Uppsala, Sweden

Prof. Carl Linnaeus

1707-1778, Botanist,

Classified plants, animals, minerals

Prof. Anders Celsius

1701-1744, Astronomist,

Temperature scale

Outline of talk

• Exposure to pain in the NICU

• Short- and long-term effects of pain

• Treatment of pain

• Developmental care and family-centered care

Promoting development of the preterm

brain includes several aspects

• Obstetric antenatal and intrapartum care

– Antenatal steroids, magnesium sulphate, mode of delivery,

experience/expertise

• Neonatal care

– Immediate care – ”golden hour”

– Ventilation, circulation, …., experience/expertise

– Nutrition (parenteral nutrition and breast milk)

– Pain and stress

– ”Developmental care” and ”family-centered care”

• Follow-up after discharge

– Early detection/intervention of neurodevelopmental problems

This infant, born at 24 gestational weeks, will be exposed to

multiple painful and potentially stressful procedures, risk of

suboptimal nutrition, noise, smell, separation from parents –

all associated with poorer development

(Barker & Rutter, Arch Dis Child 1995)

Very preterm infants are exposed to a large

number of distressing and painful procedures

(Carbajal et al , JAMA 2008)

Neonatal pain and stress responses

• ↑ heart rate

• ↑↓ respiration

• ↑ blood pressure

• ↓ oxygen saturation

• ↑↓ motor activity, crying, facial expression

• ↑ cortisol • ↑ cortical activity (EEG, EP) • ↑ cerebral blood flow (NIRS, fMRI) • ↓ brain development

(Pain 2006)

Cerebral hemodynamic changes (BP+NIRS) during

intensive-care procedures in extremely preterm

infants (Limperopoulos et al, Pediatrics 2008)

Is a nappy change stressful to neonates? (Mörelius et al, Early Hum Dev 2006)

GA <30 w

GA ≥30 w

Term control

Is a nappy change stressful to neonates? (Mörelius et al, Early Hum Dev 2006)

GA <30 w

GA ≥30 w

Term control

Is a nappy change stressful to neonates? (Mörelius et al, Early Hum Dev 2006)

GA <30 w

GA ≥30 w

Term control GA <30 w

GA ≥30 w

Term control

Neonatal

Infant

Stressor

Scale (Newnham et al,

Early Hum Dev 2009)

NICU stress associated with poorer brain

growth and reduced functional connectivity (Smith et al, Ann Neurol 2011)

Term born

control

Preterm

low stress

Preterm

high stress

Procedural pain affects brain development

Brummelte et al, Ann Neurol 2012

• N=86 very preterm infants, GA 24-32 w

• MRI at 32 w and 40 w PMA

• Greater neonatal procedural pain associated with reduced white

matter and subcortical grey matter maturation

Ranger et al, PlosONE 2013

• N=42, GA 24-32 w, without major brain injury or impairment,

• MRI at mean age 7.9 years

• Greater neonatal pain-related stress associated with thinner cortex

in 21/66 cerebral regions, predominantly frontal and parietal lobes.

Doesburg et al, Pain 2013

• School-aged children (N=22 ELGA; N=32 VLGA; N=25 term born

• Cumulative neonatal pain-related stress in ELGA (but not VLGA)

children correlated with poorer functional brain activity (MEG), and

poorer visual-perceptual abilities (Beery WMI, WISC-IV)

High burden of early skin breaks correlated with

poorer thalamic growth, poorer white matter

organization and 3-year cognitive and motor

outcomes in preterm infants (Duerden et al, J Neurosci 2018)

• N=155, GA 24-32 w, MRI at 32 w and 40 w PMA

Prevention and treatment of pain

• Reduce pain and stress

• Pharmacological management

– Sweet solutions (sucrose, glucose, dextrose)

– Paracetamol

– Opioids (morphine, fentanil)

• Non-pharmacological management

– Skin-to-skin care

– Positioning, swaddling, holding, facilitated tucking

– Breastfeeding, breast milk, non-nutritive sucking

Pharmacological pain treatment

• Sucrose is effective for reducing procedural pain (N=74

studies, 7049 infants) (Stevens et al, Cochrane Database Syst Rev 2016)

• Glucose (20-30%) have analgesic effects/alternative to

sucrose for procedural pain reduction (N=38 studies of

non-sucrose sweet solutions, 3785 infants) (Bueno et al, Pain Res Manag 2013)

• Paracetamol does not reduce procedural pain but may

reduce need for morphine following major surgery (N=9

trials, 728 infants) (Ohlsson & Shah, Cochrane Database Syst Rev 2016)

• EMLA or Amethocaine have effects of uncertain clinical

significance for needle-related pain (N=8 small studies) (Foster et al, Cochrane Database Syst Rev 2017)

• No routine use of opioids (Bellù et al, Arch Dis Child 2010 and Cochrane Database Syst Rev 2008)

Glucose administration does not mitigate

pain-associated negative structural and

function brain development (Schneider et al, Pain 2018)

N=51 preterm infants, mean GA 27.6 (2) weeks

MRI at PMA 29,32 and 41 weeks

More pain (more invasive

procedures) associated

with:

• ↓ growth of thalamic, basal

gangliga and total brain

volumes, especially in

females

• ↓ functional connectivity

between thalamus and

sensorimotor cortices

• ↓ neurodevelopment at 18

months

Long-term neurodevelopmental outcome

after neonatal morphine? (Schuurmans et al, JMFN 2015)

Non-pharmacological pain treatment

• Skin-to-skin care (SSC) alone or combined with sweet

solutions appears to reduce pain responses (N=25 studies,

2001 infants)(Johnston et al, Cochrane Database Syst Rev 2017)

• Non-pharmacological interventions can be used with

preterms, neonates, and older infants to significantly manage

pain behaviors associated with acutely painful procedures.

Most evidence for non-nutritive sucking, swaddling/

facilitated tucking, and rocking/holding. (N=63 studies,

4905 infants, SSC and music not included) (Pillai Riddell et al, Cochrane

Database Syst Rev 2015)

• If available, breastfeeding or breast milk should be used

to alleviate procedural pain in neonates rather than placebo,

positioning or no intervention. Similar effectiveness as

glucose/sucrose. (N=20 studies) (Shah et al, Cochrane Database Syst Rev

2012)

Developmental care practices

• Pain, stress – limit/reduce/comfort measures

• Light and noise – reduce

• Sleep – promote

• Family centred care (support parents as primary

care givers, no separation, skin to skin care,

breast feeding, family support, home care)

Interrupted quiet sleep due to diaper

changes (Westrup et al, Acta Paediatr 2002)

Kangaroo (mother) care/

skin to skin care

• Healthy newborns (Moore et al, Cochrane 2012)

– Benefit breastfeeding, cardiorespiratory stability, less

crying

• Low birth weight infants (Conde-Agudelo et al, Cochrane 2011)

– Lower mortality (RR 0.60, 95%CI 0.39-0.93;

nosocomial infection/sepsis (RR 0.42, 95%CI 0.24-

0.73), hypothermia (RR 0.23, 95%CI 0.10-0.55), and

length of hospital stay (mean diff. 2.4 days, 95% CI

0.7 to 4.1).

NIDCAP* and Family centred care

• NIDCAP results in shorter hospital stay and higher MDI/PDI

at 9 months (Ohlsson and Jacobs, Pediatrics 2013, meta-analysis)

• EEG and MRI development: improved brain function and

structure in very preterm (Als et al, Pediatrics 2004) and IUGR

infants (Als et al, J Perinatol 2012)

• Family centred care (RCT, GA<37 w, n=366) resulted in

shorter hospital stay (5.3 d) and less BPD (1.6% vs. 6.0%) (Örtenstrand et al, Pediatrics 2010)

• Edmonton NIDCAP Trial: Intervention resulted in shorter

hospital stay (10 days) and less BPD 29% vs. 49% (Peters et al, Pediatrics 2009)

(*Newborn Individualized Developmental Care and Assessment Program)

Infant weighing: Lower HR and pain scores

after developmental care intervention (Catelin et al, J Pain 2005)

• Three groups (n=15), very preterm, moderately preterm, and term infants

• Two weighing procedures: standard/developmental care intervention, crossover

• No differences in salivary cortisol (before/30 min after), oxygen saturation or

tissue oxygenation index (NIRS)

Developmental care

Standard care

Lower cortisol after NIDCAP intervention in

conjunction with ROP screening examination (Kleberg et al, Pediatrics 2008)

• N= 36 preterm infants (20 Swedish and 16 English) randomized at the

first ROP exam to NIDCAP/Standard care, 2nd exam crossover

• Faster decline in salivary cortisol after NIDCAP, no differences in HR,

oxygen saturation or PIPP.

A

B

Parent/infant separation – sensitive care, support, education

Skin to skin care – stability, breast milk, pain and stress

Feeding - breastfeeding

Sensory environment – timing, noise, voice

Sleep – promote and protect

Pain and stress – minimize, use pain scales, educate parents

Well educated staff – individualized care - support sleep, minimize infant stress

Systematic follow-up

Conclusions

• Neonatal pain and stress have negative effects on

brain growth and development.

• Pain exposure and stress should be reduced as

much as possible in the NICU.

• Non-pharmacological and pharmacological pain

treatment should be used selectively and after

individual considerations.

• Developmentally adapted and family-centered care

promotes the infant’s development