of : 1- Acute onset (developed respiratory distress within 48 to 72 hours ), 2- Bilateral infiltrates on CXR consistent with pulmonary edema, 3- Pulmonary artery occlusion pressure less than 18 mm Hg.

28. Diagnosis Hypoxemia as measured by the ratio of the arterial partial pressure of oxygen (Pao2) to the fraction of oxygen inspired (Fio2). Pao2/Fio2 ratio of less than or equal to 300 define an entity termed acute lung injury (ALI). ARDS was the most severe form of ALI and was defined as occurring if the Pao2/Fio2 ratio is less than or equal to 200. Many patients required positive-pressure ventilation and exhibited low respiratory system compliance.

29. ARDS - CXR

30. ARDS – CT

31. Risk Factors Sepsis, Aspiration of gastric contents, Multiple transfusions, Alcohol abuse, Diabetes might be protected against the development of ARDS (impair neutrophil function)

32. Conditions Associated with ARDS  Indirect Injury o Sepsis o Major trauma o Multiple blood transfusions o Pancreatitis o Cardiopulmonary bypass o Drug overdose o Adverse effect of medication  Direct Injury o Pneumonia o Aspiration o Pulmonary contusion o Toxic Inhalation o Near drowning o Overdose o Reperfusion injury (e.g., post-lung transplantation

33. Pathology (ARDS stages) 1- Exudative phase (Diffuse alveolar damage): There are hyaline membranes and protein-rich edema fluid in the alveolar spaces, as well as epithelial disruption and infiltration of the interstitium and air spaces with neutrophils. This phase last 7 days. 2- Proliferative phase. Hyaline membranes are reorganized and fibrosis begins to be observed. Obliteration of pulmonary capillaries and deposition of interstitial and alveolar collagen may be observed, decrease in the number of neutrophils and the extent of pulmonary edema. 3-fibrotic phase. The appearance of pulmonary fibrosis in a subset of patients with persistent (i.e., >2 weeks) ARDS.

34. Neutrophils and Inflammatory Mediators The hallmarks of ALI/ARDS is the accumulation of neutrophils in the microvasculature of the lung. Once activated, neutrophils release growth factors and cytokines and interleukin that may enhance the inflammatory response. One of the earliest manifestations of ARDS, even before hypoxemia, is a transient leukopenia due to sequestration of neutrophils in the lung vasculature. After the initial sequestration, neutrophils must translocate across the alveolar-capillary barrier to access the alveolar space.

35. THERAPY Supportive Care Hemodynamic Management Nutrition Pharmacotherapy Corticosteroids. Vasodilators. Antioxidants and Anti-inflammatory Agents Mechanical Ventilation

36. 1 - Supportive Care One of the first goals of therapy in ARDS is to treat the underlying cause. In particular, patients with sepsis may respond to aggressive source control, including antibiotics. In patients with ARDS and sepsis of unknown origin, both the lung and the abdomen should be considered and excluded as foci of infection. Preventing complications and providing supportive care (e.g., nutrition, ventilation). Prophylaxis against gastrointestinal stress ulceration and deep venous thrombosis.

37. 2 - Hemodynamic Management Preliminary data have suggested that a negative fluid balance is correlated with a reduced requirement for mechanical ventilation in ARDS. Goal-directed therapy involved administration of crystalloid, red blood cells, and vasoactive and inotropic agents by protocol to achieve : CVP of 8 to 12 mmHg, Mean BP of 65 to 90 mm Hg, Central venous saturation of 70% or greater, Hematocrit of 30% or greater. the optimal fluid and hemodynamic strategy to use in patients with ARDS remains unclear.

38. 3 - Nutrition Manipulations in diet can favorably affect the immune system and improve the outcome of "inflammatory" diseases such as sepsis and ARDS (immunonutrition ). The role of immunonutrition in the management of ARDS remains unclear.

39. 4 - Pharmacotherapy A number of agents improve oxygenation but do not affect mortality from ARDS. A number of studies of various agents suggest benefit, but prospective data are lacking.

40. 5 - Corticosteroids None of the trials using corticosteroide regimen showed any benefit from the use of steroids. Higher incidence of infection in patients who received steroids. The use of steroids during the fibroproliferative phase. Patients had lower mortality, improved oxygenation, decreased organ dysfunction, and earlier extubation, but also had a higher (but not statistically significant) rate of infection. Preliminary results from the ARDS Network showed no benefit at 30 days in the group that received corticosteroids.

41. 6 - Vasodilators Prostaglandin E1 (PGE1) to decrease neutrophil activation, improved oxygenation, there was no improvement in survival or in ventilator dependence. NO,vasodilates, improving V/Q matching, anti- inflammatory and proinflammatory properties, significant improvement in oxygenation. There was no difference in survival or in liberation from mechanical ventilation.

42. 7 - Antioxidants Agents A multicenter trial of the antioxidant N- acetylcysteine and procysteine in ARDS showed no beneficial effect of the drug. Platelet-activating factor (PAF), and acetylhydrolase showed no decrease in the development of ARDS in patients who received this drugs.

43. 8 - Mechanical Ventilation Mechanical ventilation is lifesaving and is the standard therapy for ARDS. Ventilatory management of ARDS has undergone a dramatic change within the last 15 years. Ventilation Protocol with Low Tidal Volume strategies.

44. Permissive Hypercapnia Allows the PaCO2 to rise into the 60-70 mm of Hg range, as long as the patient is adequately oxygenated (SaO2> 92%), and able to tolerate the acidosis. This strategy is used to limit the amount of barotrauma and volutrauma to the patient.

45. Prone positioning Positioning the patient in the prone position has been shown to improve oxygenation and reduce ventilator induced lung injury. However, the outcome may not be improved.

46. Ventilation Protocol Mode of ventilation: Volume assist-control Tidal volume: Less than 6 mL/kg predicted body weight Plateau pressure: Less than 30 cm H2O Frequency: 6–35 breaths/min, titrated for pH 7.30–7.45 I:E ratio: 1 : 1 to 1 : 3 Oxygenation goal: Pao2 55–80 mm Hg, or Sao2 88–95% Fio2/PEEP (cm H2O) combinations: Weaning: By pressure support, required when Fio2/PEEP ≤ 0.4/8

47. Pressure-volume curve in ARDS

48. VILI with positive pressure and high volume ventilation

49. Treatment of auto-PEEP 1- Changes in ventilator setting Increase expiratory duration - Decrease respiratory rate - Decrease tidal volume. 2- Reduction in the ventilatory demand Decrease carbohydrate intake - Reduce dead space - Reduce anxiety, pain, fever, shivering. 3- Reduction of total flow resistance Use of large bore endotracheal tubes - Frequent suctioning - Bronchodilators 4- Application of external PEEP nearly up to the level of initial PEEPi.

50. Have a good day

51. Endotracheal tube positioning

52. Endotracheal tube with movement of the neck

53. Approach to the ventilated patient in respiratory distress

54. Peak and plateau pressures

55. Drugs used to sedate critically - Ill patients Analgesics Fentanyl Hydromorphone Morphine sulfate Anesthetics Ketamine Propofol Neuroleptics Haloperidol Sedative-hypnotics Benzodiazepines Diazepam Lorazepam Midazolam Barbiturates Methohexital Thiopental

56. Analgesics inappropriate for use in the ICU Meperidine Codeine Methadone Nonsteroidal anti inflammatory drugs (NSAIDs)

57. Pharmacology of commonly used sedatives and analgesics Drug Initial dose Main.dosage Duration/min Fentanyl 25-100 mcg 0.5-2 mcg/kg/h 30-45 Morphine 2-5 mg 2-10 mg/h 240 Midazolam 0.5-2 mg 0.01-0.2 mg/kg/h 30-120 Lorazepam 0.5-2 mg 0.01-0.1 mg/kg/h 360-480 Propofol 0.5 mg/kg 5-75 mcg/kg/min 5-10 Haloperidol 2-10 mg 25% of load q6h Variable (hours)

58. Algorithm for the sedation and analgesia of mech. Vent. patients