Andrea Vianello Fisiopatologia e Terapia Intensiva Respiratoria Ospedale-Università di Padova

1. La gestione respiratoria del paziente con Malattia di Pompe e altre Malattie Neuromuscolari Andrea Vianello Fisiopatologia e Terapia Intensiva Respiratoria Ospedale-Università di Padova

2. Diseases than can benefitfrom LTMV Robert, Critical care 2007

3. Clinical Course according to Underlying Disease Category The concept of the traffic light

4. Clinical Course according to Baseline Disease Type II Glycogenosis LTMV DMD ALS

5. Advanced care initiatives in progressive NMD Prompt response to intercurrent exacerbation; “Hospital at home” as an alternative to hospitalization; Full time NIV use for 24-hrs ventilator dependent patients.

6. Prompt response to intercurrent exacerbation

7. Criteria that should define transition from home to acute care setting • Acute loss of clinical stability; • Need for escalating medical/health care that cannot be provided in home environment; • The patient’s and family’s wishes for full intervention for reversible condition.

8. Study Design No of patients (age) Interventions Main Results Limit Vianello 2000 prospective case-control 14 patients (38,8+ 23 yrs) versus 14 historical controls E= NIPPV + CM C= MV via ETI Mortality and treatment failure significantly lower in the NPPV group Severe bulbar involvement Servera 2005 prospective cohort study 17 patients (48,7+ 20 yrs) NIPPV + MI-E Successful in averting death and ETI in 79.2% of the acute episodes Severe bulbar involvement Vianello 2005 prospective case-control 11 patients (34,9+ 17,3 yrs) versus 16 historical controls E= NIPPV + MI-E+ CPT C= NIPPV+ CPT Treatment failure was significantly lower in the experimental group Padman 1994 Retrospective study 11 NMD patients(+ 4 cystic fibrosis patients) with acute on chronic respiratory failure (4-21 yrs) NIPPV • Treatment failure = 6,6% • Significant RR and PaCO2 improvement • Number of intubated patients=1 Niranjan 1998 Retrospective study 10 patients (13-21 yrs) NIPPV + MI-E Avoidance of ETI Bach 2000 Retrospective study 11 children suffering from SMA type 1 (6–26 months) 28 distinct episodes of ARF Immediately upon extubation the patients received NIPPV + MI-E NIPPV was to a large extent successful even in very young children with severe skeletal and bulbar muscle weakness. Piastra 2006 Retrospective study 10 children (3month-12yrs) NIPPV + CPT The treatment was successful in 8 of 10 patients Efficacy of NIPPV plus assisted coughing on exacerbated NMD patients E, Experimental ; C, Control; NIPPV, Non invasive positive pressure ventilation CM, Cricothyroid-mini-tracheostomy; MV, mechanical ventilation; ETI, endotracheal intubation; CPT, chest physical treatments ; MI-E, mechanical insufflation– exsufflation; NMD, neuromuscolare disease; RR, respiratory rate; ARF, acute respiratory failure; SMA, spinal muscular atrophy

9. Invasive mechanical ventilation NIV in NMD patients in the acute setting • Extreme ventilator dependency • Severe inability to cough • Severe risk of inhalation

10. DMD, 24 yrs, administered HMV. He developed bilateral CAP. Ineffective NIV approach → endotracheal intubation

11. Weaning process Treatment of ARF Assessing readiness to wean Extubation Re-intubation Suspicion SBT Admit Discharge Tobin MJ. Role and interpretation of weaning predictors. 5° International Consesus Conference in Intensive Care Medicine: Weaning from Mechanical Ventilation. Hosted by ERS, Ats, ESICM, SCCM and SRLF; Budapest April 28-29, 2005

12. Wean the patient from endotracheal tube and avoid tracheostomy!

13. PCF : 80 L/min MEP: 20 cmH2O MIP: -18 cmH2O

14. Assessing readiness to wean Clinical assessmentAdequate cough Absence of excessive tracheobronchial secretion Resolution of disease acute phase Objective measurements Clinical stability - Stable CV status (FC≤140, sBP 90-160 mmHg) - Stable metabolic staus Adeguate oxygenation - SatO2>90% on FiO2≤40% or PatO2/ FiO2≥150 mmHg - PEEP ≤ 8 cmH2O Adequate pulmonary function - fR≤ 35 breaths/min - MIP ≤-20-25 cmH2O, VT >5 mL/kg, VC >10 mL/kg - No significant respiratory acidosis Adeguate mentation - No sedation or stable neurologic patient Boles, Eur Respir J 2007

16. First attempt extubation success rate was 95%; • Six of 7 patients who initially failed extubation succeeded on subsequent attempts; • Only one patient underwent tracheostomy.

19. Protocol: NIV delivered immediately after extubation; Man and/or mech assisted coughing to clear secretions.

20. Preventive use of NIV plus assisted coughing is effective to avert the need for reintubation. Subjects with substantial swallowing dysfunction may still encounter particular difficulties

21. Greater satisfaction with home care Disadvantages of hospitalization for NMD patients Lack specific facilities for patients with physical disabilities and for their carers / family to stay; Need of adequate family support to allow daily attendance; Not appropriate for patients likely to experience problems with acclimatisation; Risk of nosocomial infections.

22. May a “Hospital at Home” model be as effective as hospitalization for the management of exacerbation in NMD patients?

23. “Hospital at home”:definition A service that provides active treatment by health care professionals, in the patient’s home, of a condition that otherwise would requirehospitalization.

24. Aim of the study Toevaluate the efficacyand safety of a hospital-at-home model for the management of Respiratory Tract Infections in NMD patients.

25. Patients • Studygroup: 26 NMD subjectssuffering from severe respiratory tract infection treated with a hospital-at-home program; • Control group: 27 subjectswhowerehospitalized Inclusioncriteria: • Respiratory tract infection: • one or more of the following symptoms or signs: fever, throat irritation or sore throat, hoarseness, and cough • diagnosis of pneumonia: concomitant presence of infiltrates on chest x-ray • Urgent need for hospitalization: • difficulty in breathing • need for continuousnoninvasiveventilatorysupport • oxyhemoglobindesaturation with need for assisted cough Exclusioncriteria: • requirement for critical care with 24-hour surveillance • living outside the geographic area covered byourdistrict nurse service • no non-professionalcaregiversor caregiver networks at home

26. Anthropometric, Clinical, Pulmonary Function, and Blood Gas Data at Study Entry

27. Interventions Non-InvasiveVentilation • Portable ventilator • Continuoususe, except for 30–60 min periods of “rest” • Oronasalmask Manually and/or Mechanically Assisted Cough • whenever SpO2, decreased, the ventilator peak inspiratory pressure increased, or the subject had an increase in dyspnea or sense of retained secretions. • first 3 days: administered by a respiratorytherapistwho visited the subjects each morning; subsequently: administered by trained nonprofessionalcaregivers Continuous SpO2 Monitoring Standard pharmacologic treatment PulmonologyVisit at Home • first 3 days: each morning • subsequently: at the discretion of the district nurses or patient’s GP District Nurse Visit at Home • assessmentofthe subject’s adherence and response to treatment • requirement for a pulmonology visit • eachmorning and afternoonuntilrecoveryfromexacerbation. Telephoneaccessto the pulmonologistsofourdivision

28. Results In the hospital-at-home group, 18 (69.2%) responded well,with an uncomplicated course, and 8 required hospitalization.

29. Outcomes and Direct Costs of Healthcare of Subjects Treated With the Hospital-at-Home Model Versus Hospitalized Subjects

30. Anthropometric, Clinical, Pulmonary Function, and Blood Gas Data at Study Entry of Subjects Successfully Treated With the Hospitalat- Home Model Versus Those Who Required Hospital Admission By multivariate analysis, hospital-at-home failure was independently correlated with type of NMD, with an odds ratio of failure of 17.3 for subjects with ALS. None of the other covariates had any significant effect on hospital-at-home failure.

31. Hospital at home for exacerbated NMD patientsConclusions 1. Management at home is a viable option 2. Careful home monitoring is mandatory 3. Patients at risk of failing at home should be timely identified 4. Hospital at home can be problematic or even ineffective in ALS subjects • 5. Non-professional caregivers play a critical role in the transition of the care from hospital to home • 6. The cost of hospital-at-home can be impressively lower than hospital care

32. From Nocturnal to Full Time NIV use 1988 2004

33. When is full time MV required? Worsening of the symptoms and dyspnoea during the day; Excessive increases in PaCO2 ; VC ≤ 300-400mL . Extension is empirically driven Toussaint, ChronicRespiratoryDisease2007

34. Ventilator-dependent patient: the one who requires ventilation for ≥ 18 hours/day

35. Potential Disadvantages of Long-Term Tracheostomy • Expense of procedure • Higher risk of respiratory infection • Formation of granulation tissue • Airway stenosis / malacia • Tracheoinnominate-artery fistula • Tracheoesophageal fistula • Impairs speech and swallowing • Skilled assistance for suctioning • Increased carer burden • Social issues around stoma and tracheostomy tube

36. To be successful with continuous NIV, the ventilator usermust realise three goals: Optimise and maintain respiratory system compliance by frequent full insufflation Able to use a variety of interfaces which are alternated night and day Able to practice techniques to enhance peak cough flows.

37. Requirements for Home Full-time Ventilation Carefully selected and motivated individuals; Intact upper airway function; Access to centres with expertise in nocturnal and diurnal ventilation; Access to adequate levels of carers who are skilled in NIV and assisted coughing techniques. Toussaint, ChronicRespiratoryDisease2007

38. Outcome of patients on continuous NIV P Soudon, Chron Respir Dis 2008

39. Outcome of patients on continuous NIV Morbidity in 42 patients receiving ventilation either via tracheostomy (TR) or noninvasive interface (NI). P Soudon, Chron Respir Dis 2008

40. A Fatal Complication of Noninvasive Ventilation The patient was a previously healthy 53-year-old man with amyotrophiclateral sclerosis who was started on nocturnal noninvasive positive-pressureventilation (inspiratory pressure, 10 cm of water; expiratorypressure, 2 cm of water). He tolerated this well and decidedthat he did not want invasive mechanical ventilation in thefuture. The patient's disease progressed, but he continued towork full-time and used noninvasive positive-pressure ventilationall night and most of the day. He obtained a second ventilator,which he kept atwork. Noah Lechtzin, M.D., M.H.S. Charles M. Weiner, M.D. Lora Clawson,M.S.N., C.R.N.P. Johns Hopkins University School of Medicine NEJM 344:533 2001 Number 7Baltimore,MD 21287

41. More than a year after noninvasive ventilation was initiated, the patient's ventilating unit failed. The machine's error code indicated that there had been a power-supply failure. Respiratory distress quickly developed, and the patient was taken to a local hospital but died of respiratory failure before ventilation could be reinstituted. NEJM 344:533 2001 Number 7

42. Full-time NIV user: minimizing the risk 2 ventilators if use of NIV in day > 4hrs. Service & Maintenance Cough machine: indications reduced cough (PF <160), poor clearance of secretions despite assisted cough techniques, physio on NIV, ambu bag Continued caregiver training and support[ventilator function, back-up battery systems, back-up ventilator function,action skills for emergencies]. Problem solving approach Clear advance directives

43. Treatment of severe ventilatory impairment in late-onset GSDII patient Long-Term Non-Invasive Ventilation Enzyme Replacement Therapy

44. Enzyme Replacement Therapy Ethiologic therapy for GSDII • Bi-weekly intravenous infusion of recombinant GAA enzyme • ERT aims to supplement endogenous GAA through delivery of purified,exogenous GAA • Pre-clinical experiments: i.v. rhGAA therapy → correction of the biochemical phenotype in cardiac, skeletal and smooth muscle in the Gaa−/−mouse model

45. Sporadic case reports, short case series, and observational studies have demonstrated that ERT has the potential to stabilize or even improve pulmonary function.(Ravaglia 2008, Van Capelle 2008, Strothotte 2010, Bembi 2010, Orlikowski 2011)

46. Long-term ERT can be effective in stabilizing respiratory function in late-onset GSDI Variation in respiratory parameters during ERT

47. 90 patients; 8 yrs of age or older, ambulatory, free of invasive ventilation randomlyassigned to receive biweekly; IV alglucosidase alfa (20 mg per kilogram) or placebofor 78 weeks; the two primary end points were distancewalked during a 6-minute walk testand percentage ofpredicted FVC.

48. Treatment with alglucosidase alfa is associated with stabilization of pulmonary function over an 18-month period.

49. The study excluded patients with severe pulmonary impairment: • Predicted FVC < 30% • Continuous NIV • Mechanical Ventilation via tracheostomy

50. Aims of the study: To investigate the long-term efficacy of ERT in patients with late-onset GSDII complicated by severe pulmonary impairment high dependency on MV Coprimary efficacy end-points the number of hospitalizations due to pulmonary exacerbations daily hours of use of HMV