NEONATAL ABSTINENCE SYNDROME

Transcription

1 NEONATAL ABSTINENCE SYNDROME P Kocherlakota MD Division of Neonatology Department of Pediatrics Maria Fareri children's Hospital at West Chester Medical Center New York Medical College, Valhalla, NY

2 DISCLOSURES I have no conflict of interest to disclose I will be advocating off label use of many medications Images and photographs used in this presentation were obtained from publicly accessed sources

3 NEW EPIDEMICS

4 HISTORY OF OPIATE ADDICTION Musee d Albert Kahn, Leon Busy, 1915

5 1986 Addiction: 2/38 patients with chronic opioid 1995 Pain: Fifth vital sign. APS & VA ( 1999) 2000 JCAHO: Pain management required 1980 Addiction: 4/11,000 patients on opioid prescription 1940 Opioids do not interfere with diagnosis Opioid Circle 2013 PDMP NY: i-stop 2016 CDC: opioids only for one week 1921 No opioids until diagnosis is certain in acute abdomen

6 OPIOID EPIDEMIC Pain-Policy Physician Public Production Pharma

7 Opioid Epidemic 2014 : 1,9 Million use Prescription pain relievers, & 586,00 use Heroin Deaths: 18,893 Prescription pain reliever overdose, & 10,574 Heroin use

8 May 16, 2016

9 WHICH COUNTRY HAS MAXIMUM PERCENTAGE OF POPULATION ADDICTED TO OPIUM/HEROIN IN THE WORLD? 10. Mexico 9. Brazil 8. US 7. Canada 6. Afghanistan 5. Russia 4. Slovakia 3. France 2. UK 1. Iran

10 CONSEQUENCES OF OPIOID EPIDEMIC

11 NAS NAS is a constellation of signs and symptoms, and is a consequence of abrupt discontinuation of chronic fetal exposure to substances, that were used, misused, or abused during pregnancy

12 INCIDENCE & LOS 6 per Thousand Live Births NICU admissions 7/ /1000 LOS 13 d 19 d NICU % Days 0.6% 4% Tolia et al. N Engl J Med 2015 ; 372;:

13 Niswonger Children's Hospital opens NAS unit Tammy Childress BRISTOL HERALD COURIER Tammy Childress May 23, 2017 Updated May 23, 2017 Lily's Place: A Neonatal Abstinence Syndrome Center Mailing Address PO Box 2 Huntington, WV Contact P: (304) F: (304)

14 NAS in States BLUE STATES RED STATES 21,732 newborns ~$1.5 billion 81.5% Medicaid US Census Division NAS US Census Division NAS East south Central 16.2 Middle Atlantic 6.8 New England 13.7 Mountain 5.1 East north central 6.9 West North Central 3.4 South Atlantic 6.9 West South Central 2.6 Patrick et al- J. Perinatology Aug 2015

15 INCIDENCE OF NAS IN NYS (PER 1000 LIVE BIRTHS)

16 NAS INCIDENCE IN NYS

17 NAS INCIDENCE IN NYS & USA NYS USA

18 NAS incidence in NYS County Number Number of deliveries Rate of NAS 1 Long Island , NYC , Mid-Hudson , Capital Region 167 9, Mohawk Valley 73 2, North Country 49 2, Tug Hill Seaway 54 3, Central NY , Southern Tier 114 4, Finger Lakes , Western NY , NY State 3, ,

19 COUNTIES WITH HIGH INCIDENCE OF NAS IN NYS County Number Number of deliveries Rate of NAS 1 Niagara Chautauqua Ontario Orleans Erie 424 9,

20 OPIOID PRESCRIPTION AMONG WOMEN OF REPRODUCTIVE AGE 50.00% 27.70% 0.00% US Private Insurance 1,000, , , , , , , , , ,000 0 Opioid prescriptions % Medicaid No Opioid prescriptions MMWR, April 29, 2016, 65:

21 MAJOR DRUGS OF ABUSE Opioids Morphine Codeine Methadone Meperidine Oxycodone Propoxyphene Hydrocodone Fentanyl Heroin Naloxone Buprenorphine Stimulants Amphetamines Dextroamphetamine Meth Benzphetamnie Cocaine Methylphenidate Pemoline Phencyclidines Nicotine Depressants Alcohol Barbiturates Diazepam Alprazolam Chloral hydrate Cannabinoids Marijuana Hashish Hallucinogens LSD Inhalants Solvents Glues Gasoline Paint thinners Aerosols Nitrites Nitrous oxide

22 SUBSTANCE USE PATTERNS IN PREGNANCY Prepared 3/3/2015 by Karina Atwell, MD UW Madison 22

23 DRUG ADDICTION AMONG WOMEN Old drug addict New drug addict Age Middle aged Young Location Urban Urban, suburban & rural Education No education High school education Gravida Usually multi Usually primi Insurance No insurance Medicaid Drugs Crack, heroin, THC Prescription opioids (Methadone, Subutex, pain killers) Co-morbid conditions HIV, STD, poorly nourished Psychiatric condition, depression Abuse Polysubstance abuse Polydrug abuse Social problems Homeless, Criminal background No criminal background Prenatal care None Minimal to normal

24 EFFECTS OF VARIOUS SUBSTANCES ON PREGNANCY & FETUS & INFANT Tobacco Alcohol Cannabis Stimulants Opiates Small for gestational age Low birth weight Miscarriage/abortion Placental abruption PROM Ectopic pregnancy Pregnancy outcomes Preterm birth Infant effects Cognitive deficits NAS Behavioral Problems Teratogenicity Infant mortality/sids

25 METHADONE Synthetic Opioid Full µ Receptor agonist NMDA receptor antagonist Long Half Life Non sedating Good bioavailability Cheap PO Schedule II drug Available from 1964

26 BUPRENORPHINE Approved in 2002 Synthetic derivative of Thebaine Partial opioid agonist K opioid receptor antagonist Schedule II drug High affinity Ceiling affect T ½ = 37 hrs

27 PRESCRIPTION OPIOIDS AND NAS DESAI ET AL BMJ 2015; 350: H / 290,605 pregnant women filling opioid prescriptions Absolute risk: 5.9 per 1000 live births Long term use Short term use (>30d) (<30d) per 1000 live births per 1000 live births Whole group Opioid drug abuse Alcohol/non opioid drug abuse Late use Early use (extend to 3rd trimester) (1st & 2nd trimester) per 1000 live births per 1000 live births Whole group Opioid drug abuse Alcohol/non opioid drug abuse

28 CELLS, CENTERS & CIRCUITS Cocaine Amphetamine Opiates THC Nicotine Ethanol Opiates THC

29 OPIOIDS, RECEPTORS & NEURONS

30 A Schematic Illustration of the Mechanism of Opioid Withdrawal in Neonates. Kocherlakota, Pediatrics 2014;134:e547-e561

31 ONSET, DURATION, AND FREQUENCY OF NAS CAUSED BY VARIOUS SUBSTANCES Drug Onset, h Frequency, % Duration, d Heroin Methadone Up to 30 or more Buprenorphine Up to 28 or more Prescription opioid meds SSRIs TCAs Opioids Non-opioids Methamphetamines Inhalants Kocherlakota, Pediatrics 2014;134:e547-e561

32 CNS SIGNS OF NAS Irritability High-pitched cry Decreased sleeping time Hyperactivity Hyper-reflexia Tremors Hypertonia Myoclonic jerks Seizures

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35 GI DYSFUNCTION Excessive sucking Poor sucking Uncoordinated sucking Poor feeding Regurgitation Projectile vomiting Hyperphagia Loose stools Watery stools

36 AUTONOMIC HYPERFUNCTION Metabolic / Vasomotor / Respiratory Disturbances: Fever Sweating Yawning Mottling Nasal stuffiness Sneezing Nasal flaring Tachypnea Retractions

37 Signs / symptoms % Tremors 90 Restlessness 85 Hyperactive reflexes 51 Regurgitation 45 Increased muscle tone 45 High pitched cry 33 Sneezing 31 Frantic sucking of fists 25 Inability to sleep 24 Stretching 22 Nasal stuffiness 18 Respiratory distress 12 Vomiting 9 Frequent yawning 9 Sweating 8 Excoriation of knees, toes and nose 7 CLINICAL SIGNS OF OPIATE WITHDRAWAL CNS symptoms appear first, Seizures 2-11% The GI symptoms may be the most severe Initial intense phase (1-2 wks) followed by Chronic relapsing phase (2-8 wks.) Delayed onset with buprenorphine, barbiturates, & benzodiazepines

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39 RISK FACTORS FOR INCREASING SEVERITY AND/OR INTENSITY OF NAS Definite Probable Term Male gender Good birth weight Methadone Polydrug abuse Smoking Combination with benzodiazepines Combination with SSRIs μ-opioid receptor (OPRM1 118 AA) positive Catechol-O-methyltransferase (COMT 158 AA) positive Kocherlakota, Pediatrics 2014;134:e547-e561

40 DIAGNOSTIC CONFIRMATION Urine Meconium Short window: (1-5 d) Long window: 20 wks. Immediate availability Ship to reference lab Immunoassay Mass spectrometry Low sensitivity Highly sensitivity Cheaper Costly

41 URINARY SCREENING FOR VARIOUS DRUGS AND APPROXIMATE DURATION OF DETECTION IN NEONATES Substance Alcohol Compound/Metabolite/ Usage Duration of Detectability Ethanol Few h Fatty acid ethyl esters Up to 5 d Ethyl glucuronide Up to 30 h Ethyl sulfate Amphetamines Barbiturate Benzodiazepines Cocaine Amphetamine 1 2 d Methamphetamine 1 2 d Short acting <2 d Long acting 1 7 d Short acting 1 7 d Long acting Up to 30 d Cocaine 6 8 h Metabolites 2 5 d (up to d with heavy use)

42 URINARY SCREENING FOR VARIOUS DRUGS AND APPROXIMATE DURATION OF DETECTION IN NEONATES Substance Marijuana Opiates Compound/Metabolite/ Usage Duration of Detectability Single use 1 3 d Moderate use 5 7 d Heavy up to 10 d Chronic heavy use up to 30 d Heroin, morphine, codeine 1 2 d Hydromorphone, oxycodone 2 4 d Methadone 2 3 d Methadone metabolite Up to 6 d Buprenorphine 2 3 d Buprenorphine 2 3 d Norbuprenorphine Phencyclidine 1 to 8 d Kocherlakota, Pediatrics 2014;134:e547-e561

43 CLINICAL ASSESSMENT OF NAS

44 Finnegan Score

45 NAS SCORING SYSTEMS Scale Finnegan Lipsitz Ostrea NNWI (Green) NWI (Zahorodny) Year N 37 v v GA Term Full term Term Items 31 items 11 Items 6 Items 7 items 7 items Scores Ranked withdrawal Opioids Opioids Opioids Opioids Opioids IR Score >5 X 2 >8 Significance > 8 Comments Comprehensive >5 Ranks mild, moderate and severe Highly subjective >4 : Treatment No guidelines for treatment No guidelines for treatment Not comprehensive

46 DRAWBACKS OF FINNEGAN SCORES Never validated Different scores for criteria for diagnosis Some signs are unrelated to severity of NAS Some signs dependent upon care Subjective Variability Definitions lacking No Normal response score Time consuming Observer fatigue Poor inter observer reliability

47 This is digital Lock, Doctor NASCORE

48 SIGNS Neural Tone Relaxed position Mild Hypertonia Moderate Hypertonia Hyperactive Moro Agitation Tremors None Mild Moderate Severe Seizures or Seizure like signs None Nonspecific movements Myoclonic Jerks Seizures Feeding (Eating) Full feeds in 20 Difficult minutes feeding Poor Feeding Poor Feeding and vomiting Cry Normal cry Irritable High pitched cry Continuous high pitched cry Sleep >3 h 2-3 h 1-2 h <1 h Axillary Temperature >101 >101 and Sweating Stools Normal Loose Loose and Frequent Watery Respiration < 60 and No retractions >100 or > 60 with Retractions

49 NASCORE IN NAS Neonates: 27 Observations: 822 Gestational age: 38.2±0.17 Birth weight: 3264±673 NAS causes: Methadone: 12 Heroin: 3 Buprenorphine: 5 Prescription opioids: 2 Multiple opioids: 5 Length of stay: 12.8±6.8 d

50 NASCORE IN NAS Chi-Square: <0.001 T test: <0.001 Pearson correlation: 96% with p <0.001 Spearman correlation: p < Regression: Cox & Snell R2 = with p< ROC: with p<0.001 KR 21 Coefficient α 0.95 Sensitivity: 85% Specificity: 69%

51 NAS A clinical diagnosis A generalized multisystem disorder A treatable and preventable condition Babies are not addicted NAS can be intense and severe If untreated, it can be fatal

52 MANAGEMENT OF NAS Non-pharmacological treatment Pharmacological treatment Social services involvement Discharge follow up

53 Ten Commandments of Non Pharmacological Treatment

54 I. non-judgmental approach II. active parental participation III. Breast feeding, breast feeding and breast feeding IV. Soft touch, soft stimulation, soft music V. swaddling, holding and kangaroo care, pacifier VI. Rooming-in, cuddlers, pediatric floor admissions VII. frequent feeding & increased calorie content VIII. multi-disciplinary supportive care. IX. immediate attention of early signs of irritability X. continuous close communication with parents

55 PRINCIPLES OF TREATMENT Compassion, Empathy, Support Culture of understanding and healing Treat addiction as a disease Drug dependency is to drug abuse/addiction Encourage mom to continue MMT Addiction may have cycles of relapse & remission Involve mother and father in the management Continuous maternal presence at bedside

56 ADVANTAGES OF BREASTFEEDING Breastfeeding is associated with Shorter LOS Shorter LOT Lower Finnegan scores Less total Morphine dose Decreased medication Later onset of NAS Other benefits of Breastfeeding Skin to Skin contact Holding and Soothing Bonding Confidence Boosting Increased maternal participation in the care of neonate 56

57 BREASTFEEDING AND INCIDENCE OF NAS REQUIRING PHARMACOLOGIC TREATMENT Author Breastfed Formula Fed Abdel Latif et al % (n=85)* 79% (n=105) Welle-Strand et al % (n=58)* 69% (n=20) Wachman et al % (n=38)* 77% (n=48) O Connor et al % (n=65) 30% (n=20) Schiff et al % (n=86)* (57% mixed) 77% 57

58 BREASTFEEDING AND LENGTH OF PHARMACOLOGICAL TREATMENT Author Breastfeeding Formula Feeding Abdel Latif et al days (n=85) 108 days (n=105) Welle-Strand et al days (n=95)* 49 days (n=29) Wachman et al days (n=38)* 27.4 days (n=48) Pandey et al days (n=10)* 22.2 days (n=19) Lembeck et al days (n=64)* 11.4(n=62) 58

59 BARRIERS TO BREAST FEEDING Social Prejudice Misconceptions about medications Mothers scared to come to hospitals Need to attend methadone clinics Difficult feeders Maternal psyche problems Gray zone issues

60 FEEDING Demand feeds Frequent small feeds Difficulty in feeding Calories: 150 cal/kg/d Lactose free: Not effective Sensitive formula: Not effective Probiotics: Not effective Increase calorie content: Add Rice cereal Breast is Best

61 NAS MANAGEMENT PROTOCOL Kocherlakota, Pediatrics 2014;134:e547-e561

62 STANDARDIZED PROTOCOLS STUDIES ASTI ET AL, 2015; 135; E A QI project to reduce LOS for NICU 92 neonates (Jan 2007 to June 2012) Oral morphine initiation protocol Oral morphine weaning protocol Adjunctive therapy protocol Finnegan scoring teaching to nurses LOS decreased from 36 d to 18 d

63 STANDARDIZED PROTOCOL STUDIES Patrick et al. Pediatrics 2016; 136; e803-e , VON, 199 centers,n = 3458, 77% > 37 wk, QI project 1. QI toolkit, 2 Interactive webinars, 3. Virtual video and facilitators guide, 4. Standardized data collection, 5. interactive coaching and feedback. TOOLKIT: Standardized 1. process of identification, evaluation, treatment, discharge management, 2. measuring & reporting rates of NAS, 3. culture of compassion, understanding & Healing

64 STATE PROTOCOLS State Hospit als N= Objective conclusions Utah v 47 To study the effect on LOT 14.9d, Variability reduced from 9.1d to 5.6d MA To study LOS LOS: 25.1 to 21.6d Less need for Secondary agent OH v 130 To study LOS & LOT LOT: 17.6 v 32.3* LOS: 22.7 v 32.1* Michigan /18 months To decrease DOT to be done

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66 QUESTIONS ABOUT TREATMENT Which drug to choose When to start If Morphine: Weight based or Score based If Methadone: Symptom based or Level based When to use adjunctive meds If choose: Phenobarbital or Clonidine

67 PHARMACOLOGICAL TREATMENT OPTIONS Medication Mechanism of Dose Action Advantages Disadvantages Morphine Natural μreceptor agonist No alcohol Sedation Methadone Synthetic complete μ-receptor agonist N-methyl-daspartate antagonist mg/kg/dose q 3 4 h Increase by 0.05 mg/kg Short half-life (9 h) Maximum dose: 1.3 mg/kg/day Apnea mg/kg/dose Long half-life q 12 h, (26 h) increase by 0.05 mg/kg q 48 h Longer duration of treatment Maximum dose: 1 mg/kg/d Constipation Frequent dosing Alcohol 8% Frequent follow-up needed (variable 12 hourly doses Half-life)

68 Medication Phenobarbital Mechanism of Action γ-amino butyric acid agonist Dose Loading dose: 16 mg/kg Maintenance dose: 1 4 mg/kg/dose q12 h Advantages Long half-life ( h) Disadvantages Possible hyperactivity, Sedation High treatment failure Monitor level Alcohol 15% Drug-drug interactions Clonidine α-adrenergic receptor agonist Initial dose: µg/kg, followed by µg/kg per dose q 4 6 h Nonnarcotic antagonist No sedation No alcohol Long half-life (44 72 h) Monitor level Hypotension, Abrupt discontinuation may cause rapid rise of blood pressure and heart rate Buprenorphine Semi-synthetic partial μ-receptor agonist, κ-receptor antagonist Dose: 4 5 µg/kg/dose q 8 h Maximum dose: 60 µg/kg/d Sublingual route Alcohol 30% Adjuvant medications required Half-life (12 h)

69 MORPHINE VS METHADONE IN NAS Author N Results Comments Young et al 2015 Morphine: 13 Methadone: 13 LOS: vs 44.23* LOT: 7.46 vs 38.08* Small sample Different protocols LOS: 36 vs 40 Retrospective DTO & NMS Lainwala et al Morphine: Methadone: 29 Hall et al 2014 Morphine: 232 LOT: 15.6 vs 16.2 Methadone: 151 LOS: 21.6 vs 21.5 Protocol driven Phenobarbital Patrick et al 2014 Morphine Methadone: N= 1424 LOT: 22.2 vs 17.4 * LOS: 25.0 vs 21* Hospitals: Morphine: 10 vs Methadone:10 Retrospective Karna et al 2015 Morphine:254 Methadone: 88 LOT: 16±10 vs 19±23 Phenobarbital 99 vs15 24±15 vs 37±10 Brown et al 2015 Morphine: 16 Methadone: 15 LOS: 21 vs 14* Randomized, Prospective

70 WEIGHT BASED VS SCORE BASED Variable Weight based Morphine treatment (n=18) Score based Morphine treatment (n=57) P-value Score at initiation 3 scores > 8 or 2 scores >11 1st score >or equal to 9 1st dose of Morphine Score tiers Attached to score Morphine escalation If any score higher than current tier Attached to score > 9 Weaning 0.05 mg/kg/d 0.02 mg per dose Peak NAS Score 13(11-14) 15(14-16) <0.01 LOS 24 (12-33) 20(14-29) 0.89 Morphine onset (H) 55(24-83) 48 (29-65) 0.59 Total Morphine dose 9.22 ( ) ) ( ) 0.88 Total Morphine/Birth 3.2 ( ) weight Chisamore et al 2016

71 Medication Use in NAS TOLIA VN ET AL. N ENGL J MED 2015;372:

72 CLONIDINE TREATMENT IN NAS

73 BUPRENORPHINE TREATMENT IN NAS

74 BUPRENORPHINE TREATMENT in NAS Kraft et al 2017

75 PHARMACOLOGIC TREATMENT RULES The Rule of Total score = 24 3 consecutive scores of 8 2 consecutive scores 12 or higher 2. Remember Mean, Median, and Mode for 24h 3. Change and challenge every 24h or 48h

76 MORPHINE 1. Concentration of PO Morphine 0.5 mg per ml 2. Starting dose of PO Morphine is 0.05 mg/kg/dose 3. Increase or decrease the dose by 0.5 ml per day

77 INDICATIONS FOR CPS REFERRAL NO, Late or Limited Prenatal care Past History of Drug abuse Past H/O CPS referral to Previous deliveries Urine Positive for illicit substances, Cocaine, Heroin Incarcerated Teenage Both partners are in MAT H/O Domestic abuse Maternal psyche problems Poor bonding

78 DISCHARGE PLAN Baby is feeding well, sleeping well, & gaining weight Off opiate medication for 1-2 days Can go home on meds (Phenobarbital/methadone) Safe home environment (40% mothers relapse in first 2 m) Caregiver able to calm & feed infant (Irritability lasts 1-2m) Mottling, sneezing, stuffiness persists for months Anticipatory guidance (readmission risk, abuse ) Supportive care, prevention of SIDS (ABC, Smoking) Early and frequent follow-up (Peds, development, Hep C) Home-care/Foster home Visual problems not uncommon Visiting Nurse is mandatory

79 CONCLUSIONS NAS is increasing, approx: 6 per 1000 live births Urine/meconium toxicology is not optional Finnegan scores are popular Breast feeding decreases LOS Mother s presence in NICU itself is best treatment Rooming-in or floor admission can be tried Standardized Protocol is need of the day Non pharmacological measures are first priority Don t forget rule number 24 Morphine is preferred medication All babies need to be strictly followed up regularly

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