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

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1 Siesta: Should Dexmedetomidine Be Used for Sedation in the Neonatal Intensive Care Unit? Letitia M. DeLaine, B.S., Pharm.D. PGY1 Pharmacy Resident 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.

2 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 Neonate/Infant Adults/Elderly Parameter Decreased oral absorption Decreased oral absorption Increased gastric ph Increased gastric ph Increasing intestinal motility Delayed gastric emptying Absorption Immature enzyme systems Reduced GI blood flow Prolonged time to maximal drug plasma Decreased intestinal motility levels Distribution Metabolism Elimination Increased total body water Decreased total body fat Decreased total plasma proteins Immature active transport systems Immature metabolism Immature enzyme systems Decreased renal tubular mass and size Decreased renal clearance Decreased lean body mass Decreased serum albumin Decreased total body water Increased body fat Increased drug potency Increased drug duration of action Delayed metabolism Decreased clearance Reduced renal blood flow and renal mass (5,6,7,25, 26, 27,28, 30) B. Fetal Development 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 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 Score 1 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 hemorrhage 2 (IVH), ventriculomegaly, and periventricular leukomalacia (PVL) 1 See Appendix 2 Fetal Development (Table 8) 2 See Appendix 2 Fetal Development (Table 9) DeLaine Page 2

3 Table 2: Fetal Development (5,6) Gestational Age (GA) (weeks) Fetal Age (weeks) Development Sleep/Wake cycles Lung formation (bronchioles, alveolar ducts) continues Rapid brain development Surfactant is produced rhythmic breathing occurs Eyelids open 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 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 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 DeLaine Page 3

4 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 DeLaine Page 4

5 (15, 16, 19, 29, 30, 31, 32) E. Measurement of Pain and Sedation in Neonates 1. Many assessment tools 3 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 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 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) DeLaine Page 5

6 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): To define the incidence of clinical outcomes of preterm neonates Purpose 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 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 Methods 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 Babies 4 (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 Preterm neonates between weeks gestation Inclusion Criteria Intubation requiring ventilator support <8 hours Postnatal age >72 hours Continuous positive airway pressure ventilation 8 hours Major congenital abnormalities (having surgical, medical or cosmetic importance and requiring Exclusion Criteria 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 Balanced randomization in blocks, stratified by each center Performed via automated telephone response system Randomization Randomized group allocation faxed to participating NICU and hospital pharmacy One pharmacist per site had access to codes regarding drug assignment Poor neurological outcomes were defined as neonatal death (0 28 days of life without NICU Efficacy Assessment discharge), IVH grade III or IV, or PVL Satisfactory outcomes were defined as survival without IVH or maximal grade II and no PVL Intent- to- treat analysis Binary and categorical outcomes were compared using Χ 2 Statistics 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) DeLaine Page 6

7 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): 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/D 10 W (n=21) pvalue Gestation, mean (SD), week 28.6 (2.5) 29.2(2.2) 28.1 (2.2) 0.33 Male % 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 (122.1) 81 (94.1) (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 Poor neurologic outcomes o 24% of placebo group o 32% of midazolam group o 4% of morphine group o Likelihood ratio Χ 2 = 7.04, P=0.3 Efficacy Outcomes 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) DeLaine Page 7

8 Safety Outcomes Author s Conclusions Strengths 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 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 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 Study design Randomization with masked study drug infusions Attempt to decrease confounding data by assessment of maternal data Appropriate morphine bolus dosing ( mcg/kg) Limitations Usage of non- validated assessment tools Well- designed study that attempts to demonstrate morphine superiority compared to midazolam and Conclusions 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 DeLaine Page 8

9 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 May 22;363 (9422): 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 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 Methods Cranial ultrasound was used to asses composite primary outcome at 4 7 days and: o Days days for infants born <30 weeks gestation o Days 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 Neonates born at weeks gestation Inclusion Criteria Intubation within 72 hours of birth Mechanical ventilation use for <8 hours at enrollment 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) Exclusion Criteria Intrauterine growth retardation (IUGR) (birth weight <5 th 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 Automated telephone response system with faxed confirmation of treatment codes to participating NICU and/or hospital pharmacy Randomization Neonates were stratified based upon gestational age (23 26 weeks, weeks, and weeks) Grade III or IV IVH by Papile method of classification Outcomes 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 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 Statistics o 80% power o Intention- to- treat analysis Group outcomes were compared by Fisher s exact tests and Χ preterm neonates screened o 1574 did not meet inclusion criteria o 444 met excluded 2236 eligible for enrollment Results 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 DeLaine Page 9

10 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 May 22;363 (9422): Baseline Characteristics Morphine group (n=449) Placebo group (n=449) Male 235 (52.3%) 232 (51.7%) Female 214 (47.7%) 217 (48.3%) weeks GA 176 (39.2%) 174 (38.8%) weeks GA 190 (42.3%) 190 (42.3%) weeks GA 83 (18.5%) 85 (18.9%) Small for GA 5 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 Morphine group Placebo group pvalue OVERALL Severe IVH 55/411 (13%) 46/429 (11%) PVL 27/367 (7%) 34/367 (9%) Death 58/449 (13%) 47/449 (11%) Composite Outcome 115/419 (27%) 105/408 (26%) 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 = Efficacy Outcomes Open- Label Morphine No Open- Label Morphine pvalue Morphine Group Overall Results Severe IVH 36/190 (19%) 19/219 (9%) PVL 14/163 (9%) 13/202 (6%) Death 32/202 (16%) 26/244 (11%) Composite outcome 62/193 (32%) 53/225 (24%) Placebo Group Overall Results Severe IVH 40/235 (17%) 6/189 (3%) < PVL 26/199 (13%) 8/166 (5%) Death 33/242 (14%) 14/201 (17%) Composite outcome 78/228 (34%) 27/179 (15%) < Heart rates and respiratory rates were lower in the morphine group compared to the placebo group o HR p = o RR p < 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 <10 th percentile for gestational age DeLaine Page 10

11 Safety Outcomes Author s Conclusions 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 = o Time to full- volume NG feeds p = Death o Morphine group 58/449 (13%) o Placebo group 47/449 (11%) 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 (14, 15, 19, 20) G. Summary of Current Pain and Sedation Strategies Morphine Fentanyl Midazolam (15, 19, 20) Table 5: Advantages and Disadvantages of Available Agents in Preterm Neonates Agent Advantages Disadvantages Increased ventilator synchrony Decreased adrenaline concentrations No impact on incidence of severe IVH, PVL, or death Decreased adrenaline and cortisol concentrations Less impact on GI motility compared to morphine Tachyphylaxis Hypotension Prolongation of mechanical ventilation Prolongation of time to full enteral feedings Rapid tachyphylaxis Limited trials assessing acute neurologic outcomes Increased ventilator requirements during continuous infusion Chest wall rigidity during rapid infusion Decreased sedation scores Increased severe IVH, PVL, or death Hypotension Myoclonus DeLaine Page 11

12 (15, 18, 21, 22, 23) H. Novel Strategies of Pain And Sedation Control in Neonates 1. Dexmedetomidine a. Highly selective α 2 - 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 Feb;164(2): 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 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 mg/kg/dose o Fentanyl mcg/kg bolus or 1 2 mcg/kg/hour infusion o Morphine mg/kg bolus or 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 weeks Anticipated to require a minimum of 6 hours of continuous intravenous sedation in an intensive care setting DeLaine Page 12

13 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 Feb;164(2): Exclusion Weight <1 kg Criteria 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) Efficacy Outcomes Baseline characteristics in patients were similar Dose level 1 Dose level 2 Dose level 3 Total (n=14) (n=14) (n=14) (n=42) I: rescue sedation, n (%) 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 ( 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 DeLaine Page 13

14 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 Feb;164(2): Safety AEs reported in a total of 26 patients (62%) Outcomes 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 Data from this study provide pivotal information on efficacy, safety, and pharmacokinetics of Conclusions 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): To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically Purpose ventilated premature neonates Design Retrospective observational historical case control trial 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) Methods 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 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 Inclusion Criteria 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 Primary efficacy outcome was the need for adjunctive analgesia or sedation during the treatment Outcomes period DeLaine Page 14

15 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): Statistics Data are presented as means ± standard deviations Student s t- test and Χ 2 were used for statistical analysis of selected data A total of 48 patients were included in the analysis Results o 24 in the fentanyl historical control group o 24 in the dexmedetomidine group Fentanyl group Dexmedetomidine group (n=24) (n=24) pvalue GA (wk) 24.9 ± ± Birth weight (g) 675 ± ± Baseline Male/female 15/9 13/ Characteristics 5- min APGAR 6.3 ± ± CRIB- II 6 score 11 ± 2 10 ± No statistical differences between baseline characteristics however there was a substantial difference in birth weight between groups Fentanyl group Dexmedetomidine group Adjunctive Fentanyl (mean # doses/day) Prior to study entry 4.8 ± ± 2.8 During study period 1.4 ± ± 0.91 Adjunctive Lorazepam (mean # of doses/day) Prior to study entry 3.5 ± ± 3 During study period 1.6 ± ± 0.62 % of treatment days requiring no adjunctive sedation 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 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 %, respectively) Dexmedetomidine patients also had lower mean total fentanyl and lorazepam exposures Efficacy Outcomes 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 Dexmedetomidine group (n=24) (n=24) pvalue Respiratory Outcomes Days on mechanical ventilation 28.4 ± ±7.3 < % of patients requiring dexamethasone for ventilator weaning <0.02 Number of chest x- rays during hospitalization 49 ± ± 8.8 < Gastrointestinal Outcomes Meconium stool (day of life) 12.4 ± ± 6.4 <0.03 Time from meconium to transitional stool (days) 22.4 ± ±5.2 < Transitional stool (day of life) 33.6 ± ± 8.8 < Start of enteral feeds (day of life) 11.3 ± ± Time from start of feeds to full feeds (days) 50.8 ± ± 10.8 < See Appendix 3 Measurement of Pain and Sedation in Neonates (Table 14) DeLaine Page 15

16 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 Dexmedetomidine presents a novel option for the management of pain and sedation of premature Conclusions 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 Increased ventilator synchrony Tachyphylaxis Decreased adrenaline concentrations Hypotension Morphine No impact on incidence of severe IVH, PVL, or Prolongation of mechanical ventilation death Prolongation of time to full enteral feedings Fentanyl Midazolam Dexmedetomidine 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 Decreased sedation scores Increased severe IVH, PVL, or death Hypotension Myoclonus Decreased adjunctive sedation compared to Potential hypotension fentanyl Decreased incidence of delirium compared to benzodiazepine and opioid Minimal respiratory depression Minimal impact on GI motility Decreased incidence of sepsis DeLaine Page 16

17 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 Page 17

18 References 1. Holford N, Young- A H, and Anderson B. A Pharmacokinetic Standard for Babies and Adults. J Pharm Sci 2013;102: Bressler R and Bahl J. Principles of Drug Therapy for the Elderly Patient. Mayo Clin Proc. 2003;78: Kearns G, Abdel- Rahman S, Alander S et al. Developmental Pharmacology Drug Disposition, Action and Therapy in Infants and Children. N Engl J Med Sept 18:349(12): Dotta A and Chukhlantseva N. Ontogeny and Drug Metabolism in Newborns. J Matern Fetal Neonatal Med Oct;25 Suppl 4: Moore K and Persaud T. The Developing Human: Clinically Oriented Embryology. 9 th Ed. Philadelphia, PA: Saunders; Smits A, Annaert P, Allegaert K. Drug disposition and clinical practice in neonates: Cross talk between developmental physiology and pharmacology. Int J Pharm 2013 Aug 16;452(1 2): Vohr B. Neurodevelopmental Outcomes of Extremely Preterm Infants. Clin Perinatol Mar;41(1): Kugelman A and Colin A. Late Preterm Infants: Near Term But Still in a Critical Developmental Time Period. Pediatrics Oct;132(4): Colvin M, McGuire W and Fowlie P. ABCs of preterm birth: Neurodevelopmental outcomes after preterm birth. BMJ Dec 11;329(7479): ) 10. Moster D, Lie RT, and Markestad T. Long- term medical and social consequences of preterm birth. N Engl J Med Jul 17;359(3): Speer C, Sweet D, Halliday H. Surfactant therapy: past, present and future. Early Hum Dev Jun;89 Suppl 1: S22 S Jeenakeri R. and Drayton M. Management of respiratory distress syndrome. J Paeditr Child Health April; 19(4): Subiramanian S and Sweet D. Management of neonatal respiratory distress syndrome. J Paeditr Child Health Dec; 22(12): Cravero J and Blike G. Review of Pediatric Sedation. Anesth Analg 2004;99: McPherson C. Sedation and Analgesia in Mechanically Ventilated Preterm Neonates: Continue Standard of Care or Experiment? J Pediatr Pharmacol Ther. 2012;17(4): McPherson C and Grunau R. Neonatal Pain Control and Neurologic Effects of Anesthetics and Sedatives in Preterm Infants. Clin Perinatol Mar;41(1): Young T and Mangum B. Neofax Thomas Reuters. 23rd Ed. 18. Lexi- Comp Online Database. Hudson, OH: Lexi- Comp; Accessed January 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): 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 May 22;363 (9422): 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 Feb;164(2): 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): 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 American College of Obstetricians and Gynecologists. ACOG Committee Opinion No 579: Definition of term pregnancy. Obstet Gynecol Nov;122(5): MacDorman M, Hoyert D, and Matthews T. Recent declines in infant mortality in the United States, NCHS Data Brief Apr;(120): National Institute of Neurological Disorders and Stroke. National Institutes of Health. United States Department of Health and Human Services. NINDS Periventricular Leukomalacia Information Page. Updated March 4, Accessed March 17, DeLaine Page 18

19 27. Papile L, Burstein J, Burstein R et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 grams. J Pediatr Apr:92(4): American Academy of Pediatrics; Committee on Fetus and Newborn. American College of Obstetricians and Gynecologists; Committee on Obstetric Practice. The Apgar Score. Adv Neonatal Care Aug;6(4): De Jonghe B, Cook D, Appere- De- Vecchi C et. al. Using and Understanding sedation scoring systems: a systematic review. Intensive Care Med Mar; 26(3): Ambuel B, Hamlett K, Marx C et al. Assessing distress in pediatric intensive care environments: The COMFORT Scale. J Pediatr Psychol Feb;17(1):95 109) 31. Stevens B, Johnston C, Petryshen P et al. Premature Infant Pain Profile: development and initial validation. Clin J Pain Mar;12(1): Hummel P, Puchalski M, Creech S et al. Clinical Reliability and validity of the N- PASS: neonatal pain, agitation and sedation scale with prolonged pain. J Perinatol Jan;28(1): Cockburn F, Cooke R, et al. The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. The International Neonatal Network. Lancet Jul 24;342(8865): Parry G, Tucker J, and Tarnow- Mordi W et al. CRIB- II: an update of the clinical risk index for babies score. Lancet May 24;361(9371): American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non- Anesthesiologists. Practice guidelines for sedation and analgesia by non- anesthesiologists. Anesthesiology Apr;96(4): DeLaine Page 19

20 Appendix 1 Definitions 7 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 DeLaine Page 20

21 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) Appearance (skin color) Flaccid Blue, pale Some flexion of extremities Body pink, extremities blue Active motion (sneeze, cough, pull away) 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 DeLaine Page 21

22 Appendix 3 - Measurement of Pain and Sedation in Neonates (29, 30) Table 10: COMFORT Scale Alertness Droopily asleep Lightly asleep Drowsy Fully awake & alert Hyper- alert Calmness/Agitation Calm Slightly Anxious Anxious Very Anxious Panicky Respiratory Response Physical Movement Mean Arterial Pressure (baseline measurement required) Heart Rate (baseline measurement required) No coughing and no spontaneous respiration No spontaneous movement Blood pressure below baseline Heart rate below baseline Spontaneous respiration minimal responses to vent Occasional slight movement Blood pressure consistently at baseline Heart rate consistently at baseline Occasional cough or resistance to vent Frequent, slight movement Infrequent elevations of 15% or more (1 3 during observation period) Infrequent elevations of 15% or more (1 3 during observation period0 Muscle Tone Relaxed/none Relaxed muscle tone Normal muscle tone Actively breathing against ventilator or coughs regularly Vigorous movement in extremities only Frequent observations of 15% or more (more than 3 during observation period) Frequent elevations of 15% or more (more than 3 during observation period) Increased tone/flexion fingers or toes Fights ventilator, coughing or choking Vigorous movement including head and torso Sustained elevation greater than or equal to 15% Sustained elevation greater than or equal to 15% 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 Score Chart Gestational age 36 weeks /7 weeks /7 weeks <28 weeks Observe Infant 15 seconds Observe baseline heart rate (HR) & oxygen saturation (SaO 2 ) Observe infant 30 seconds Behavioral state Heart rate max Oxygen saturation min Brow bulge Eye squeeze Nasolabial furrow Active/awake Eyes open Facial movements 0 4 bpm increase 0 2.4% decrease None 0 9 % of time None 0 9 % of time None 0 9 % of time Quiet/awake Eyes open No facial movements 5 14 bpm increase % decrease Minimum 10 39% of time Minimum 10 39% of time Minimum 10 39% of time Active/sleep Eyes closed Facial movements bpm increase Quiet/sleep Eyes closed No facial movements 25 bpm increase 5 7.4% decrease 7.5% increase Moderate 40 69% of time Moderate 40 69% of time Moderate 40 69% of time Maximum 70% of time Maximum 70% of time Maximum 70% of time DeLaine Page 22

23 Appendix 3 (cont d) - Measurement of Pain and Sedation in Neonates Assessment Criteria Crying/Irritability Behavior state Facial Expression Extremities tone Vital signs (HR, RR, BP, SaO 2 ) Table 12: Neonatal Pain, Agitation and Sedation Scale (N- PASS) (32) No cry with painful stimuli Sedation Normal Pain/Agitation Moans or cries Irritable or crying at Appropriate crying minimally with intervals Not irritable painful stimuli Consolable No arousal to any stimuli No spontaneous movement Mouth is lax No expression No grasp reflex Flaccid tone No variability with stimuli Hypoventilation or apnea Arouses minimally to stimuli Little spontaneous movement Minimal expression with stimuli Weak grasp reflex Decreased muscle tone <10% variability from baseline with stimuli Appropriate for gestational age Relaxed Appropriate Relaxed hands and feet Normal tone Within baseline or normal for gestational age Restless, squirming Awakens frequently Any pain expression intermittent Intermittent clenched toes, fists or finger splay Body is not tense >10 20% increase from baseline SaO % with stimulation and quick increase High- pitched or silent- continuous cry Inconsolable Arching, kicking Constantly awake Arouses minimally/no movement (not sedated) Any pain expression continual Continual clenched toes, fists or finger splay Body is tense >20% increase from baseline SaO 2 75% with stimulation with slow increase Out of sync with vent Birth weight (grams) Gestation (weeks) Congenital malformations (excluding inevitably lethal malformations) Maximum base excess in first 12 hours (mmol/l) Minimum appropriate fraction of inspired oxygen (FiO 2 ) in first 12 hours Maximum appropriate FiO 2 in first 12 hours Table 13: Clinical Risk Index for Babies (CRIB) (33) Factor Score > > None 0 Not acutely life- threatening 1 Acutely life- threatening 3 > to to < < DeLaine Page 23

24 Appendix 3 (cont d) - Measurement of Pain and Sedation in Neonates Table 14: Clinical Risk Index for Babies II (34) DeLaine Page 24