Pain Management and Sedation in the NICU

Pain Management and Sedation in the NICU N. Ambalavanan MD Assistant Professor, Division of Neonatology University of Alabama at Birmingham Feb 2003 Common Misconceptions (“Myths”)  Myth 1: The neural and endocrine systems of the newborn infant are not developed to the stage that allows for transmission of painful stimuli (i.e. that they can’t feel pain)  Myth 2: Newborn infants cannot “remember” pain and, therefore, there can be no sequelae of pain  Myth 3: Pain cannot be assessed in the newborn infant  Myth 4: Newborn infants are easily comforted without analgesics (Adapted from the CPS statement on neonatal pain) Outline of Talk  Rationale :  Definitions  Problems with neonatal  Pain assessment why do it? pain management  Pain alleviation  Clinical recommendations  Appendix Rationale: why do it?  Neonates and infants can perceive pain...  …which can have adverse short-term consequences…  …and perhaps adverse long term consequences (?)  Pain may be attenuated by analgesia Rationale: perception of pain  Perception of pain: – Neonates and infants perceive pain on behavioral, physiological, and biochemical measures (KJS Anand et al: PCNA 1989; 36:795 & NEJM 1987; 317: 1321; Craig KD et al: Pain 1993; 53: 287 & Pain 1987;28:395) – Even the fetus in utero mounts a hormonal (cortisol and b-endorphin) response to needling (Giannakoulopoulos X et al. Lancet 1994; 344: 77) Rationale: perception of pain  Parental perception of pain: Vivid memories of parental stress (even 3 years post-NICU) related to neonatal appearance and behavior, and the pain and procedures endured by the neonate. Rationale: short-term effects  Adverse short-term consequences: – Stress hormone level inversely correlated with severity of illness. Catecholamine levels higher in non-survivors, who have a lower fall in norepinephrine levels with sedation (Barker DP et al. Arch Dis Child Fetal Neonatal Ed. 1996; 75:F187) – Exposure of preterm neonates to repetitive pain and stress leads to clinical instability and complications (KJS Anand. Crit Care Med 1993; 21: S358) Rationale: long-term effects  Adverse long-term consequences: – Circumcision increases pain response to subsequent vaccination (Taddio A et al: Lancet 1997;349: 599) – Permanent structural and functional changes may occur in infants exposed to multiple painful and stressful events (Porter FL et al: J Dev Behav Pediatr 1999;20:253) Rationale: effect of analgesics  Analgesia is effective – Anesthesia improves clinical outcomes in surgical neonates (Anand KJS et al. Lancet 1987;1:243) – Multiple clinical studies have shown reduction in stress markers and pain scores with the use of analgesics / sedatives in ventilated neonates. Rationale: effect of analgesics – The NOPAIN pilot study: • Morphine analgesia given by continuous lowdose infusion reduced the risk of poor neurologic outcome (death/ IVH III or IV / PVL) from 24% in placebo group and 32% in midazolam group to 4% in the morphine group. (Total n=67) (The NOPAIN pilot study. Anand KJS et al. Arch Pediatr Adol Med 1999; 153; 331) Rationale: effect of analgesics  The NEOPAIN Multicenter study – OBJECTIVE: To investigate whether pre-emptive morphine analgesia decreases death, IVH (Grade III or IV), or PVL in ventilated preterm neonates. – DESIGN/METHODS: • Ventilated preterm neonates from 16 NICUs received blinded placebo (N=414) or low-dose morphine (N=406) therapy. • Randomization and morphine infusion rates were stratified by GA (23-26 wk @ 10mcg/kg/hr; 27-29 wk @ 20mcg/kg/hr; 30-32 wk @ 30mcg/kg/hr). • Early and late cranial ultrasonograms were assessed centrally for IVH and PVL by two radiologists. (The NEOPAIN Multicenter Trial Group. Presented at PAS 2002) Rationale: effect of analgesics  The NEOPAIN Multicenter study (contd.) – Results: • No differences in mortality (10.9% vs. 13.1%), severe IVH (10.8% vs. 12.1%), or PVL (10.2% vs. 8.3%) in the placebo vs. morphine groups. • In 27-29 wk neonates, composite of death, IVH, or PVL seemed to occur more frequently in the morphine group (16.7% vs. 26.4%, p=0.06). • No differences occurred in the secondary outcomes between the two randomized groups. Rationale: effect of analgesics  Effect on long-term outcome: – Insufficient data exist – In one study of 87 children assessed at 5-6 years, exposure to morphine in the neonatal period did not have any adverse effects on tests of intelligence, motor function, or behavior, although there was a trend towards better performance in the morphine group in all three tests (MacGregor et al: Arch Dis Child Fetal Neonatal Ed 79: F40-43, 1998) Some definitions...  Stress: A mentally or emotionally disruptive condition occurring in response to adverse external influences and capable of affecting physical health, or a stimulus which leads to such a condition  Stress Response: The physiologic response, including motor, visceral, humoral, and behavioral responses of the neonate to stress More definitions…  Pain: An unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the study of Pain: IASP)  Discomfort: Something that would ordinarily be considered to disturb one's comfort or cause annoyance Neonatal pain management: problems  Confusion regarding Stress vs. Pain – Pain is always stressful – Stress is not always due to pain or associated with pain  Pain assessment – pain is subjective in its assessment – no “gold standard” for evaluating neonatal pain (especially in ELBW neonates) – Indications for analgesia therefore uncertain Neonatal pain management: problems  Analgesia in the newborn period – Pharmacodynamics and pharmacokinetics of analgesics vary, depending on the: • agent • gestational age • postnatal age • underlying disease process • and many other factors Neonatal pain management: problems  Where is the evidence? – Lack of sufficient data on value of analgesia regarding important short-term and long-term outcomes in both full-term and preterm infants – However, absence of evidence is not evidence of absence! – Large variation and lack of equipoise among centers regarding pain control practices. Pain assessment methods  Behavioral assessment – Subjective - crying, agitation etc – Semi-objective - scoring systems such as NIPS, PIPP (also includes HR, SpO2) , NFCS etc  Physiologic variables – HR, BP, SpO2, intracranial pressure etc  Biochemical assessment – Cortisol, catecholamines, b -endorphin etc Pain assessment: which method?  Often a lack of significant correlation between physiologic, biochemical, and behavioral indicators of pain - there is no “gold standard”  Behavioral indicators (e.g. Subjective, Scoring systems: NFCS, NIPS, PIPP) often used as they are: – easier to measure – baseline better established – non-invasive (esp. for repeated measurements) – more “honest signal” of pain Physiologic assessment  Physiologic indicators (FT= full term; PT= preterm) • Heart rate : usually increased (FT, PT) • SpO2, TcPO2 : usually decreased (FT, PT) • Vagal tone: decreased (FT) • Respiratory rate: increased (FT) • ICP: increased (PT) • Variability in HR and RR: increased (PT) • Skin conductance, sweating Physiologic assessment  Many physiologic indicators cannot be unequivocally interpreted as pain as they are more clearly associated with stress (Stevens B et al. Clin J Pain 12: 13, 1996) Biochemical indicators  Catecholamines (Epinephrine, Norepinephrine)  Cortisol (blood, saliva, or urine can be used)  b-Endorphin  Growth hormone, glucose, glucagon, renin, aldosterone, and lactate have also been noted to increase with pain  Insulin secretion is usually suppressed Pain management  Systematic approach to prevent pain required, rather than “as needed” basis  Risks and benefits of pain management techniques must be considered and individualized  Prevention of : – Acute pain (surgery, procedure) – Pain due to disease process/ post surgical/ post procedure – Minimize stress due to noxious stimuli Prevention of acute pain  Anesthesia – General – Regional (epidural, nerve blocks etc) – Local (lidocaine, EMLA etc) • Lidocaine (DPNB) or EMLA effective for circumcision • DPNB better than EMLA for circumcision • EMLA not effective for heel lancing • EMLA does not cause methemoglobinemia with single applications at > 26 wks GA – Opioids (Morphine/Fentanyl) Post-op / disease related pain  Regional blocks (e.g. intercostal block for thoracotomy, caudal block for hernia)  Systemic analgesics: – Opioids : best to titrate dose to effect. Facial activity shows analgesia, but is not correlated with plasma levels – Acetaminophen: orally or rectally is safe but efficacy not well studied – Natural sweeteners: Sucrose or Glucose effective for pain relief during minor procedures Pain alleviation : basics  Prevention – Control stress (limit noxious stimuli) – Limit painful procedures (only if necessary; use non-invasive monitoring whenever possible; art lines or CV lines rather than repeated punctures) – Skilled caregivers with appropriate techniques (venipuncture less painful than heel lancing) – Swaddling, non-nutritive sucking, positioning for minor procedures (Prevention and management of stress and/or pain in the newborn infant. CPS statement) Minimization of stress  Non-pharmacological: – Avoid excessive noise, light. Comfort measures such as swaddling, positioning, non-nutritive sucking.  Pharmacological: – Sedatives (benzodiazepines, barbiturates, phenothiazines, chloral hydrate) Analgesics: opioids  Morphine or Fentanyl most often used. Avoid Demerol (Meperidine)  Requires frequent and thorough assessment of adequacy of pain relief and possible side effects  Dose: – Morphine: 0.1 mg/kg IV over 5-10 min q4-8h (or) 100 mcg/kg over 1 h followed by 10 mcg/kg/hr – Fentanyl: 1-4 mcg/kg IV over 5-10 min q2-4h (or) 1-5 mcg/kg/hr Analgesics: opioids  Adverse effects include respiratory depression and glottic/chest wall rigidity (due to fentanyl / alfentanil rapid infusions: give slowly. If they occur, give muscle relaxants/ narcan)  Avoid use > 5 days. Wean 20% per day if > 5 days. Wean by 10% per day if withdrawal symptoms.  Continuous infusion (vs. bolus) decreases apnea, but higher total dose may be required for analgesia. Sedatives: benzodiazepines     Benzodiazepines are NOT analgesics. They have sedativehypnotic, amnesic, anxiolytic, muscle relaxant, and antiepileptic properties. Midazolam (Versed) has a short half-life and is approved by the FDA for neonatal use. Although an effective sedative, it can cause abnormal movements and adverse hemodynamic effects . – Dose: 0.1 mg/kg IV over 5 min q2-4h. Can also be used continuous IV (10-50 mcg/kg/h), intranasal, sublingual, oral Lorazepam (Ativan): insufficient data; variable duration of action (3-24 h) and half-life. Dose: 0.1 mg/kg/dose slow IV Diazepam not recommended due to long half-life. Other sedatives  Chloral hydrate: Trichloroethanol (TCE) is the active metabolite. TCE and its metabolite TCA accumulate with repeated doses and can cause CNS & CVS depression and hyperbilirubinemia. Not an analgesic. Single doses (25-75 mg/kg po/pr) are safe in neonates.  Phenobarbital / phenothiazines: evidence of benefit is lacking. Half-life may be very long. Other agents:  Pancuronium (Pavulon): Muscle-relaxant not a sedative or analgesic. Always use in combination with sedation and analgesia (e.g. morphine or fentanyl) – Watch for hypotension, monitor BP continuously – Main use is in infants with severe PPHN on HFOV, with inadequate response to fentanyl/morphine infusion alone – Dose: 0.1 mg/kg IV q 2-4 Some final thoughts...  Research on long-term outcomes is essential  Is neonatal pain relief by itself an adequate and distinct outcome, in the absence of other benefits or adverse effects?  If opioids are safe and effective and have equivalent long term outcomes, is it ethical to tolerate a small increase in short-term side effects (e.g. bowel dysmotility or prolongation of ventilation) for improved pain relief? Appendix  Basis for long-term effects  Neonatal Pain Scoring Systems Rationale: long-term effects  Adverse long-term consequences (contd.): – ELBW children noted to have altered pain sensitivity unrelated to temperament or parental style (Grunau RV et al: Pain 1994; 58: 341) – Neonatal pain and stress may program the brain’s response to future stimuli (Winberg J. Acta Pediatr 1998; 87:723) – Lowered pain threshold common in ex-premies, but with lower facial responsiveness Basis for long-term effects  Development of HPA responses to stress is modified by sensory experiences during the neonatal period (Levine S et al. Physiol Behav 1967;2:55 & Science 1962; 135:795; and Ader R et al. Physiol Behav 1969;4:303)  Mechanisms for these changes probably due to plasticity in neonatal limbic structures and related to expression of corticosteroid, vasopressin receptor systems regulating HPA. (Francis D et al. Ann NY Acad Sci 1996;794:136) Basis for long-term effects  Neonatal handling, maternal separation, infections, pain/stress etc can lead to permanent changes in endocrine, behavior, and immune systems. (Anand KJ: Biol Neonate 1998;73:1) Rationale: time for decisions?  Randomized controlled trials are essential to evaluate if an increased use of analgesics and improved pain control in prematurely born neonates is associated with improved long term neuro-developmental outcomes.  It may be important that analgesics be used only in neonates with pain (not stress alone), as animal studies show that opioids act differently on the brain in the presence of pain. Behavioral assessment  Sedation score: (Jacqz-Aigrain et al, Lancet 344:646, 1994) – Facial expression - calm and relaxed (0) or pronounced (1) – Sucking - absent (0) or strong and rhythmic (1) – Spontaneous motor activity – normal (0) or agitated (1) – Excitability, responsiveness to stimulation- normal (0) or tremulous, clonic movements (1) – Excessive flexion of fingers and toes - absent (0) or present & constant (1)  Scores of 0 or 1 suggest satisfactory sedation  Primarily a score for sedation in intubated neonates.  Simple, rapid, and construct validity established Behavioral assessment (contd.)  Neonatal Infant Pain Scale (NIPS) (Lawrence et al, Neonatal Netw.12:59, 1993) – Face: relaxed (0) or grimace (1) – Cry: no (0), whimper (1), vigorous (2) – Breathing patterns: relaxed (0) or change in breathing (1) – Arms: relaxed/restrained (0) or flexed/extended (1) – Legs: relaxed/restrained (0) or flexed/extended (1) – State of arousal: sleeping/awake (0) or fussy (1) Behavioral assessment (contd.)  Neonatal Infant Pain Scale (NIPS) (contd.) – Scoring in one-minute intervals; x 2 before time/ procedure, x 5 during time/procedure, and x 3 after time/procedure. Total scores for each minute range from 0-7 – Good system to measure responses to acute painful stimuli in non-intubated babies. – Full validation done, but score is time-consuming, and items such as breathing patterns and cry difficult to interpret in intubated neonates Behavioral assessment (contd.)  Premature Infant Pain Profile (PIPP) (Stevens B et al. Clin J Pain12: 13, 1996). – Gestational age: >36 wks (0), 32-35.6 (1), 28-31.6 (2), < 28 wks (3) – Behavioral state: active/awake, eyes open, facial movements (0), quiet/awake, eyes open, no facial movements(1), active/sleep, eyes closed, facial movements (2), quiet/sleep, eyes closed, no facial movements – Heart rate: 0-4 bpm increase (0), 5-14 (1), 15-24(2), >25 increase (3) Behavioral assessment (contd.)  Premature Infant Pain Profile (PIPP) (contd.) – O2 saturation: 0-2.4% decrease (0), 2.4-4.9% (1), 57.4% (2), >7.5% decrease (3) – Brow bulge: None, 0-9% of time (0), Minimum, 1039% (1), Moderate (40-69%), Maximum (>70%) – Eye squeeze: None, 0-9% of time (0), Minimum, 1039% (1), Moderate (40-69%), Maximum (>70%) – Nasolabial furrow: None, 0-9% of time (0), Minimum, 10-39% (1), Moderate (40-69%), Maximum (>70%) Behavioral assessment (contd.)  Premature Infant Pain Profile (PIPP) (contd.) – Observe baseline HR, SpO2 in 15 s before event. Scoring in 30 s after event. – Scores for 7 indicators summed for total pain score. Max score dependent on GA: youngest up to 21, larger up to 18. – Scores of <6 indicate minimal or no pain, >12 moderate to severe pain. Behavioral assessment (contd.)  Premature Infant Pain Profile (PIPP) (contd.) – Validated research tool, cumbersome and timeconsuming for clinical purposes. Use in intubated neonates is questionable because: 1. baseline obtained while infant is under chronic stress 2. if pre-intubation baseline is used, O2 saturation not an indicator of pain but rather of disease process 3. items such as nasolabial furrow difficult to discern Behavioral assessment (contd.)  Neonatal Facial Coding System (NFCS) (Grunau RVE, Craig KD: Pain expression in neonates. Pain 28: 395, 1987) • Eight items: – Brow bulge; Eye squeeze; Nasolabial furrow; Open lips; Stretch mouth (vertical or horizontal); Lip purse; Taut tongue; Chin quiver – Each present feature scores one, total score eight (modified NFCS in Guinsburg et al. J Pediatr 132: 954-959, 1998) Behavioral assessment (contd.)  Neonatal Facial Coding System (NFCS) (contd.) – Some facial actions (lip purse, tongue protrusion, chin quiver) occur in non-pain situations. Other facial actions (Horizontal or vertical mouth stretch, taut tongue) are present less than 50% of the time in pain situations – Difficult to assess face in intubated neonates Other behavioral scales • Modified post-operative comfort score (Attia J et al. Intensive Care Med 13: 459, 1987) • Pokela’s behavioral pain score (Pokela ML: Pediatrics 93: 379, 1994) • Behavioral state score (adapted from Bruck et al. Biol Neonate 4: 32, 1962 by Orsini et al. J Pediatr 129: 140, 1996) • Infant Body Coding System (IBCS) (Craig KD et al. Pain 52: 287-300, 1993) • Modified Behavioral Pain Scale (MBPS) developed from CHEOPS by Taddio et al. (Taddio et al. J Pain Symptom Manage 10:456, 1995)