Sedation and pain relief in
neonatal care
PERINATOLOGI KURS 2010,
KI
Marco Bartocci, MD, PhD
Neonatal Intensive Care Unit
Neonatal Research Unit
Karolinska University Hospital
Karolinska Institutet
Stockholm
contents
• Physiologic background of supraspinal
pain perception
• Clinical approach
• Pain scales
• Pain drugs in NICU
Supraspinal pain processing
• The pain system is a dynamic interactive
system creating an interoceptive view
(relating to stimuli arising within the body)
of the body integrity (Price, Science 2000)
• Pain perception involves multilayered
networks of nociception, nerves, neurons
and glia, distributed in multiple spinal and
supraspinal areas. (Woolf, Science 2000)
What is pain?
Pain is a subjective sensory and
emotional experience that requires the
presence of consciousness to permit
recognition of a stimulus as unpleasant.
Next questions
•Is the brain of the newborn ready (mature enough)
to process painful stimuli?
•When do we become conscious of ourselves?
•How can a newborn communicate his/her pain?
Development of pain
•Sensory receptors in the moth already at 7 wks
•Peri-oral cutaneuos 77,5 wks
• Palmar cutaneuos 1010,5 wks
(Humphrey, 1964)
•Abdominal cutaneuos around 15 wks
•Spinal reflex arc in response to noxious stimulus from 8 wks (Okado & Kojma 1984)
•Neuron for nociception in the dorsal root ganglion from 19 wks (Kostantinidou 1995)
•Receptors on the skin from week 20
•Synapses develop around week 20
•Thalamic afferents reach the subplate zone 20 wks (Rakic, Kostovich, Hevner 1984)
• Thalamic afferents reach the cortical plate (Rakic, Kostovich, Golman 1984)
•Myelinisering till brainstem, thalamus at week 30
NICU
•Endorfins present at week 20
•Nociceptive connections develop between week 22 and 24
•Somatosensory evoked potential with distinct constant component 29 wks (Klimach ‘88)
•EEG denoting clear shifting wakefulness-sleeping differences 30 wks Clancy 2003
Why pain perception is potentially
possible already in early of development
1. Number of nociceptive nerve fibers in the skin of
the neonate is similar to and possibly even greater
than the number found in the adult.
2. Despite the incomplete myelination of pain fibers,
pain transmission is preserved. The short distances
in the immature brain compensate any slowing of
velocity that may be caused by the lack of
myelinisation.
3. There is abundance of pain neurotransmitters in
the newborn brain and in the fetal brain.
4. There are receptive fields of neurons in the
somatosensory cortex.
Why newborn infants may potentially feel
more pain than adults?
Pain transmission and neurotransmitters are extremely
well developed at birth as well as in the premature, but
modulatory and inhibitory circuits are still immature and
partially lacking (physiological imbalance excitatory vs.
inhibitory fibres)
Physiological background:
1. There is a delay in the maturation of descending
inhibitory pathways from supraspinal areas
2. There is a delayed maturation of interneurons in
the “substantia gelatinosa”
3. There is a deficiency of inhibitory
neurotransmitters
Development of pain response
Lower gestational age may be associated to
lower pain thresholds in early
development (Anand 1998; Fitzgerald et al.
1988), eventually resulting in greater cortical
responses in the more immature preterm
neonates following pain stimuli
Which cortical areas are
involved in pain processing?
How nociceptive/painful stimuli
arrive at the cortical level in
preterm newborn infants?
Other areas:
Hypothalamus, anterior
cyngulate gyrus,
amygdala,
hyppocampus, nucleus
accumbens, cerebellum
Inhibitory and
facilitatory effects
amygdala
basal ganglia
(etc.)
The newborn is not “a little adult”
• The structures and mechanisms involved
in pain processing during early
development are unique and different from
those of the adult.
• Many of these structures and mechanisms
are not maintained beyond specific
periods of early development
Narsinghani & Anand 2000
Fitzgerald 2005
Pain processing in the brainstem
Medulla
• 5-10 wks  development of medullary nuclei
– Formation of the rhombencephalon (hindbrain)
• 10 wks  vagal afferents, visceral afferents
(nucleus of the solitary tract), general
somatic afferent nuclei (trigeminal nuclei)
Pain processing in the brainstem
Medullary nuclei
• Rostral ventromedial medullla (RVM)
– Pain modulatory circuitry (especially chronic pain)
– Inhibitory and facilitatory effects
– Bilateral nociception bladder and colorectal distension
(Visceral Sensory Information)
(Robbins, Neurosci Lett 2005)
– Connections with the Periaqueductal Grey (PAG) and
involved in hyperalgesia and allodynia (prostaglandinPGE2 effect)
(Heinrecher, Pain 2004, Robbins 2005)
– μ-opioid agonists activate neurons in RVM (despite
RVM neurons are quite resistant to the development of
μ-opioid tolerance)
(Mourgan, Pain 2005)
Pain processing in the brainstem
Medullary nuclei
• Dorsal raphe nucleus (DRN) and
nucleus raphe magnus (NRM)
– They are crucial in opioid induced analgesia
(Fields, Nature Review Neurosci 2004)
– They are implicated in stress-induced
analgesia
(Freitas, Exp Neurol 2005)
– Intra-oral sucrose activates neurons in the
PAG, DRN and NRM modulating the
descending pain pathways
(Anseloni, Neurosci 2005; Miyase, Neurosci Lett 2005)
Pain processing in the brainstem
Medullary nuclei
• Nucleus tractus solitarius (NTS)
– Especially involved in visceral afferent input
– Descending inhibitory and facilitatory loops to the spinal
cord
– Referred pain and viscerotopic specificity
(Hua, Am J Phys 2004)
– Autonomic response to visceral stimulation
(deLange, Neurosci Lett 2005)
– Viscerosomatic hyperalgesia (visceral distension)
Involved in the “irritable bowel syndrome”
(Anand, J Pediatr 2004)
Pain processing in the brainstem
Medullary nuclei
• Trigeminal nuclear complex
– 2 distinct nuclei:
• interpolaris/caudalis transition zone (Vi/Vc)
– Sensory processing deep tissue, somatovisceral, HPA axis and
descending modulation of pain
• and subnucleus caudalis
– Sensory discriminative aspects of pain
(Dubner, J Orof Pain 2004)
– Focused on oro-facial and dental pain
– Crucial importance in the newborn in NICU as 2 of the most
common interventions stimulate the trigeminus (intubation
and oral suctioning)
(Simons, Arch Ped Adol Med 2003)
– Possibly involved in the so called mechanism of “Long Term
potentiation (LTP) and may contribute to the “Oral aversion
syndrome” noted in ex-prematures.
(Smith, 2007; Ljang, Pain 2005)
Pain processing in the brainstem
Pons nuclei
• Parabrachialis complex (PBC)
– Particularly involved in emotional, autonomic
and neuroendocrine features of painful
stimulation
– Projects to amygdala (emotional affect),
hypothalamus and ventrolateral medulla
(autonomic adaptation), PAG (emotional
behaviour).
(Richard, J Comput Neurol 205)
Pain processing in the brainstem
Pons nuclei
• Pontine reticular formation
– Particularly involved in somatic motor
responses, arousal and emotional feature of
pain via medial thalamic and prefrontal
cortical connection.
(Gauriau, Exp Physiol 2002)
Pictures of a neonates showing emotional features just before a venipuncture…..
Pain processing in the brainstem
Pons nuclei
• Locus ceruleus/sub ceruleus (LC/SC)
– Neurons in LC are activated by acute and
inflammatory pain
– Chronic pain suppresses LC activity to
produce hyperalgesia
(Imbe, Pain 2004; Freitas Exp Neurol 2005)
Pain processing in the brainstem
Midbrain
• It develops from the mesencephalon between the 9th
and the 16th gestational week
• It consists of:
– Periaqueductal grey (PAG) and Ventral tegmental area
• Modulatory system of pain
• PAG Stress-induced analgesia, sucrose-mediated analgesia,
visceral reaction to pain
(Cavum, Brain Res 2004; Anseloni Neurosci 2005)
• Opioid and non-opioid mechanisms of endogenous analgesia are
located in PAG
• Different maturational stages of the opioid receptors in PAG may
lead to different effects
(Rahman, Brain Res Dev Brain Res 1995)
Supraspinal Pain processing
Thalamus
• Relay station conveying sensory, motor and
autonomic information.
• It is visible at 6 weeks of gestation
• Special sensory projection nuclei (lateral
geniculate body – visual; medial geniculate body
– auditory)
• General sensory projections nuclei (especially
involved in pain processing)
– ventral posterolateral (VPL) - somatosensory
– Ventral posteromedial (VPM)
– Posterior nuclear group (Po) and the triangular pain
processing
Supraspinal Pain processing
Sucortical level
• Anterior cyngulate gyrus
It develops fully at about 24 weeks of
gestation
– Intensity, sensory-integrative, affective and
cognitive modulation
– Habituation
(Bingel, Pain 2007)
Other subcortical areas
• Hypothalamus (16-20 weeks of gestation)
– Integration discending/ascending information to pain,
stress and emotion
– Connection with other subcortical areas
• Amygdala (12-16 weeks of gestation)
– Stress component. Neuroendocrine responses.
• Hippocampus (15-16 weeks of gestation)
– Anxiety  hyperalgesia. Chronic and repetitive pain
and stress abundant glucocorticoid receptors
• Nucleus accumbens (early in gestation)
– Suppression of chronic pain. Antinociception via
opioid receptors, dopamine D2 receptors, and
calcitonin gene-related receptors
Supraspinal Pain processing
Cortex
• Primary somatosensory cortex (S1)
– Somatotopic mapping with narrow receptive
fields
– Not yet clear its role in conscious experience
of pain
• Secondary somatosensory cortex (S2)
– Large, bilateral receptive fields
– More likely directly involved in the processing
of the noxious stimulus.
Number of
patients
Mean
Median
Minimum
Maximum
SD
Gestational age
(weeks)
40
32.0
32.0
28.0
36.0
3.0
Postnatal age (hours)
40
30.7
30.0
25.0
42.0
4.8
Weight (grams)
40
1899.5
1772.5
1200.0
3100.0
590.3
Venepuncture duration
(seconds)
40
48.3
49.0
35.0
60.0
6.7
Gestational age
20
32.7
33
28.0
36.0
3.0
Postnatal age
20
29.5
28.5
25.0
40.0
4.3
Weight
20
1958.0
2005
1200.0
3010.0
567.0
Venepuncture duration
20
49.8
50
35.0
60.0
6.9
Gestational age
20
31.4
31
28.0
36.0
2.9
Postnatal age
20
32.0
30
25.0
42.0
5.2
Weight
20
1841.0
1595
1200.0
3100.0
621.9
Venepuncture duration
20
46.7
45.5
39.0
59.0
6.2
All subjects
Females
Males
Bartocci et al, Pain 2006
CBV
Stimulus
Neural
response
Blood
Oxygen
level
CBF
CMRO2
Stimulus
Hb O2
Hb H
Hb tot
Bartocci et al, Pain 2006
primary somatosensory cortex and parts
of the secondary somatosensory cortex,
insula, cingulate cortex, thalamus, and the
amygdala.
E
E
R
R
Cortical areas illuminated
by NIRS
Areas of the preterm brain
likely to be illuminated by NIRS
Bartocci et al, Pain 2006
Figure 1b
Near Infrared Spectroscopy NIRS
• Photon 1 is scattered
and reaches the
detector
• Photon 2 is absorbed
after a number of
scattering events
• Photon 3 leaves the
head without being
detected
H. Obrig et al. International Journal of Psychophysiology 2000
Venipuncture
Tactile stimulus
30 seconds
Period: P0 Baseline
NIRS recording
60 seconds
Period: P1 Tactile
NIRS recording
60 seconds
Period: P2 Pain
NIRS recording
60 seconds
6
Venipuncture
5
[Hb tot] left
4
mmol/L
NIRS
3
2
1
[Hb tot] right
0
-1
100
Sat O2
80
%
60
180
HR
160
bpm
140
0
60 s
Μmol/L
5
4
3
Hb O2 left
2
Hb O2 right
Hb H left
1
Hb H right
0
sec
-1
tactile
-2
venipuncture
60 sec
Bartocci et al Pain 2006
6
A
*
A. Comparison of the cortical [HbO2]
increases between the female (black
columns) and male (white columns)
neonates following venipuncture.
**
5
microMol/L
4
Females
Males
3
2
1
0
[Hb O2 ]diff
left hem isphere
[Hb O2 ]diff
right hem isphere
6
5
B
*
microMol/L
4
3
2
1
0
[Hb O2 ]diff
venipuncture on the left hand
[Hb O2 ]diff
venipuncture on the right hand
B. Differences in cortical [HbO2] changes
following venipuncture on the left or the
right hand. Black bars denote [HbO2]
increases on the left hemisphere and
white bars on the right hemisphere.
5.5
5.0
4.5
4.0
3.5
[Hb O2] left
[Hb O2] right
*
3.0
2.5
MicroMol/L
2.0
1.5
1.0
*
0.5
0.0
*
-0.5
Baseline
Tactile
Venipuncture
Cortical activity in the somatosensory cortex during tactile and painful stimulation
(venipunture).
Bartocci et al, 2006
7
6
5
*
[Hb O2] parietal
[Hb O2] occipital
4
3
] 2microM/L
[Hb O
*
2
1
0
-1
-2
baseline
tactile
venipuncture
Bartocci et al, Pain 2006
9
8
8
7
7
6
6
5
5
diff
right
]2 mmol/L
[HbO
leftdiff
]2mmol/L
[HbO
4
3
3
2
2
1
24
4
26
28
30
32
34
36
38
40
PNA (hours)
42
1
24
44
26
28
30
32
34
36
38
40
PNA (hours)
95% confidence
42
44
95% confidence
9
9
8
8
7
7
6
6
5
5
4
diff
right
]2 mmol/L
[HbO
leftdiff
]2mmol/L
[HbO
4
3
2
1
27
3
2
1
0
28
29
30
31
32
GA (weeks)
33
34
35
36
37
95% confidence
-1
27
28
29
30
31
32
GA (weeks)
33
34
35
36
37
95% confidence
Conclusion from our study
• Painful and tactile stimuli elicit specific
haemodynamic responses in the somatosensory
cortex, implying conscious sensory perception in
preterm neonates.
• Somatosensory cortical activation occurs
bilaterally following unilateral stimulation and
these changes are more pronounced in male
neonates or preterm neonates at lower
gestational ages.
Mean PMA at time of study (weeks),
35.0 (5.2); range, 25.7– 45.6
The long latencies of the cortical responses
in the youngest infants are likely attributable
to the low conduction velocities and slow
synaptic responses in the nociceptive
circuitry
Slater et al. The Journal of Neuroscience, 2006
squeezing
12
10
venipuncture
puncture
squeezing
[HbO2]
squeezing
microMol/L
8
6
4
2
0
-2
-4
[HbH]
-6
time
1 min
Effect of squeezing during heel lancing
Unpublished data
Changes of [HbO2] mMol/L
10
8
Intramuscular injection of vit K
30 min after birth.
Injection on the left leg.
Recording over the right
sensory cortex.
6
4
disinfection
12
2
0
-2
10 sec
injection
Unpublished data
Thanks to Felicia Nordenstam
Slater et al, PLoS 2008
Non-noxious touch stimulation
Neuroimage 2010
Noxious heel lance stimulation
7 infants; born 24–32 weeks
8 infants; born 37–40 weeks
mean PCA at time of heel lance 39.2 ± 1.2
weeks
Conclusions – 1
• More and more evidence has been gathered
about the anatomical and maturational potentials
for supraspinal pain processing in newborn
infants, particularly in prematures.
• Some of the nociceptive pathways or
mechanisms may not be maintained beyond
specific periods of early development. This fact
has to be taken into account both in research
and clinical practice.
Conclusions – 2
• There is starting evidence indicating that in
newborn infants, especially those born extremely
premature, supraspinal pain processing may be
not accompanied by corresponding detectable
behavioural changes.
• Procedures with low pain scores based on
behavioural assessment tools alone may not be
pain free.
• Advances in functional neuroimaging and
electrophysiology and molecular neuroscience
will provide better understanding of pain
processing and therefore increase the possibility
of a better pain assessment and treatment.
Pain assessment
Most neonatal intensive care units rely on
subjective assessments made by nursing
and medical staff to determine whether a
baby requires analgesia or sedation and
whether this treatment is effective. Staff
perceptions vary considerably, resulting in
under-treatment or over-treatment of pain
(Lago et al., 2005; Walker, 2005).
The “first pain” and
the “second pain”
The most of the procedures may have a
double impact to the discomfort of the baby:
 acutely during the tissue damaging
procedure (‘‘first pain’’)
 after the procedure (‘‘second pain’’)
Boyle et al. Pain 2006
Newborns at 26 (23–31) weeks and birth
weight of 845 (500–1935) grams.
Pain Scales
Commonly used methods for assessment of pain in
newborns
Premature
Infant Pain
Profile (PIPP)
Neonatal Facial
coding scale
(NFCS)
Neonatal infant
Pain scale
(NIPS)
Cries score
Variables
assessed
GA, Behavioral
state, HR,
saO2, brow
bulge, eye
squeeze, nasolabial furrow
Brow bulge, eye
squeeze, nasolabial furrow,
open lips,
stretch mouth,
lip purse, taut
tongue, chin
quiver, tongue
protrusion
Facial
expression, cry,
breathing
patterns, arms,
legs, state of
arousal
Crying,
increase saO2,
increased vital
signs,
expression,
sleeplessness
Reliability
Intra and interrater reliability
>0.93
Intra and interrater reliability
>0.85
Inter-rater
reliability >0.92
Inter-rater
reliability >0.72
Clinical utility
Used at the
bedside
Used at the
bedside
Not yet
established
Preferred by
nurses in USA
Indicator
Description
Result
Facial activity
1.
2.
3.
4.
Relaxed facial activity
Frequent grimaces, lasting grimaces
Permanent grimaces resembling crying or blank face
Transient grimaces with frowning, lip purse and chin quiver or tautness
Body
movements
1.
2.
3.
4.
Relaxed body movements
Transient agitation, often quiet
Frequent agitation but can be calmed down
Permanent agitation with contraction of fingers and toes and hypertonia
of limbs or infrequent, slow movements and prostration
Quality
of sleep
1.
2.
3.
4.
Falls asleep easily
Falls asleep with difficulty
Frequent, spontaneous arousals, independent of nursing, restless sleep
Sleepless
Quality of
contact
with nurses
1.
2.
3.
Smiles, attentive to voice
Transient apprehension during interactions with nurses
Difficulty communicating with nurses. Cries in response to minor
stimulation
Consolability
1.
2.
3.
4.
Quiet, total relaxation
Calms down quickly in response to stroking or voice, or with sucking
Disconsolate. Sucks desperately
Calms down with difficulty
EDIN Scale
TOTAL SCORE:
FLACC
Assessment
Sedation
Normal
-2
-1
0
1
2
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 silentcontinuous cry
Inconsolable
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 or
Arouses minimally / no
movement (not
sedated)
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
 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% from
baseline
SaO2 76-85% with
stimulation – quick

 > 20% from baseline
SaO2  75% with
stimulation – slow

Out of sync with vent
Criteria
Crying
Irritabili
ty
Behavior
State
Facial
Expressio
n
If the newborn is premature:
+3 if < 28 weeks gestation / corrected age.
+2 if 28 - 31 weeks gestation / corrected age.
+1 if 32 - 35 weeks gestation / corrected age.
Pain / Agitation
N-PASS = Neonatal Pain Agitation Scale
By Hummel and Puchaski, 2000
Film
“good sedation”
• Born at 25 week
• NEC operation at 28 weeks
• 1st day post-operation
– Morphine infusion 10 microg/kg/h
– Clonidine infusion 7,5 microg/kg/d
– L-bupivacaine: 0,2 mg/kg/h in the wound
catheter
FANS
Faceless Acute Neonatal pain Scale
• Heart rate variation 0: < 10%
• 1: > 10%
• 2: > 50%
• Acute discomfort 1: Bradycardia (FC< 100/bpm) or desaturation SpO2<
85%
• Limb movements
•
•
•
•
•
0: Calm, slight
1: Mild intermittent with return to calm
2: Moderate
3: Marked, continuous
4: Global hypotonia
• Vocal expression
•
•
•
•
0: Absent
1: Brief moaning, anxious
2: Intermittent screaming
3: Constant screaming
Milesi et al, 2009
ALPS 1
Pain Assessment Scale for Term Neonates By B. Larsson
0
1
2
Avslappnat
Relaxed
Spänt uttryck
Tense expression
Spänt uttryck/Gråtgrimas
Tense/grimacing
Respiratory pattern
Avslappnat
Regular
Förändrat
Changed
EXTREMITETS
TONUS
Avslappnad
Relaxed
Ökad tonus
Increased tonus
Stel/Slapp
Rigid/hypotoni
HAND/FOT
Avslappnad
Relaxed
Lätt knuten
Moderately closed
Knuten näve, vita
knogar
Kniper med tår
Fisting/white knuckle
AKTIVITET
Avslappnad
Vaken/sover lugnt
Normal sleep
Orolig
Agitated
Hyperaktiv/Apatisk
Hyperactivity/ apatic
ANSIKTSUTTRYCK
Face expression
ANDNINGSMÖNSTER
Ansträngd
andning/Gruntar
Respiratory
efforts/Retractions
ALPS 0 (suggestion) <28 weeks
0
1
2
ANSIKTSUTTRYCK
Avslappnat
Spänt uttryck
Sträcker ut tungan
Spänt uttryck/Gråtgrimas
Tappar hakan
ANDNINGSMÖNSTER
Avslappnat
Ökad andn.frekv,
lätt ansträngd
Mer oregelbunden
Korta andn.pauser <
2 sek
Ansträngd andning
Omväxlande djup och
ytlig andning
Andningspauser
EXTREMITETSTONUS
Avslappnad
Växlar i
balans/slapp
i balans/spänd
Spänd/Slapp
HAND/FOT
Avslappnad
Lätt knuten
Knuten näve, kniper
med tår
Spretar med fingrar
eller tår
Slapp
AKTIVITET
Avslappnad
Vaken/sover
lugnt
Lätt motorisk oro
Ihållande motorisk oro
Drar sig bakåt
Apatisk
x
x
x
x x
x
7
3
•No intervention
• eventuellt NPI
ALPS ≤ 3
ALPS >5
NP
I
ALPS >5
ALPS 4 eller 5
1.
ALPS ≤3
NP
I
Increase MO inf 2,5microg/kg/t (max 40mikrog/kg/hour)
a)
b)
2.
When MO 15microg/kg/h start Klonidine infusion 0,4mikrog/kg/h
When MO 20-25-30 microg/kg/h increase Catapresan inf 0,1mikrog/kg/h (max dos 0,7mikrog/kg/h)
If MO inf and Clonidine inf are max dos start Ketanest inf. 0,05mg/kg/h
ALPS >5
•If MO inf 2,5microg/kg/h(max 40 mikrog/kg/h)
•Start Fentanyl 1 mikrog/kg
ALPS >5
ALPS ≤3
ALPS 4 eller 5
•Give Fentanyl 1 mikrog/kg
ALPS >5
NPI=non pharmacological interventions
(dvs. Non nutrive sucking, repositioning, etc.)
Pain assessment every 30 min
Pain assessment before procedures
Pain assessment 10min after procedures
Pain assessment 10 min after bolusdos narcotics
ALPS >5
ALPS 4 eller 5
ALPS ≤3
•Give Ketanest 0,2mg/kg bolus
•Increase MO inf 2,5microg/kg/timme (max 40
mikrog/kg/h)
•Increase Clonidine infusion 0,1 mikrog/kg/t up to max
0,7 mikrog/kg/t
•If MO inf and Clonidine inf max dos give Ketanest inf.
0,05mg/kg/h
ALPS ≤3
•Give Clonidine 2 mikrog/kg (CAVE side effects!)
•Increase MO inf 2,5microg/kg/timme (max 40 mikrog/kg/timme)
•Start Clonidine infusion 0,4mikrog/kg/h (if no significant side effects) if MO inf 15 mikro/kg/h
ALPS 4 eller 5
ALPS ≤3
Weaning from the postoperative pain treatment
during the first 24 hours
ALPS ≤ 3 for
6 timmar
•Take out Ketanest inf.
•Reduce MO inf 2,5mikrog/kg/h
•If the baby is on both MO and Clonidine, start reducing
MO 2,5mikrog/kg/h and after Clonidine 0,1mikrog/kg/h
when MO is at 10 and 5 mikrog/kg/h
•Stop MO when at 5-2,5 mikrog/kg/h
•Stop Clonidine when at 0,2 mikrog/kg/h
Weaning from the postoperative pain treatment
after the first 24 hours
ALPS ≤ 3 for
4 timmar
•Take out Ketanest inf.
•Reduce MO inf 2,5mikrog/kg/h
•If the baby is on both MO and Clonidine, start reducing
MO 2,5mikrog/kg/h and after Clonidine 0,1mikrog/kg/h
when MO is at 10 and 5 mikrog/kg/h
•Stop MO when at 5-2,5 mikrog/kg/h
•Stop Clonidine when at 0,2 mikrog/kg/h
•Keep assessing pain
Pain assessment in the “at risk” newborn
Infants at risk for neurological impairment may
suffer more pain than healthy infants due to
 discounting or denial of signals of acute distress by
health professionals and parents (Walco et al., 1994)
 misconceptions about the capacity and sensitivity for
pain (Stevens et al., 2007)
 effects of underlying disease on the nociceptive system
 inadequate knowledge to systematically study the
problem (Oberlander et al., 1999; Oberlander and
O’Donnell, 2001)
 the inability to use analgesic methods used in other
infants (e.g., non-nutritive sucking) (Stevens et al., 2007)
Higfh risk for NI
Moderate risk for NI
Low risk for NI
Stevens et al., Pain 2007
IVH and pain processing in
preterm
non-noxious touch
Similarity between
evoked potentials in
preterm infant with and
without IVH.
noxious heel lance
Neuroimage 2010
Contents
• Pain development
– Pain vs. Nociception
• Pain assessment
– Importance of pain assessment
– Pain scales
– Examples
• Pain treatment
–Painful procedures
– NIDCAP
– Drugs
Hpothesis
• More attention should be paid to small
procedures. In a recent study about 45% of small
painful/discomfort procedures are not adequately
treated. (Simons et al 2003, Arch Pediatr Adolesc Med)
• We should reconsider treating pain during and
after emergency procedures
When we should measure pain
•Diagnostic
•Therapeutic
•Clinical
Diagnostic
– Arterial puncture, venipuncture, heel
puncture
– Bronscopy
– Endoscopy
– Lumbar puncture
– ROP examination
– Suprapubic bladder tap
– X-ray (particular cases)
Therapeutic
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Bladder catheterization
Chest tube insertion/removal
Oro/naso gastric tube insertion
Intramuscular injection
Peripheral venous catheterization
Mechanical ventilation
Removal of adhesive tape
Suture removal
Tracheal intubation
All surgical procedures
Ventricular tap
Central line insertion/removal (?)
Tracheal extubation (?)
Dressing change (?)
Postural drainage (?)
Chest physiotherapy (?)
Orogastric suctioning
• Orogastric suctioning during the neonatal
period results in global chronic somatic
and visceral hyperalgesia in adult life.
Smith et al., 2007
Clinical condition
– Mechanical ventilation (especially HFOV)
– Chest tube
– Post-operative
– Fractures
– NEC
– Plexus injuries
– Cephalhematoma
– Traumatic deliveries
– Skin injuries and infiltration
– Pneumothorax (without chest tube)
Pain treatment
non-pharmacological interventions
•
•
•
•
Glucose
Nutritive and non-nutritive sucking
Containment
Nidcap
Glucose:
Analgesic or “just an illusion”
• Stress is high even after glucose
administration (Ped res 2006)
• Oral sucrose does not significantly affect
activity in neonatal brain or spinal cord
nociceptive circuits, and therefore might
not be an effective analgesic drug (Lancet,
2010)
Behavioral responses do not match with
neurophysiologic signal and stress
hormones
Glukos
• Sucrose on the tongue (not via V-tube) stimulates the release
of endogenous opioids. Iof the newborn gets naloxone at the
same time, endogenous opioids may be blocked, resulting in
loosing the analgesic effect.
• The best behavioural response to glucose is observed when in
combination pacifier. Containment enhances the effect.
• Glucose 30% (300mg/mnl) is a potent solution with a very high
osmolality (about 7 times stronger than a normal formula) that
can be hazardous to the immature mucosa of the stomach and
intestine.
Glukos
• Extrem prematura barn < v.28
– Ingen peroral Glukos förrän barnets mag- och
tarmsystem har tolererat matintag under 1 vecka.
• Prematura barn > v.28
– 0,1 – 0,4 ml Glukos per tillfälle.
• Vid misstänkt NEC eller efter bukoperation
– Ingen Glukos peroralt före påbörjad matupptrappning.
• Fullgångna barn
– 1,0 ml Glukos, vb kan ytterligare 0,5 + 0,5 ml ges
(max 2 ml) per tillfälle.
L
a
n
c
Suppressing neuronal
activity in the
surrounding area
Inhibitory neurons
- -
-
Other neuron
Other neuron
Specific neurons (ex. visual,
gustatory??)
Attention, interest. Taste?
Smell? Perception.
Macknik, Martinez-Conde, Nature 2007
Macknik, Scientific Am. 2010
Pain treatment
• Short term pain (procedural pain)
–
–
–
–
–
–
–
Fentanyl 0.5-1 microg/kg
Remifentanyl 0,1-0,2 microg/kg
Ketamine 0,125-0,3mg/kg uo to 3mg/kg
Morphine 0.05-0.2 mg/kg
Clonidine 3-4microg/kg ggr 3-4/day
Propofol 0,5-1,5 mg/kg
Ketolarac 1mg/kg (10 min) (very seldom)
• Long term pain (
–
–
–
–
Morphine, Ketogan 10-50 micro/kg/h
Clonidine 9-20microg/day
Paracetamol 7,5-15mg/kg x3-4
Gabapentin (neuropatisk smärta)
The morphine issue….
• Morphine does not appear to provide
adequate analgesia for the acute pain
caused by invasive procedures among
ventilated preterm neonates. Pediatrics
2005, Carbajal et al.
• Morphine does not reduces IVH in
ventilated preterm newborn. NEOPAIN
study. Lancet 2004, Anand et al.
Opioids
• Exposure to morphine in early life may affect the development
and the expression of pain receptors and thus how pain is
going to be perceived in later life (anand 2000)
• There is insufficient evidence to recommend routine use of
opioids in mechanically ventilated newborns. Opioids should be
used selectively, when indicated by clinical judgment and
evaluation of pain indicators. (Anand 2006)
Our doses….
Namn
Conc.
(substans)
Morfin
epidural
(morfin
hydrochlorh
ydrat)
0.4mg/ml
injection
Dos
0.1-0.2
mg/kg
Solut.
NaCl
9mg/ml
Glu 5%,
0.04mg/ml 5-40 μg/kg/h 10%
infusion
Other
Inj.: Under ca
15min.
Inf:: Avoid too
quick weaning
Effect of oral naloxone
hydrochloride on gastrointestinal
transit in premature infants treated
with morphine
p = 0.014
Mean food intake (ml/kg/day)
p = 0.183
Perfalgan (Paracetamol iv)
Age at operation
Below v28
Infusion Perfalgan
7 mg/kg x 3
V. 28-32
7,5 mg/kg x 3
V. 33-36
7,5 mg/kg x 4
Over 37 weeks
10-15 mg/kg x 4
Dosen bör halveras efter ca 4-5 dagar eller till barn med nedsatt leverfunktion.
PM - Smärtlindring under pleuradrän insättning
1. Optimize the enviroment
The operator should have a comfortable work place.
The baby should stay in the nest and be held and contained
Prepared all the tools to reduce the time of the procedure
Evaluation of potential hazardous conditions hypotension,
bleeding, etc
2. Morphine 0,4mg/ml
0,1-0,2 mg/kg bolus
Catapresan
(Clonidine)
15 or 1.5
microg/ml
1-3 microg/kg x3-4
max 9-12
microg/kg/dygn
0,1-0,4 microg/kg/t
(inf)
Ketanest
(Ketamine)
25 or 25
mg/ml
0.01-0.05 mg/kg/t inf
0.125-0.25 mg/kg inj
upp till 1-2 mg/kg
OBS! Det tar ca 1150 min minst innan
morfinet har effekt
Glu5%
or NaCl
CAVE HR,
BT! Tar BT
before
injektion/
infusion startas
Glu5%
or NaCl
Need of sedation?
Midazolam 1mg/ml
0,05-0,1 mg/kg bolus
3. Local analgesia
Tamponated xylocain 2%
(2ml NaHCO3 + 8 ml xylocain)
OBS! Observe if the analgesia
is enough!
OBS! If need give more
morphine (0.02-0.03mg/kg) or
other drugs
Chest tube insertion
4. Continous Morfin inf. (0,04mg/ml)
5-20microg/kg/timme
•If the baby is very calm consider nu MO inf. And consider
Clonidine if BP is stable.
5. Morfin weaning
•Pain assessment is fundamental
•About 6-8 hours interval between the
dos lowering down to the lower dos
•The longer is the infusion the longer is
the weaning time
•Consider other drugs Clonidine or
ketamine during the weaning
•Paracetamol should be kept about 1-2
days after morphine is ceased
•Naloxon hydrochlorid p.o.
Morfin infusion
After the chest tube is positioned assess pain and
give iv paracetamol (Perfalgan 10mg/ml) 7,5 10mg/kg iv x 4/d. (Better iv than rectally, Alvedon
Pain assessment!
rekt 30mg/kgx3 first day followed by 10-20mg/kg
x3)
Pain treatment
local anaesthesia
•
•
•
•
•
EMLA
LMX
Xylocaine
Chirocaine (L-bupivacaine)
Rupivacaine
EMLA
– EMLA-krämen innehåller lidokain och prilokain
som tränger in i huden och ger en lokal
hudanestesi. Prilokainet som finns i krämen kan i
kombination med Sulfa, Trimetroprim-Sulfa
(Bactrim) eller NO kan öka Met-Hb. Över vecka 30
• Barn > 30 gestationsveckor – 1 månad efter fullgången
tid
• 0,5 gram (0,5 ml) EMLA högst 1 gång per dygn i högst en
timme.
Local anesthesia
with subcutaneous catheter
Levobupivacaine (Chirocaine®)
Levobupivacaine is an amide-type local
anaesthetic. As with all local anaesthetic
agents, levobupivacaine inhibits conduction
of the action potential in nerves involved in
sensory and motor activity and sympathetic
activity
Infusionsvätska Chirocaine 1,25mg/ml
(L-bupivacaine)
Dos: 2 mg/kg x 4 eller som kontinuerlig infusion, 8-15 mg/kg/dygn
Group A: Morphine infusion at a starting dose of 10 microg/kg/h +
paracetamol (Perfalgan®) 7,5mg/kg 4 times daily
Group B: Morphine infusion at a starting dose of 10 microg/kg/h +
paracetamol (Perfalgan®) 7,5mg/kg 4 times daily + Chirocaine®
(1,25mg/ml) and a dose of 2 mg/kg subcutaneously 4 times daily.
Morphine infusion (microg/kg) tot
800
600
400
200
0
p<0.05
w ithout local anaesthesia
group A
w ith local anaesthesia
group B
Best Practice & Research Clinical Anaesthesiology, 2010
Local anesthesia for the
insertion of naso-gastric
tube in premature infants
Lidocaine, 5mg/ml
2 puff (0,5mg) lidocaine in the nose/pharynx
1 min before insertion
2.5
ALPS/NIPS score
2
1.5
ALPS diff
NIPS diff
1
0.5
0
Placebo
Lidocaine
Social influences
Pain event
Familial context
Pain experience
Child
Community context
Cultural context
Pain expression
Assessment of pain
Caregiver
Intervention
from International Association for the Study of Pain
Take home message
• Newborns at all gestational ages are receptive,
more susceptible and vulnerable to both
nociception and painful stimuli.
• Nociceptive and painful stimuli during the
neonatal period might impair the capacity to
perceive, express and describe pain later in life.
• Adequate pain prevention and treatment are
based on pain systematic and standardized
assessment  pain scale, courses, up-to-date
• There is the need to develop new strategies and
alternatives to opioid treatment  research on
pharmacodynamic and pharmacocynetic urges!