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Siesta: Should Dexmedetomidine Be Used for Sedation in the Neonatal Intensive Care Unit?

Letitia M. DeLaine, B.S., Pharm.D. PGY1 Pharmacy Resident 2013 – 2014

Children’s Hospital of San Antonio/CHRISTUS Santa Rosa Healthcare System April 4, 2014

Pharmacotherapy Rounds The University of Texas Health Science Center at San Antonio

Learning Objectives

• Describe complications associated with preterm birth • Discuss efficacy and safety concerns of current therapies used for neonatal sedation

• Evaluate literature supporting the use of dexmedetomidine for moderate sedation in neonates.

DeLaine

A. Pediatric Pharmacokinetics (1,2,3,4,6) 1. The ongoing growth and development in pediatric patients causes drastic pharmacokinetic changes 2. Role of ontogeny in the disposition and action of drugs

a. Pediatric patients ≠ “miniature men and women” b. Neonates ≠ “small children”

Table 1: Comparison of Neonatal/Infant and Adults/Elderly Pharmacokinetics (1,2,3,4) Pharmacokinetic

Parameter Neonate/Infant Adults/Elderly

Absorption

• Decreased oral absorption • Increased gastric pH • Increasing intestinal motility • Immature enzyme systems • Prolonged time to maximal drug plasma

levels

• Decreased oral absorption • Increased gastric pH • Delayed gastric emptying • Reduced GI blood flow • Decreased intestinal motility

Distribution

• Increased total body water • Decreased total body fat • Decreased total plasma proteins

• Decreased lean body mass • Decreased serum albumin • Decreased total body water • Increased body fat

Metabolism • Immature active transport systems • Immature metabolism • Immature enzyme systems

• Increased drug potency • Increased drug duration of action • Delayed metabolism

Elimination • Decreased renal tubular mass and size • Decreased renal clearance

• Decreased clearance • Reduced renal blood flow and renal

mass

B. Fetal Development (5,6,7,25, 26, 27,28, 30) 1. Fetus –child in the latter stages of development before birth. 2. Neonate – a newborn child in the first 28 days after birth 3. Preterm neonate – infant born prior to 37 weeks gestational age

a. Advances in medicine have improved survival rates for preterm neonates and infants of limited viability, those born between 22 – 25 weeks gestational age

b. American Academy of Pediatrics recommends withholding or discontinuing resuscitation measures when outcomes include almost certain death or unacceptable levels of morbidity, which includes infants <23 weeks or <400 grams

c. The Apgar Score1 may be used to determine infant status and response to resuscitation 1 minute, 5 minutes, and 10 minutes

d. Neonatal morbidity may be due to intraventricular hemorrhage2 (IVH), ventriculomegaly, and periventricular leukomalacia (PVL)

1 See Appendix 2 – Fetal Development (Table 8) 2 See Appendix 2 – Fetal Development (Table 9)

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Table 2: Fetal Development (5,6) Gestational Age (GA) (weeks) Fetal Age (weeks) Development

24 – 26 22 – 24

• Sleep/Wake cycles • Lung formation (bronchioles,

alveolar ducts) continues • Rapid brain development

27 – 32 25 – 30 • Surfactant is produced – rhythmic

breathing occurs • Eyelids open

33 – 36 31 – 34 • GI motility becomes organized • Nephrogenesis has completed

C. Complications Associated with Preterm Birth (7, 8, 9, 10, 11, 12, 13, 25, 26) 1. Most common neonatal intensive care unit (NICU) admission is prematurity 2. Improvements in survival rates not proportionally associated with improvements in adverse outcomes 3. >28 week gestation or <1000 mg birth weight is a risk factor of significant neurodevelopmental impairment

a. 20 – 32 weeks gestation is important for brain growth and development i. Neurogenesis, neuronal migration, maturation, apoptosis and synaptogenesis occur

during this time ii. Extremely preterm infants (EPT) have a higher risk of compromised neurodevelopment

due to hypoxia, ischemia, infection, poor nutrition, or illness b. Brain damage related to periventricular hemorrhage is a strong predictor or future neurodevelopmental problems

c. Clinical consequences include serious neuromotor problems, visual and hearing impairments, learning difficulties, psychological, behavioral and social problems

d. Preterm infants are at an increased risk of developing cerebral palsy (CP) i. Most common functional complications of cerebral palsy in preterm neonates are CP

related paralysis leading to inability to walk or feed independently ii. 50% of infants born before 28 weeks gestation will need some form of additional

educational support iii. Decreased brain volume, microstructure abnormalities and alterations in neural

connectivity has been associated with low gestational age and may attribute to learning challenges

e. Neurosensory deficits are commonly seen in this patient population i. Retinopathy of prematurity is a common cause of visual impairments in this age group ii. Hearing impairment requiring amplification has been reported in 3% of infants born at

<28 weeks GA f. Respiratory distress syndrome (RDS) is primarily caused by surfactant deficiency and structural immaturity

i. Natural surfactant production occurs around 27 – 32 weeks gestation ii. Neonatal RDS is present at birth and quickly progresses to respiratory failure, including

pneumothorax and death, without intervention iii. Incidence increases with decreasing gestation iv. Characterized by cyanosis, grunting, sternal and intercostal recession and tachypnea v. The invention of exogenous surfactant has led to improved survival vi. Many preterm infants require ventilator support

g. Other complications include inguinal hernia, necrotizing entercolitis, and patent ductus arteriosis

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4. Late preterm infants are not fully mature and will miss critical in-‐utero brain and lung growth a. LP newborns are the fastest growing subset of neonates and have a threefold higher infant mortality rate compared with term births

b. Intrauterine growth retardation (IUGR) is the most common cause for birth in LP infants and is an increased risk of death

c. LP infants are at increased risk of resuscitation at birth, feeding difficulty, jaundice, hypoglycemia, temperature instability, apnea, and respiratory distress.

d. arteriosis (McPherson & Grunau) 5. Studies have shown medical and social disabilities in adulthood will increase with decreasing gestational age

at birth 6. Neonates born > 32 weeks gestation have similar neurodevelopmental outcomes to babies born at term

D. Review of Pain and Sedation Neonatal Patients (14, 15, 16) 1. Pain in the preterm neonate has been unrecognized and misunderstood

a. Ascending neural pathways responsible for nociception mature earlier than descending inhibitory pathways (responsible for localization and mitigation of pain)

b. Nociceptive neurons in the dorsal horn of the spinal cord have increased excitability leading to hyperalgesia and allodynia in infants

c. Increase exposure to stress and pain has been associated with decreased brain growth in the frontal and parietal lobes and alterations in organization and neuronal connections in the temporal lobes

d. Repetitive pain exposure has been associated with decreased body and brain growth, poor cognitive and motor function and altered spontaneous cortical oscillations in the resting brain at various ages

2. Neonates in the neonatal intensive care unit (NICU) experience a median of 10 painful procedures day a. Minor procedures, major surgery, to life-‐saving interventions such as mechanical ventilation

3. Pain and stress result from labor and delivery difficulties, adaptation to the extrauterine environment, diseases associated with prematurity and multiple procedures required after birth

4. Approximately 20% of preterm infants undergo a surgical procedure prior to discharge from the NICU 5. Sedation is not a primary therapy but a treatment of procedural side effects 6. Reasons to sedate pediatric patients:

a. Reduction in crying and struggling b. Increased parental satisfaction

7. Inadequate sedation has been linked to anxiety in children and their families 8. Procedure completion is considered a successful sedation regimen 9. Goals of pediatric sedation:

a. Anxiety relief b. Pain control c. Control of excessive movement

10. Pain and stress have been shown to aid in development/exacerbation of early IVH or ischemic lesions leading to PVL

11. Studies have shown that preterm infants exposed to surgery and anesthesia have a greater incidence of moderate to severe white matter injury and smaller total brain volumes

12. Preclinical data from newborn rodents and nonhuman primates demonstrated early anesthetic exposure leads to neuroapoptosis

a. Cell death begins early after exposure and increases with each subsequent exposure b. Limited data exist about long term neurodevelopmental outcomes associated with sedatives and analgesics in preterm neonates

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E. Measurement of Pain and Sedation in Neonates (15, 16, 19, 29, 30, 31, 32) 1. Many assessment tools3 are used to assess pain, agitation, and sedation in neonate, however none

validated or used consistently a. Each measure behavioral and physical responses to pain b. COMFORT Scale

i. 8 indicators (alertness, calmness/agitation, respiratory response, physical movement, blood pressure, heart rate, muscle tone, facial tension)

ii. Score range of 8 – 40 iii. Scores between 17 – 26 indicate adequate pain control and sedation

c. Premature Infant Pain Profile (PIPP) i. Seven item, four point scale of assessment ii. Takes gestational age into account to discriminate between pain and nonpain situations iii. Higher scores indicate painful situations for the infant

d. Neonatal Pain, Agitation and Sedation Scale i. Sedation is scored from 0 – -‐2 for each criteria ii. Desired levels of sedation will cause score variation

a. Deep sedation –score of -‐10 to -‐5 as a goal b. Light sedation – score of -‐5 to -‐2 as a goal

iii. Pain is scored from 0 – +2 for each criteria a. Higher scores indicate increased pain b. Treatment/intervention is recommended if score >3

F. Management of Pain and Sedation in Neonates (14, 15, 16, 17, 18, 19, 20) 1. Nonpharmacological Methods of Sedation/Analgesia

a. Foundation of pain and agitation relief for mildly painful routine procedures b. Nonnutritive, swaddling, kangaroo care with or without breastfeeding, music therapy, multisensorial stimulation has been shown to reduce pain scores

2. Pharmacological Methods of Sedation/Analgesia a. Pharmacologic sedation during mechanical ventilation is not currently recommended in preterm neonates due to concerns with safety and efficacy

b. Benzodiazepine and opiate (morphine and fentanyl) use is common in clinical practice due to lack of alternatives

c. Sucrose i. Mechanism of action is not completely understood ii. Data suggest pain response is mediated through opioid receptors, dopaminergic

pathways, and cholinergic pathways iii. Neonatal pain markers – facial grimacing, crying, and motor activity – have been shown

to decrease after sucrose administration for minor painful procedures iv. It may exert a sedative, rather than analgesic, effect in the brain of the neonate based

on clinical and electroencephalographic findings v. No impact on measures of motor development when compared to placebo when given

for invasive procedures in the first week of life in preterm infants born at <31 weeks gestation

d. Midazolam i. Binds to stereospecific benzodiazepine receptors on the postsynaptic ɣ-‐aminobutyric

acid (GABA) neuron in the central nervous system ii. Water solubility and rapid clearance makes this drug ideal for use in neonates

3 See Appendix 3 – Measurement of Pain and Sedation in Neonates (Table 10, 11, 12)

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iii. Elimination is delayed in preterm neonates due to functional immaturity of hepatic and renal systems

iv. Increased risk of myoclonus in neonates when compared to older populations that may complicate sedation/analgesic assessments

v. Bolus dosing of 200 mcg/kg may produce hypotension that results in decreased oxygen saturation, cerebral oxygenation index, and cerebral blood flow velocity

vi. No data currently on long-‐term neurodevelopmental impact in this population

Table 3: Anand K, Barton B, McIntosh N, et al. Analgesia and Sedation in Preterm Neonates Who Require Ventilatory Support: Results from the NOPAIN Trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999;153(4):331 – 338. 19

Purpose • To define the incidence of clinical outcomes of preterm neonates • To estimate the effect size and adverse effects associated with analgesia and sedation • To calculate the sample size for a definitive test of this hypothesis

Design • Double blind, randomized, placebo-‐controlled, multicenter trial

Methods

• Neonates randomized to receive one of three treatments as long as clinically necessary for a maximum of 14 days

o Midazolam 0.01 mg/mL in 10% dextrose o Morphine 0.05 mg/mL in 10% dextrose o Placebo (10% dextrose)

• Additional morphine analgesia was provided if deemed necessary by a clinician • Level of sedation and pain response measured prior to study drug initiation, at 24 hours of

continued infusion, at 10 hour post infusion and 12 hours post infusion • Severity of illness was measured by Clinical Risk Index for Babies4 (CRIB) and the Neonatal Medical

Index • Level of sedation was assess by the COMFORT score • Responses to pain were measure by the Premature Infant Pain Profile (PIPP) score

Inclusion Criteria • Preterm neonates between 24 – 32 weeks gestation • Intubation requiring ventilator support <8 hours

Exclusion Criteria

• Postnatal age >72 hours • Continuous positive airway pressure ventilation ≥ 8 hours • Major congenital abnormalities (having surgical, medical or cosmetic importance and requiring

therapeutic interventions within 7 days after birth) • Severe intrapartum asphyxia (defined as 5-‐minute APGAR score ≤3) • Participation in other research studies that interfered with NOPAIN study procedures or outcomes

Randomization

• Balanced randomization in blocks, stratified by each center • Performed via automated telephone response system • Randomized group allocation faxed to participating NICU and hospital pharmacy • One pharmacist per site had access to codes regarding drug assignment

Efficacy Assessment • Poor neurological outcomes were defined as neonatal death (0 – 28 days of life without NICU

discharge), IVH grade III or IV, or PVL • Satisfactory outcomes were defined as survival without IVH or maximal grade II and no PVL

Statistics

• Intent-‐to-‐treat analysis • Binary and categorical outcomes were compared using Χ2 • Linear regression analysis used to compare mean outcome levels • Type 1 error level of p<0.05 was specified for the primary clinical outcome

4 See Appendix 3 – Measurement of Pain and Sedation in Neonates (Table 13)

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Table 3 (cont’d): Anand K, Barton B, McIntosh N, et al. Analgesia and Sedation in Preterm Neonates Who Require Ventilatory Support: Results from the NOPAIN Trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999;153(4):331 – 338. 19 Results • 170 neonates identified from 9 participating centers

o 37 met exclusion criteria o 57 excluded for parental refusal o 9 excluded for various other reasons (religious objections, lack of central line access, change

in health maintenance organization assignment or research staff not notified) o 67 recruited and completed study

Baseline Characteristics

Variable Midazolam (n=22) Morphine (n=24) Placebo/D10W (n=21) pValue Gestation, mean (SD), week 28.6 (2.5) 29.2(2.2) 28.1 (2.2) 0.33 Male % 54.5 46.2 57.1 0.73 Birth weight, mean (SD), grams 1245 (445) 1230 (475) 1049 (419) 0.36 Entry weight, mean (SD), grams 1224 (491) 1265 (501) 1188 (524) 0.91 Duration of study drug, mean (SD), hours of infusion 122.2 (122.1) 81 (94.1) 121.1 (120.8) 0.37 CRIB score, mean (SD) 5.7 (3.5) 4.5 (3.1) 6.6 (4) 0.24

• Severity of illness at birth, measured by CRIB score, was similar • Maternal data such as age, education level, income and drug use (prescription vs. nonprescription)

was collected and no statistically significant differences were noted

Efficacy Outcomes

• Poor neurologic outcomes o 24% of placebo group o 32% of midazolam group o 4% of morphine group o Likelihood ratio Χ2 = 7.04, P=0.3

Frequency of Neurologic Outcomes by Treatment Group, No. (%)

Midazolam Morphine Placebo Mortality 1 (4.6) 0 2 (9.5) Pneumothorax 1 (4.6) 0 1 (4.8) PVL 4 (18.2) 1 (4.2) 1 (4.8) IVH grade I 4 (18.2) 2 (8.3) 1 (4.8) VH grade II 1 (4.6) 1 (4.2) 0 IVH grade III 3 (13.6) 0 2 (9.5) IVH grade IV 2 (9.1) 0 1 (4.8)

Preterm Infant Pain Profile (PIPP) and COMFORT scores, Mean (SD) COMFORT Before drug 15.9 (3.8) 17.3 (4.6) 15.6 (3.2) During drug 14.9 (4.6) 14.7 (3.2) 17.5 (4.2) After drug 15.8 (4.7) 18.9 (4) 16.2 (4.1) PIPP Before drug 10.5 (4.1) 11.5 (4.0) 11.4 (3.8) During drug 8.9 (3.3) 7.9 (2.3) 12.7 (3.8) After drug 8.9 (4.4) 10.2 (2.9) 9.9 (3.7)

• COMFORT scores were not altered significantly from baseline in any group

o Before, during and after drug infusion scores were similar in all groups except morphine group

o Decreased sedation was noted in the morphine group (p=0.005) • Pain response during endotracheal suctioning, measured by PIPP scores, were reduced during

morphine and midazolam infusions (p<0.001 and p=0.002, respectively) when compared to placebo o PIPP decreases were reduced during morphine infusion compared to baseline (p=0.002)

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• No differences were noted in secondary outcomes – assessed by number of days required for

mechanical ventilation, continuous positive airway pressure or oxygen therapy, duration of NICU stay and tolerance of enteral feeds

• Additional morphine usage on days 1, 2, 3 and 4 – 14 was not statistically significant for any group

Safety Outcomes

• Death o 2 neonates from placebo group o 1 neonate in midazolam group o 0 neonates in morphine group

• Pneumothorax o 1 neonate from placebo group o 1 neonate from midazolam group o 0 neonates in morphine group

Author’s Conclusions

• Data supports the benefit of short-‐term sedation and analgesia in preterm neonates that require ventilator support

• Data suggest that morphine administered prophylactically may improve neurological outcomes • Decreased PIPP scores in morphine and midazolam group could reflect sedation effects of study drugs

or analgesic effects of additional morphine • Lack of statistical difference in COMFORT scores could be due to lack of tool validation in this

population • Increase in COMFORT scores in the morphine group post infusion may demonstrate agitation

associated with opioid withdrawal

Strengths

• Study design • Randomization with masked study drug infusions • Attempt to decrease confounding data by assessment of maternal data • Appropriate morphine bolus dosing (50 – 200 mcg/kg)

Limitations • Usage of non-‐validated assessment tools

Conclusions • Well-‐designed study that attempts to demonstrate morphine superiority compared to midazolam and placebo

e. Opioids i. Fentanyl is a synthetic µ-‐opioid agonist

a. Ideal for procedural sedation due to fast onset and short duration of action b. Metabolism to inactive metabolites is delayed in neonates c. Tachyphylaxis develops quickly due to delayed renal elimination and drug

accumulation d. Decreases stress response and behavioral state scores in preterm neonates e. Increased ventilator pressure requirements indicate respiratory depression f. Severe GI effects and chest wall rigidity may occur

ii. Morphine is the prototypical µ-‐opioid receptor agonist a. Incomplete metabolism in preterm neonates leads to rapid tachyphylaxis b. Delayed elimination results in accumulation of morphine and metabolites

when administered via continuous infusion c. Increases ventilator synchrony and decreases stress responses, measured by

adrenaline concentrations d. Prolongs duration of mechanical ventilation due to respiratory depression e. Decreases GI motility and delays time required to reach full enteral feeds f. NOPAIN demonstrated decreased incidence of (IVH, PVL, death) when

compared to midazolam and placebo g. Preclinical data demonstrate negative impacts on developing brains including

apoptosis and decreased neuronal density and dendritic length h. Studies are conflicting about long-‐term neurodevelopment after morphine

administration

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Table 4: Anand K, Hall R, and Desea N et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomized trial. Neurologic Outcomes and Pre-‐emptive Analgesia in Neonates. Lancet. 2004 May 22;363 (9422):1673 – 1682. 20

Purpose • To investigate whether pre-‐emptive morphine analgesia decreases the rate of composite primary outcome of neonatal death, severe IVH and PVL in preterm neonates

Design • Randomized, blinded, multicenter trial

Methods

• Neonates randomized to receive either morphine or placebo o Doses determined by gestational age and pharmacokinetic data o Study drug bolus for analgesia or increase in infusion rate was not permitted o Infusion rate was increased if neonate grew to a higher gestational stratum

• Open-‐label morphine was allowed for both study groups • Use of midazolam or other sedative analgesics was not permitted • Cranial ultrasound was used to asses composite primary outcome at 4 – 7 days and:

o Days 28 – 35 days for infants born <30 weeks gestation o Days 14 – 28 days for infants born ≥30 weeks gestation

• Pain was assessed during tracheal suctioning before start of study drug infusion, at hour 24 of infusion, hour 72 of infusion and 12 hours post infusion

o Heart rate and oxygen saturation were recorded 2 minutes before and after suctioning

Inclusion Criteria • Neonates born at 23 – 32 weeks gestation • Intubation within 72 hours of birth • Mechanical ventilation use for <8 hours at enrollment

Exclusion Criteria

• Major congenital anomalies (requiring surgical, medical or cosmetic importance and necessitating therapeutic intervention within 7 days of birth)

• Birth asphyxia (APGAR at 5 min ≤3 or cord-‐blood pH <7.00) • Intrauterine growth retardation (IUGR) (birth weight <5th percentile for gestational age) • Maternal opioid addiction (history of drug intake within 72 hours before delivery or positive maternal

urine test) • Participation in other clinical trials

Randomization

• Automated telephone response system with faxed confirmation of treatment codes to participating NICU and/or hospital pharmacy

• Neonates were stratified based upon gestational age (23 – 26 weeks, 27 – 29 weeks, and 30 – 32 weeks)

Outcomes • Grade III or IV IVH by Papile method of classification • PVL defined by cystic echolucency adjacent to lateral ventricles • Death within 28 days of birth without discharge from the NICU • Composite outcome – severe IVH, PVL and/or neonatal death

Statistics

• 470 neonates per group according to sample size calculations to show a reduction of rate of composite primary outcome from 25% in placebo group and 17.5% in morphine group

o α = 0.05 o 80% power o Intention-‐to-‐treat analysis

• Group outcomes were compared by Fisher’s exact tests and Χ2

Results

• 4253 preterm neonates screened o 1574 did not meet inclusion criteria o 444 met excluded

• 2236 eligible for enrollment o 1338 not enrolled (parental refusal, extubation, hospital transfer, research staff not notified

or other reasons) • 898 randomized

o 449 enrolled in morphine group – 446 complete assessments o 449 enrolled in placebo group – 444 complete assessments

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Table 4 (cont’d): Anand K, Hall R, Desea N et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomized trial. Neurologic Outcomes and Pre-‐emptive Analgesia in Neonates. Lancet. 2004 May 22;363 (9422):1673 – 1682. 20


Morphine group (n=449)

Placebo group (n=449)

Male 235 (52.3%) 232 (51.7%) Female 214 (47.7%) 217 (48.3%) 23 – 26 weeks GA 176 (39.2%) 174 (38.8%) 27 – 29 weeks GA 190 (42.3%) 190 (42.3%) 30 – 32 weeks GA 83 (18.5%) 85 (18.9%) Small for GA5 25 (5.6%) 28 (6.2%) Mean (SD) birth weight, grams 1037 (340) 1054 (354) Median (IQR) CRIB score 4 (1 – 8) 4 (1 – 8)

• No differences noted between treatment groups

Efficacy Outcomes

Morphine group Placebo group pValue OVERALL Severe IVH 55/411 (13%) 46/429 (11%) 0.2362 PVL 27/367 (7%) 34/367 (9%) 0.3493 Death 58/449 (13%) 47/449 (11%) 0.2533 Composite Outcome 115/419 (27%) 105/408 (26%) 0.5777

• No statistically significant difference was noted in frequency of composite outcomes overall or in each

gestational stratum • Open-‐label morphine was given to fewer neonates in the morphine group than the placebo group

o 202 (45.3%) versus 242 (54.6%) o p = 0.0054

Open-‐Label Morphine No Open-‐Label Morphine pValue

Morphine Group – Overall Results Severe IVH 36/190 (19%) 19/219 (9%) 0.0024 PVL 14/163 (9%) 13/202 (6%) 0.4346 Death 32/202 (16%) 26/244 (11%) 0.1051 Composite outcome 62/193 (32%) 53/225 (24%) 0.0505

Placebo Group – Overall Results Severe IVH 40/235 (17%) 6/189 (3%) <0.0001 PVL 26/199 (13%) 8/166 (5%) 0.0070 Death 33/242 (14%) 14/201 (17%) 0.0232 Composite outcome 78/228 (34%) 27/179 (15%) <0.0001

• Heart rates and respiratory rates were lower in the morphine group compared to the placebo group

o HR p = 0.0048 o RR p < 0.0001

• PIPP scores at 24 hours post infusion were lower in the morphine group compared to the placebo

group overall • Hypotension occurred more frequently in the morphine group compared to the placebo group after

the loading dose (p=0.0085) and 24 hours post infusion (p=0.0006) o 39 neonates that developed hypotension were assessed (26 in morphine group and 13 in

placebo group) o 5 developed severe IVH – 3 in morphine group; 2 in placebo group o 4 developed PVL – 2 in morphine group; 2 in placebo group

5 Birth weight <10th percentile for gestational age

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o 5 deaths – 2 in morphine group; 3 in placebo group o 33% composite primary outcome in neonates that develop hypotension (n=6 – 25%

morphine group; n=7 – 64% placebo group) • Duration of mechanical ventilation and time to tolerate full-‐volume nasogastric (NG) feeds was longer

in the morphine group when compared to placebo o Duration of mechanical ventilation p = 0.0446 o Time to full-‐volume NG feeds p = 0.0338

Safety Outcomes

• Death o Morphine group – 58/449 (13%) o Placebo group – 47/449 (11%)

Author’s Conclusions

• Continuous morphine infusions did not change the frequency of primary study outcomes in preterm neonates overall

• During subgroup analysis, those receiving open-‐label morphine exhibited higher neonatal mortality, severe IVH and PVL over those who did not receive open-‐label morphine

• Severe IVH and pain may be misconstrued in this patient population as they both present as irritability • 5 – 7 year follow-‐up of a subset of NEOPAIN subjects showed no difference in overall intelligence

quotient but morphine-‐treated children had smaller head circumference, impaired short-‐term memory and more social problems when compared to placebo-‐treated children

Strengths • Large sample size • Randomization with masked study drug infusions • Minimization of bias • Appropriate infusion rates/doses (10 – 30 mcg/kg/hour)

Limitations • No comparator used • Did not meet power • Cranial ultrasounds not performed prior to study drug initiation

Conclusions • Although power was not met, data prove that bolus doses of morphine not continuous morphine infusions are associated with an increased frequency of worse neurological outcomes

• However, continuous morphine infusion does increase the rate of neurological events in preterm neonates that are mechanically ventilated but not hypotensive prior to the start of morphine infusions

G. Summary of Current Pain and Sedation Strategies (14, 15, 19, 20)

Table 5: Advantages and Disadvantages of Available Agents in Preterm Neonates (15, 19, 20) Agent Advantages Disadvantages

Morphine

• Increased ventilator synchrony • Decreased adrenaline

concentrations • No impact on incidence of severe

IVH, PVL, or death

• Tachyphylaxis • Hypotension • Prolongation of mechanical

ventilation • Prolongation of time to full enteral

feedings

Fentanyl

• Decreased adrenaline and cortisol concentrations

• Less impact on GI motility compared to morphine

• Rapid tachyphylaxis • Limited trials assessing acute

neurologic outcomes • Increased ventilator requirements

during continuous infusion • Chest wall rigidity during rapid

infusion

Midazolam • Decreased sedation scores • Increased severe IVH, PVL, or death

• Hypotension • Myoclonus

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H. Novel Strategies of Pain And Sedation Control in Neonates (15, 18, 21, 22, 23) 1. Dexmedetomidine

a. Highly selective α2-‐adrenergic agonist shown to provide analgesia, anxiolysis and sedation b. FDA approved for sedation in adult patients c. Not FDA approved for use in pediatric patients however data regarding its use in pediatrics is increasing

d. May cause rapid changes in heart rate and blood pressure secondary to smooth muscle constriction and direct stimulation of peripheral α receptors

e. Bradycardia and hypotension could be life-‐threatening if used concomitantly with negative inotropes or chronotropes or in patients with cardiovascular compromise

f. Advantages to its use over other agents is lack of respiratory depression, fast onset of action, and the ability for repeat administration

Table 6: Chrysostomou C, Schulman S, Castellanos H et al. A Phase II/III, Multicenter, Safety, Efficacy, and Pharmacokinetic Study of Dexmedetomidine in Preterm and Term Neonates. J Pediatr. 2014 Feb;164(2):276 – 282. 21 Purpose • To investigate safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full-‐term

neonates ≥28 weeks to ≤44 weeks gestational age Design • Phase II/III, open-‐label, multicenter trial Methods • Patients assigned to either group I (≥28 to <36 weeks) or group II (≥36 weeks to ≤44 weeks) based on

gestational age determined by the date of the mother’s last menstrual cycle plus the weeks after birth to the day of enrollment

• Patients in each group were sequentially assigned to 1 of 3 escalating dose levels o Level 1

Loading dose (LD) 0.05 mcg/mg Maintenance dose (MD) 0.05 mcg/kg/hour

o Level 2 LD 0.1 mcg/kg MD 0.1 mcg/kg/hour

o Level 3 LD 0.2 mcg/kg MD 0.2 mcg/kg/hour

• Study drug was administered via controlled infusion device • LD given over 10 – 20 minutes followed by MD continuous infusion given over 6 – 24 hours • The need for sedation/analgesia was assessed using Neonatal Pain, Agitation, Sedation Scale (N-‐PASS)

o Significant pain or agitation (score >3) warranted supplemental therapy o Supplemental therapy could also be administered at investigator discretion o Midazolam 0.05 – 0.15 mg/kg/dose o Fentanyl 0.5 – 2 mcg/kg bolus or 1 – 2 mcg/kg/hour infusion o Morphine 0.025 – 0.1 mg/kg bolus or 0.01 – 0.02 mg/kg/hour infusion

• Use of other sedatives/analgesics (other than dexmedetomidine, midazolam, fentanyl and morphine) continuous infusion or repeated dosing of any neuromuscular blocking agent, alpha-‐2 agonist/antagonists other than dexmedetomidine and anesthetics or analgesics administered via the epidural or spinal route were prohibited

Inclusion Criteria

• Initially intubated and mechanically ventilated neonates • Gestational age ≥28 – ≤44 weeks • Anticipated to require a minimum of 6 hours of continuous intravenous sedation in an intensive care setting

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Table 6 (cont’d): Chrysostomou C, Schulman S, Castellanos H et al. A Phase II/III, Multicenter, Safety, Efficacy, and Pharmacokinetic Study of Dexmedetomidine in Preterm and Term Neonates. J Pediatr. 2014 Feb;164(2):276 – 282. 21 Exclusion Criteria

• Weight <1 kg • Heart rate (HR) <120 bpm • Second or third degree heart block (unless a pacemaker was in place) • Neurologic conditions prohibiting accurate evaluation of sedation, such as catastrophic brain injury

(patients who survive extensive brain damage but with residual severe neurologic impairment) or other severe mental disorders that would make the response to sedative unpredictable and/or assessment of the Neonatal Pain, Agitation, Sedation Scale (N-‐PASS) unreliable

• Immobility from neuromuscular disease or continuous infusion of neuromuscular blocking agent • Exposure to any investigational drug within 30 days before dexmedetomidine administration • Previous exposure to dexmedetomidine as part of an investigational study • Allergies to/contraindications to fentanyl, morphine, midazolam or dexmedetomidine • ALT >115 U/L (2 – 2.5 times the upper limit of normal)

Outcomes • Primary efficacy endpoint was the number of patients requiring midazolam for sedation during dexmedetomidine administrations

• Secondary endpoints included the use of medications (fentanyl or morphine) for analgesia, change from baseline in vital signs (HR, blood pressure, respiratory rate) and oxygen saturation, time spent with a total N-‐PASS score >3 and time to extubation from dexmedetomidine initiation

Statistics • Authors assumed 90% of subjects in the low-‐dose group and 45% of subjects in the high-‐dose group would require additional sedation

• 14 subjects in each group would be 72% power to detect a difference with α = 0.05 Results • Study was completed in 2 phases with initial enrollment of 42 patients

o 18 in group I o 24 in group II

Baseline Characteristics Group I

(n=18) Group II (n=24)

Total (n=42)

Gestational age, week, mean (SD) 31.8 (2.1) 38.7 (2.0) 35.7 (4) Age at screening, week, mean (SD) 0.78 (0.9) 1.99 (1.7) 1.48 (1.5) Sex, female, n (%) 11 (61) 5 (21) 16 (38) Weight, kg, mean (SD) 1.7 (0.6) 3.3 (0.6) 2.6 (1)

• Baseline characteristics in patients were similar

Efficacy Outcomes Dose level 1

(n=14) Dose level 2

(n=14) Dose level 3

(n=14) Total (n=42)

I: rescue sedation, n (%) 0 0 0 0 II: rescue sedation, n (%) 1 (12) 1 (12) 2 (25) 4 (17) I: rescue analgesia, n (%) 1 (17) 1 (17) 1 (17) 3 (17) II: rescue analgesia, n (%) 4 (50) 4 (50) 6 (75) 14 (58) I: time in N-‐PASS>3, h median (range) 0.5 (0 – 1) 0 (0) 0 (0 – 1.9) 0 (0–1.9) II: time in N-‐PASS>3, h median (range) 0 (0 – 1) 0.1 (0 – 5) 0.3 (0 – 2) 0.1 (0–5)

• 5% of all N-‐PASS assessments, taken at various times, were >3 • Patients at all dose levels had a total N-‐PASS score >3 for only a short time • 8 patients (20%) were extubated at a median of 4.3 hours (0.17 – 21 hours) after dexmedetomidine

initiation • HR and BP decreased by an average of 12% and 14%, respectively • Patients in group I had lower clearance (0.3 vs. 0.9 L/hr/kg), increased elimination (7.6 vs. 3.2 hours)

and increased area under the curve concentrations (2049 vs. 357 pg/mL/mcg) compared to group II

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Table 6 (cont’d): Chrysostomou C, Schulman S, Castellanos H et al. A Phase II/III, Multicenter, Safety, Efficacy, and Pharmacokinetic Study of Dexmedetomidine in Preterm and Term Neonates. J Pediatr. 2014 Feb;164(2):276 – 282. 21 Safety Outcomes

• AEs reported in a total of 26 patients (62%) o 11 (61%) in group I o 15 (62.5%) in group II

• 3 patients (7%) reported 4 AEs related to dexmedetomidine o Diastolic hypertension in group 1, dose level 2 o Hyper tension in group II, dose level 1 o Significant agitation in group II, dose level 3

• No serious AEs reported and no AEs that led to drug discontinuation Author’s Conclusions

• Data from this study provide pivotal information on efficacy, safety, and pharmacokinetics of dexmedetomidine in term and preterm neonates

• The majority of patients were adequately sedated only a few required extra sedation • Adverse effects related to drug exposure were predictable and dose-‐dependent • Increased unbound drug concentrations, elimination half-‐life and area under the curve concentrations

and decreased clearance in preterm neonates demonstrate the need for lower dosing in this population to avoid increased sedative/analgesic effects and side effects

Strengths • First study assessing pharmacokinetics, efficacy and safety in preterm and term neonates • Multicenter study with large sample size • Provides information about dosing in neonatal population

Limitations • Potential bias due to confounders • Did not include patients ≤28 weeks gestational age • No long-‐term neurodevelopmental data available

Conclusions • Data from this study provides the groundwork for further studies assessing use of dexmedetomidine in this patient population. This also provides data on the pharmacokinetics of dexmedetomidine associated with this patient population

Table 7: O’Mara K, Gal P, Wimmer J. Dexmedetomidine Versus Standard Therapy with Fentanyl for Sedation in Mechanically Ventilated Premature Neonates. J Pediatr Pharmacol Ther. 2012;17(3):252 – 262. 22

Purpose • To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates

Design • Retrospective observational historical case control trial

Methods

• Subjects were matched in cohort pairs based on gestational age being within one week of the other • Dexmedetomidine was initiated within 48 hours of life (either empirically or in those who met

predefined criteria for continuous infusion sedation) o Patients who required at least 5 doses of fentanyl 1 mcg/kg, lorazepam 0.1 mg/kg or any

combination of the 2 agents in a 24 hour period • Adjunctive sedation was defined as any bolus dose(s) of fentanyl 1 mcg/kg or lorazepam 0.1 mg/kg

given in addition to the continuous infusion or scheduled boluses of treatment drug

Inclusion Criteria

• Premature neonates born at Women’s Hospital of Greensboro • Fentanyl historical controls were selected from the NICU database when matched with baseline

characteristics • Dexmedetomidine neonates

o <36 weeks gestation at birth o Less than 2 weeks of life at study entry o Receiving mechanical ventilation o Born between September 2008 and May 2010

• Fentanyl neonates o Received fentanyl via continuous infusion or scheduled intravenous (IV) boluses for sedation

within the first 48 hours of life o Born between January 2005 and May 2010

Exclusion Criteria • Any major congenital anomaly considered incompatible with life

Outcomes • Primary efficacy outcome was the need for adjunctive analgesia or sedation during the treatment period

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Table 7 (cont’d): O’Mara K, Gal P, Wimmer J. Dexmedetomidine Versus Standard Therapy with Fentanyl for Sedation in Mechanically Ventilated Premature Neonates. J Pediatr Pharmacol Ther. 2012;17(3):252 – 262. 22

Statistics • Data are presented as means ± standard deviations • Student’s t-‐test and Χ2 were used for statistical analysis of selected data

Results • A total of 48 patients were included in the analysis

o 24 in the fentanyl historical control group o 24 in the dexmedetomidine group


Fentanyl group (n=24)

Dexmedetomidine group (n=24) pValue

GA (wk) 24.9 ± 1.6 25.5 ± 1.7 0.095 Birth weight (g) 675 ± 164.2 832 ± 204.2 0.051 Male/female 15/9 13/11 0.55 5-‐min APGAR 6.3 ± 1.5 6.4 ± 1.7 0.78 CRIB-‐II6 score 11 ± 2 10 ± 2.4 0.167

• No statistical differences between baseline characteristics however there was a substantial difference

in birth weight between groups

Efficacy Outcomes

Fentanyl group Dexmedetomidine group Adjunctive Fentanyl (mean # doses/day)

Prior to study entry 4.8 ± 1.6 3.5 ± 2.8 During study period 1.4 ± 0.68 1 ± 0.91

Adjunctive Lorazepam (mean # of doses/day) Prior to study entry 3.5 ± 1.6 3 ± 3 During study period 1.6 ± 0.69 0.73 ± 0.62 % of treatment days requiring no adjunctive sedation 16.5 54.1

• Mean treatment durations for fentanyl and dexmedetomidine were 20 and 12.4 days, respectively • Mean number of sedative boluses per day was similar (fentanyl + lorazepam boluses in fentanyl group

= 3 vs. 1.73 in dexmedetomidine group) • Dexmedetomidine patients had a larger percentage of treatment days that did not require adjunctive

sedation compared to the fentanyl group (54.1 % vs. 16.5 %, respectively) • Dexmedetomidine patients also had lower mean total fentanyl and lorazepam exposures • No patients required intervention for hypotension and no patients in the dexmedetomidine group

experienced any appreciable effect on either blood pressure or heart rate

Fentanyl group (n=24)

Dexmedetomidine group (n=24) pValue

Respiratory Outcomes Days on mechanical ventilation 28.4 ± 9.9 14.4 ±7.3 <0.0001 % of patients requiring dexamethasone for ventilator weaning 45.8 18.2 <0.02 Number of chest x-‐rays during hospitalization 49 ± 13.8 28.8 ± 8.8 <0.0001

Gastrointestinal Outcomes Meconium stool (day of life) 12.4 ±7.7 7.6 ± 6.4 <0.03 Time from meconium to transitional stool (days) 22.4 ± 13.2 7.5 ±5.2 <0.0002 Transitional stool (day of life) 33.6 ± 13.8 15.2 ± 8.8 <0.0001 Start of enteral feeds (day of life) 11.3 ± 5.5 8.5 ± 3.4 0.0574 Time from start of feeds to full feeds (days) 50.8 ± 18.1 26.8 ± 10.8 <0.0001

6 See Appendix 3 – Measurement of Pain and Sedation in Neonates (Table 14)

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• Significantly shorter duration of mechanical ventilation was noted in the dexmedetomidine group

compared to the fentanyl group • 83% of patients were extubated while receiving dexmedetomidine while no patients were extubated

while receiving fentanyl • Patients in the dexmedetomidine group experienced an insignificant decreased in combined outcomes

of severe IVH (grades III-‐IV) and PVL compared to the fentanyl group (2% vs. 7%, respectively) Author’s Conclusions

• Dexmedetomidine presents a novel option for the management of pain and sedation of premature neonates

• Data demonstrates dexmedetomidine provides adequate sedation development of hemodynamic instability

• Premature neonates treated with dexmedetomidine in this study required less adjunctive analgesia and sedation medications

• Despite having similar baseline respiratory disease, as evidenced by CRIB-‐II scores, patients in the dexmedetomidine were extubated approximately 2 weeks earlier than patients in the fentanyl group

Strengths • Comparator used • Patient population • Adds to current literature about dexmedetomidine usage in premature neonates

Limitations • Retrospective, case-‐control design • Small sample size • Differences in birth weight/baseline characteristics • No long-‐term neurological developmental outcome data available

Conclusions • This study adds to the limited data available about dexmedetomidine usage in premature neonates • Dexmedetomidine usage appears to be advantageous against fentanyl in premature neonates when

comparing usage of adjunctive sedation and analgesia

Table 5 (revised): Advantages and Disadvantages of Available Agents in Preterm Neonates (15) Agent Advantages Disadvantages

Morphine

• Increased ventilator synchrony • Decreased adrenaline concentrations • No impact on incidence of severe IVH, PVL, or

death

• Tachyphylaxis • Hypotension • Prolongation of mechanical ventilation • Prolongation of time to full enteral feedings

Fentanyl

• Decreased adrenaline and cortisol concentrations • Less impact on GI motility compared to morphine

• Rapid tachyphylaxis • Limited trials assessing acute neurologic

outcomes • Increased ventilator requirements during

continuous infusion • Chest wall rigidity during rapid infusion

Midazolam • Decreased sedation scores • Increased severe IVH, PVL, or death

• Hypotension • Myoclonus

Dexmedetomidine

• Decreased adjunctive sedation compared to fentanyl

• Decreased incidence of delirium compared to benzodiazepine and opioid

• Minimal respiratory depression • Minimal impact on GI motility • Decreased incidence of sepsis

• Potential hypotension

DeLaine

I. Should Dexmedetomidine Be Used for Sedation In Neonates? (7, 9, 10, 15, 16, 21, 22, 23) 1. Premature birth is associated with many complications 2. Current medications used for sedation in premature infants are effective but associated with many adverse

effects a. Opiates are associated with prolonged respiratory depression, increased ventilator pressures, prolonged time to enteral feeds, and tachyphylaxis

b. Midazolam has shown increased incidence of severe neurologic outcomes 3. Further studies with larger patient populations are needed to determine short-‐term and long-‐term safety

and efficacy of medications used for sedation and analgesia in neonates 4. Currently, dexmedetomidine is only approved for use in adults but its use should be expanded to include

pediatric and neonatal patients a. Long-‐term safety and efficacy data is needed b. Dexmedetomidine has demonstrated efficacy and safety over current medications used for moderate sedation in this population

c. The risk of adverse effects, primarily cardiac in nature, should limit its use to hemodynamically stable pediatric and neonatal patients

d. Doses should be initiated at 0.3 mcg/kg/hour and increased incrementally for desired response by a provider credentialed to administer sedatives

DeLaine

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164 13. Subiramanian S and Sweet D. Management of neonatal respiratory distress syndrome. J Paeditr Child Health. 2012 Dec;

22(12): 518 – 522. 14. Cravero J and Blike G. Review of Pediatric Sedation. Anesth Analg 2004;99:1355 – 1364 15. McPherson C. Sedation and Analgesia in Mechanically Ventilated Preterm Neonates: Continue Standard of Care or

Experiment? J Pediatr Pharmacol Ther. 2012;17(4):351 – 264 16. McPherson C and Grunau R. Neonatal Pain Control and Neurologic Effects of Anesthetics and Sedatives in Preterm Infants.

Clin Perinatol. 2014 Mar;41(1):209 – 227 17. Young T and Mangum B. Neofax. 2010. Thomas Reuters. 23rd Ed. 18. Lexi-‐Comp Online Database. Hudson, OH: Lexi-‐Comp; 2013. www.online.lexi.com. Accessed January 3, 2014. 19. Anand K, Barton B, McIntosh N, et al. Analgesia and Sedation in Preterm Neonates Who Require Ventilatory Support:

Results from the NOPAIN Trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Arch Pediatr Adolesc Med. 1999;153(4):331 – 338

20. Anand K, Hall R, and Desea N et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomized trial. Neurologic Outcomes and Pre-‐emptive Analgesia in Neonates. Lancet. 2004 May 22;363 (9422):1673 – 1682

21. Chrysostomou C, Schulman S, Castellanos H et al. A Phase II/III, Multicenter, Safety, Efficacy, and Pharmacokinetic Study of Dexmedetomidine in Preterm and Term Neonates. J Pediatr. 2014 Feb;164(2):276 – 282

22. O’Mara K, Gal P, Wimmer J. Dexmedetomidine versus Standard Therapy with Fentanyl for Sedation in Mechanically Ventilated Premature Neonates. J Pediatr Pharmacol Ther. 2012;17(3):252 – 262

23. Lam F, Bhutta A, Tobias J, et al. Hemodynamic Effects of Dexmedetomidine in Critically Ill Neonates and Infants with Heart Disease. Pediatric Cardiology; Published online: 11 February 2012.

24. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No 579: Definition of term pregnancy. Obstet Gynecol. 2013 Nov;122(5):1139-‐40

25. MacDorman M, Hoyert D, and Matthews T. Recent declines in infant mortality in the United States, 2005 – 2011. NCHS Data Brief. 2013 Apr;(120):1 – 8.

26. National Institute of Neurological Disorders and Stroke. National Institutes of Health. United States Department of Health and Human Services. NINDS Periventricular Leukomalacia Information Page. http://www.ninds.nih.gov/disorders/periventricular_leukomalacia/periventricular_leukomalacia.htm. Updated March 4, 2014. Accessed March 17, 2014.

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Appendix 1 – Definitions7

1. Allodynia – pain resulting from a stimulus which would not normally provoke pain (e.g. light touch of the skin). 2. Cerebral Palsy (CP) – disorder of movement and posture that involves abnormalities in tone, reflexes, coordination,

and movement, delays in motor milestone achievement, and aberration in primitive reflexes that is permanent but not unchanging and is causes my non-‐progressive interference, lesion, or abnormality of the developing immature brain.

3. Deep Sedation/Analgesia – a drug-‐induced depression of consciousness during which patients cannot be aroused but respond purposefully following repeated or painful stimulation. The ability to independently maintain ventilator function may be impaired. Patients may require assistance in maintaining a patent airway and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

4. Extremely preterm infant (EPT) – gestational age ≤26-‐6/7 weeks. 5. Fetal Age – actual age of the growing baby. 6. General anesthesia – a drug-‐induced loss of consciousness during which patients are not arousable, even if by painful

stimulation. The ability to independently maintain ventilator function is often impaired. Patients often require assistance in maintaining a patent airway and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-‐induced depression of neuromuscular function. Cardiovascular function may be impaired.

7. Gestational Age (GA) – age of the pregnancy from the last normal menstrual period. 8. Hyperalgesia – increased sensitivity to pain or enhanced intensity of pain sensation. 9. Intraventricular hemorrhage (IVH) – bleeding into the fluid-‐filled areas (ventricles) inside the brain. 10. Late preterm (LP) infants – those born at 34-‐0/7 to 36-‐6/7 week gestational age. 11. Minimal sedation (anxiolysis) – a drug –induced state during which patients respond normally to verbal commands.

Although cognitive function and coordination may be impaired, ventilator and cardiovascular functions are unaffected.

12. Moderate Sedation/Analgesia (conscious sedation) – a drug-‐induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

13. Periventricular leukomalacia (PVL) – characterized by death of white matter brain tissue caused by lack of oxygen or blood flow to the periventricular area of the brain; results in death or loss of brain tissue.

14. Preterm Birth – birth before 37 completed weeks of gestation 15. Respiratory distress syndrome (RDS) – pulmonary insufficiency due to the lack of surfactant and structural immaturity

of the lungs. 16. Retinopathy of prematurity (ROP) – a disorder commonly affecting infants born <32 weeks gestation and the most

common cause of visual impairments in premature infants. 17. Surfactant – a surface active lipoprotein mixture which coats the alveoli and prevents collapse of the lungs by

reducing surface tension of pulmonary fluids. 18. Term Pregnancy – all deliveries between 37 0/7 weeks gestation and 41 6/7 weeks gestation. Use of this phrase is

discouraged by the American College of Obstetricians and Gynecologists. 19. Very low birth weight infant (VLBW) – infant weighing <1501 grams at birth

7 Word/phrases are underlined

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Appendix 2 – Fetal Development

Table 8: APGAR Scoring Scale (28) 0 points 1 point 2 points Total points

Activity (muscle tone) Absent Arms and legs flexed Active movement Pulse Absent Below 100 bpm Over 100 bpm

Grimace (reflex irritability)

Flaccid Some flexion of extremities

Active motion (sneeze, cough, pull away)

Appearance (skin color) Blue, pale Body pink, extremities

blue Completely pink

Respiration Absent Slow, irregular Vigorous cry Severely depressed 0 – 3

Moderately depressed 4 – 6 Excellent condition 7 -‐ 10

Table 9: Intraventricular Hemorrhage Grading Scale (27) Grade Location Prognosis

I Restricted to subependymal region/germinal matrix Good

II Extension into normal sized ventricles and typically filling less than 50% of ventricle volume Overall good

II Extension into dilated ventricles ~20% mortality

IV Extension into dilated ventricles with parenchymal hemorrhage (represents a venous infarction) ~90% mortality

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Appendix 3 -‐ Measurement of Pain and Sedation in Neonates

Table 10: COMFORT Scale (29, 30) 1 2 3 4 5

Alertness Droopily asleep Lightly asleep Drowsy Fully awake & alert Hyper-‐alert

Calmness/Agitation Calm Slightly Anxious Anxious Very Anxious Panicky

Respiratory Response

No coughing and no spontaneous respiration

Spontaneous respiration minimal responses to vent

Occasional cough or resistance to vent

Actively breathing against ventilator or coughs regularly

Fights ventilator, coughing or choking

Physical Movement No spontaneous movement

Occasional slight movement

Frequent, slight movement

Vigorous movement in extremities only

Vigorous movement including head and

torso Mean Arterial Pressure (baseline measurement required)

Blood pressure below baseline

Blood pressure consistently at

baseline

Infrequent elevations of 15% or more (1 – 3 during observation period)

Frequent observations of 15% or more (more than 3 during observation

period)

Sustained elevation greater than or equal to 15%

Heart Rate (baseline measurement required)

Heart rate below baseline

Heart rate consistently at

baseline

Infrequent elevations of 15% or more (1 – 3 during observation period0

Frequent elevations of 15% or more

(more than 3 during observation period)

Sustained elevation greater than or equal to 15%

Muscle Tone Relaxed/none Relaxed muscle tone Normal muscle tone Increased

tone/flexion –fingers or toes

Extreme rigidity/flexion of fingers or toes

Facial Tension relaxed Normal tone Some tension Full facial tension Hyper-‐alert

Table 11: Premature Infant Pain Profile (PIPP) (31) Process Indicator 0 1 2 3 Score

Chart Gestational age ≥36 weeks 32 – 36-‐6/7

weeks 28 – 31-‐6/7 weeks <28 weeks

Observe Infant 15 seconds

Behavioral state Active/awake Eyes open

Facial movements

Quiet/awake Eyes open No facial

movements

Active/sleep Eyes closed

Facial movements

Quiet/sleep Eyes closed No facial

movements

Observe baseline heart rate (HR) & oxygen saturation

(SaO2)

Heart rate max 0 – 4 bpm increase

5 – 14 bpm increase

15 – 24 bpm increase ≥25 bpm increase

Oxygen saturation min 0 – 2.4% decrease

2.5 – 4.9% decrease 5 – 7.4% decrease ≥7.5% increase

Observe infant 30 seconds

Brow bulge None

0 – 9 % of time Minimum

10 – 39% of time Moderate

40 – 69% of time Maximum

≥70% of time

Eye squeeze None 0 – 9 % of time

Minimum 10 – 39% of time

Moderate 40 – 69% of time

Maximum ≥70% of time

Nasolabial furrow

None 0 – 9 % of time

Minimum 10 – 39% of time

Moderate 40 – 69% of time

Maximum ≥70% of time

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Appendix 3 (cont’d) -‐ Measurement of Pain and Sedation in Neonates

Table 12: Neonatal Pain, Agitation and Sedation Scale (N-‐PASS) (32) Assessment Criteria Sedation Normal Pain/Agitation

-‐2 -‐1 0 1 2

Crying/Irritability No cry with painful stimuli

Moans or cries minimally with painful stimuli

Appropriate crying Not irritable

Irritable or crying at intervals Consolable

High-‐pitched or silent-‐continuous cry

Inconsolable

Behavior state

No arousal to any stimuli

No spontaneous movement

Arouses minimally to stimuli

Little spontaneous movement

Appropriate for gestational age

Restless, squirming Awakens frequently

Arching, kicking Constantly awake

Arouses minimally/no movement (not

sedated)

Facial Expression Mouth is lax No expression

Minimal expression with stimuli

Relaxed Appropriate

Any pain expression intermittent

Any pain expression continual

Extremities tone No grasp reflex Flaccid tone

Weak grasp reflex Decreased muscle

tone

Relaxed hands and feet

Normal tone

Intermittent clenched toes, fists or finger splay

Body is not tense

Continual clenched toes, fists or finger

splay Body is tense

Vital signs (HR, RR, BP, SaO2)

No variability with stimuli

Hypoventilation or apnea

<10% variability from baseline with

stimuli

Within baseline or normal for

gestational age

>10 – 20% increase from baseline

SaO2 76 – 85% with stimulation and quick increase

>20% increase from baseline

SaO2 ≤75% with stimulation with slow increase

Out of sync with vent

Table 13: Clinical Risk Index for Babies (CRIB) (33) Factor Score

Birth weight (grams)

>1350 0 851 – 1350 1 701 – 850 4 ≤700 7

Gestation (weeks) >24 0 ≤24 1

Congenital malformations (excluding inevitably lethal malformations)

None 0 Not acutely life-‐threatening 1 Acutely life-‐threatening 3

Maximum base excess in first 12 hours (mmol/L)

> -‐7.0 0 -‐7 to -‐9.9 1

-‐10 to -‐14.9 2 ≤15.0 4

Minimum appropriate fraction of inspired oxygen (FiO2) in first 12 hours

<0.40 0 0.41 – 0.80 2 0.81 – 0.90 3 0.91 – 1.00 5

Maximum appropriate FiO2 in first 12 hours

<0.40 0 0.41 – 0.80 1 0.81 – 0.90 3 0.91 – 1.0 5

DeLaine

Appendix 3 (cont’d) -‐ Measurement of Pain and Sedation in Neonates

Table 14: Clinical Risk Index for Babies – II (34)

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