1. Care of Patients with CCHS: North American Experience Iris A. Perez, MD Assistant Professor of Pediatrics Keck School of Medicine University of Southern California Children’s Hospital Los Angeles

2. Diagnosis PHOX2B Screening Test and/or Sequencing Test Exclusion of other causes of hypoventilation Chest X-ray ± chest CT Neurologic evaluation ± muscle biopsy Echocardiogram MRI ± CT scan of the brain and brainstem Metabolic screen

3. Philosophy of Chronic Ventilatory Support Ensure optimal ventilation and oxygenation during wakefulness and sleep. No consensus on best modality. Positive pressure ventilation via tracheostomy in 1 st years of life Consider diaphragm pacing while awake in full time ventilator dependent patients. Noninvasive ventilation around 6 years in stable patients requiring ventilatory support during sleep. Maintain P ET co 2 35-40 mmHg; S p o 2 ≥ 95%. Chen, M.L., and T.G. Keens. Paediatr. Resp. Rev., 5: 182-189, 2004. Weese-Mayer, D.E., et al. Pediatr. Pulmonol., 44: 521-535, 2009. Weese-Mayer, D.E., et al. Amer. J. Resp. Crit. Care Med., 160: 368-373, 1999. Weese-Mayer, D.E., et al. Amer. J. Resp. Crit. Care Med., 181: 626-644, 2010.

4. Treatment of CCHS Mechanical assisted ventilation whenever CCHS patients hypoventilate. CCHS children with 20/25 and 20/26 PHOX2B PARM usually require ventilatory support only during sleep. CCHS children with 20/27 or higher PHOX2B PARM usually require full-time ventilatory support awake and asleep. Chen, M.L., and T.G. Keens. Paediatr. Resp. Rev., 5: 182-189, 2004. Weese-Mayer, D.E., et al. Pediatr. Pulmonol., 44: 521-535, 2009. Weese-Mayer, D.E., et al. Amer. J. Resp. Crit. Care Med., 160: 368-373, 1999. Weese-Mayer, D.E., et al. Amer. J. Resp. Crit. Care Med., 181: 626-644, 2010.

5. Modes of Ventilation Positive Pressure Ventilation via tracheostomy – Relatively small tracheostomy tube – Pressure limited or pressure control mode Noninvasive Positive Pressure Ventilation (NPPV) – Timed mode – Midface hypoplasia has been reported Diaphragm Pacing Weese-Mayer, D.E., et al. Amer. J. Resp. Crit. Care Med., 181: 626-644, 2010.

6. Diaphragm Pacing Goals: – Remove tracheostomy in stable sleep only dependent patients – Allow freedom from ventilator during day in full time ventilator dependent patients Portable; improves quality of life Obstructive sleep apnea can be a complication in decannulated patients.

7. Courtesy of Tom Keens, M.D.

8. Diaphragm Pacing at CHLA Thomas G. Keens. Sheila S. Kun Iris A. Perez Mary T. Jansen J. Gordon McComb Cathy Shin

9. Chen, M.L., et al. Expert Rev. Med. Devices, 2: 577-585, 2005. Figure Courtesy of Bill Franz

10. Time to Establish Diaphragm Pacing Time (weeks) Procedure 0Surgical implantation. 6-8 Initiate Pacing (1-2 hours/day) 12-16 Increase Pacing Time (muscle training) Chen, M.L., et al. Expert Rev. Med. Devices, 2: 577-585, 2005.

11. Diaphragm Pacing at CHLA Initiated in the hospital. 2-3 night hospital admission for monitoring and pacer setting adjustment. First time: Begin pacing with the child awake in a friendly, supportive, non-threatening environment. Diaphragm pacing for 1-1.5 hours at start. Increased by 1 -2 hour each night. Chen, M.L., et al. Expert Rev. Med. Devices, 2: 577-585, 2005.

12. Criteria for Pacing Without Tracheostomy CCHS requiring ventilatory support only during sleep. Not requiring daytime naps. Stable medical course requiring infrequent hospitalizations. Not requiring full-time ventilatory support during acute respiratory illnesses. Accepts that diaphragm pacing is not as secure a method of ventilation, and intubation may be required for serious illness. Chen, M.L., et al. Expert Rev. Med. Devices, 2: 577-585, 2005.

13. Transition from Trach to Pacing Establish adequate ventilation with diaphragm pacing using open trach for at least 3 months. Down-size tracheostomy. Overnight sleep study with diaphragm pacing and capped trach. If S p o 2 >95% and P ET co 2 <40 torr, decannulate. Chen, M.L., et al. Expert Rev. Med. Devices, 2: 577-585, 2005.

14. Home Care Multidisciplinary approach working closely with home care provider Parent/caregiver education prior to discharge and during clinic visits Home nursing : 16 hrs/day Monitoring Equipment : P ET co 2 ; pulse oximeter Pulse oximeter set to alarm at S p o 2 ≤ 85%; P ET co 2 monitor alarm at P ET co 2 ≥ 55 mmHg.

15. Educational Video and Booklet

16. Follow-Up P ET co 2 and S p o 2 monitoring during the day at each clinic visit. Polysomnography to adjust ventilator settings Team evaluation at least 2 times a year and referrals are made as needed Tracheostomy tube assessment by patient’s otolaryngologist

17. Polysomnography

20. Recommended Testing Autonomic testing Assessment for Hirschsprung’s Disease Neurocognitive Assessment 72-h Holter Recording and Echocardiogram Chest and Abdominal imaging to assess for tumors of neural crest origin. Weese-Mayer, D.E., et al. Amer. J. Resp. Crit. Care Med., 181: 626-644, 2010.

21. Adolescent and Adult Issues in CCHS Care Adolescent and Adult Issues in CCHS Care

22. Alcohol Abuse in CCHS Chen, M.L., et al. Pediatr. Pulmonol., 41: 283-285, 2005. Pine, D.S., et al. Amer. J. Psychiatr., 151: 864-870, 1994. Three fatal or near-fatal events with alcohol abuse. Three fatal or near-fatal events with alcohol abuse. CNS depressant effects of alcohol can be fatal in CCHS. CNS depressant effects of alcohol can be fatal in CCHS. Anxiety may have a protective effect, but it may be lacking in CCHS. Anxiety may have a protective effect, but it may be lacking in CCHS. CCHS patients and families need to be counseled about the unique dangers of alcohol and drug abuse. CCHS patients and families need to be counseled about the unique dangers of alcohol and drug abuse.

23. 2 nd pregnancy of CCHS mother.2 nd pregnancy of CCHS mother. Prenatal diagnosis of CCHS by amniocentesis.Prenatal diagnosis of CCHS by amniocentesis. Prenatal education of all OB and pediatric staff at distant birth hospital.Prenatal education of all OB and pediatric staff at distant birth hospital. BPAP for mother after Caesarian section.BPAP for mother after Caesarian section. Prompt intubation, assisted ventilation and trach for CCHS baby.Prompt intubation, assisted ventilation and trach for CCHS baby. Discharged home at 1- month of age.Discharged home at 1- month of age.

24. CCHS Adolescent and Adult Issues Alcohol and drug abuse. Alcohol and drug abuse. Counsel about drug and alcohol use and consequences. Counsel about drug and alcohol use and consequences. Potential risks of pregnancy. Potential risks of pregnancy. Frequent respiratory monitoring during pregnancy. Frequent respiratory monitoring during pregnancy. Autosomal dominant transmission of CCHS to children. Autosomal dominant transmission of CCHS to children. Genetic counseling in adolescence and before marriage. Genetic counseling in adolescence and before marriage. Transition of medical care to internists. Transition of medical care to internists.