Practical Approach to Analgesia and Sedation

in the Neonatal Intensive Care Unit

Gopi Menon, K.J.S. Anand, and Neil McIntosh

The anatomic and physiological bases for nociception are present even in very preterm neonates.
Neonates show the same behavioral, endocrine, and metabolic responses to noxious stimuli as older
subjects. Preterm infants appear to be more sensitive to painful stimuli and have heightened
responses to successive stimuli. Infants receiving intensive care are subjected to frequent stressful
procedures and also chronic noxious influences related to the environment of care. Inflammatory
conditions such as necrotizing enterocolitis may also cause pain. Untreated pain in babies is associ-
ated with increased major morbidity and mortality. Nonpharmacological interventions, including
environmental modification and comforting during procedures reduce stress. Intravenous opiates are
the mainstay of pharmacological analgesia. A pure sedative agent can provide physiological stability
in settings in which there are less acutely painful stimuli or when there are adverse effects from, or
tolerance to, opiates. Local anesthesia of skin and mucous membranes is helpful for invasive
procedures. Antipyretic analgesics such as acetaminophen have a role in inflammatory pain.
Copyright 9 1998 by W.B. Saunders Company

n a m o d e r n neonatal intensive care unit noxious stimulus i n d e p e n d e n t of any j u d g m e n t

I (NICU), babies are regularly exposed to con- of higher consciousness, memory, or possible
ditions that would be considered noxious by emotional effects or suffering. This is what is
older children and adults. Recently, studies have measured, directly or indirectly, in studies of
begun to show the efficacy and safety of phar- neonatal pain, although the existence of con-
macotherapy, which has led to its regular use in sciousness or the emotional c o m p o n e n t s of pain
neonatal intensive care. in the neonate c a n n o t be excluded by default. ~,2
The terminology and assumptions used for Newborn babies show behavioral, endocrine,
pain in adults have resulted in some confusion, and metabolic responses that are associated with
and in the denial o f its relevance to the new- pain and distress in older people. However, the
born. A statement o f definitions may help im- term pain is widely used to mean nociception as
prove clinical awareness of these p h e n o m e n a in described above, and that is how the term will be
the busy NICU. used t h r o u g h o u t this article.
Stress is the term applied to the spectrum of
physiological responses normally generated by
certain external stimuli or internal cues. These The Physiological Effects o f Pain
are important adaptive responses and probably Pain produces many physiological changes in-
cause no harm. T h e r e may be no conscious cluding those related to (1) the cardiovascular
awareness o f stress and there is certainly no as- and respiratory system, (2) e n d o c r i n e and met-
sociated suffering. Distress is the suffering result- abolic processes, (3) the i m m u n e system, and
ing from the emotional effects of excessive (4) coagulation and hemostasis. 3
stress. Its recognition by the patient requires All invasive p r o c e d u r e s may create undesir-
higher consciousness, and is often affected by
comparison with past experience. Its recogni-
From the Department of Child Life and Health, University of Edin-
tion by the observer depends on either a verbal burgh, Simpson Memorial Maternity Pavilion, Edinburgh, Scot-
description of the experience by the subject or, land, UK; and the Department of Pediatrics and Anesthesiology,
in the younger subject, the inference of suffer- University of Arkansas for Medical Sciences, Little Rock, AR.
ing from behavioral cues. Pain is a description of Address reporint requests to Gopi Menon, MA, MRCP, Consultant
Neonatologist, Simpson Memorial Maternity Pavilion, University of
a particular form of distress that is easily related Edinburgh, Edinburgh, Scotland, UK.
to the adult. Nociception is a term used to describe Copyright 9 1998 by W.B. Saunders Company
the effects (metabolic, neurobehavioral) o f a 0146-0005/98/2205-0007508.00/0

Seminars in Perinatology, Vol 22, No 5 (October), 1998: pp 417-424 417

418 Menon, Anand, and Mclntosh

able stress responses. T h e degree of risk related havioral and developmental sequelae resulting
to stress depends on its severity, its duration, and from premature birth and the exposure to re-
the maturity of the infant. Routine handling of petitive painful experiences during neonatal in-
neonates during intensive care results in hypox- tensive care.
emia which can be r e d u c e d by analgesia. 4 Neo-
natal heel prick and circumcision cause large
Increased Pain Sensitivity in P r e t e r m
increases in heart rate and blood pressure 5 and,
Neonates
in addition, circumcision causes a drop in trans-
cutaneous oxygen prevented by local analgesia. 6 Multiple lines of evidence suggest an increased
Endotracheal intubation results in hypoxia and sensitivity to pain in p r e t e r m neonates. Using
rises in blood pressure 7 and intracranial pres- calibrated plastic filaments, Fitzgerald et aP 7
sure, and the latter is abolished by anesthesia, s studied developmental changes in the threshold
Cardiovascular responses to tracheal suction are for the flexor withdrawal reflex, because it
abolished by opiate analgesia. 9 closely corresponds with the pain threshold and
Because o f the magnitude of the physiologi- is exquisitely sensitive to inhibition by opioids
cal response, many studies have looked at surgi- and other analgesics. Flexor reflex thresholds
cal stress. In neonates undergoing cardiac sur- were directly related with increasing gestational
gery, opiate anesthesia dampens changes in age, with significantly lower thresholds in pre-
heart rate and blood pressure, reduces endo- term neonates c o m p a r e d with full-term neo-
crine and metabolic responses, and decreases nates. In addition to mechanical stimuli, pain
metabolic, infective and cardiovascular compli- thresholds measured by thermal stimuli were
cations, and postoperative mortality. 1~ Pro- also decreased in neonatal rat pups c o m p a r e d
longed postoperative analgesia reduces the risk with older rats. 18 Repeated stimulation and local
of thrombotic complications in these patients? ~ tissue injury were associated with prolonged pe-
Preterm infants are likely to be at greater risk riods of sensory hypersensitivity in neonatal rat
because of the immaturity of these metabolic, puPs or p r e t e r m neonates, 17,19 and these
immune, cardiorespiratory, endocrine, and changes were abolished by topical analgesia. 2~
other systems. In p r e t e r m neonates u n d e r g o i n g The early and a b u n d a n t expression of puta-
thoracotomy for ligation of ductus arteriosus, tive neurotransmitters mediating nociception,
fentanyl anesthesia r e d u c e d their stress re- and delayed expression of descending inhibitory
sponses and clinical morbidity, including reduc- neurotransmitters 21 further indicates an in-
tions in the occurence of p n e u m o t h o r a x and creased excitability in the dorsal h o r n of the
intraventricular h e m o r r h a g e (IVH), as well as premature spinal cord. An increased magnitude
duration of ventilator dependency. 11 of hormonal, metabolic, or cardiovascular re-
sponses to surgical operations in preterm and
full-term neonates,22, 23 and higher plasma con-
Types o f P a i n
centrations o f analgesics and anesthetics re-
Noxious influences may be episodic and related quired to produce clinical signs of anesthesia in
to specific procedures (procedural pain), or may neonates c o m p a r e d with older age groups, 24-26
be m o r e chronic in nature. T h e routine and also indirectly support the concept of increased
f r e q u e n t o c c u r r e n c e of these sources of noxious pain sensitivity.
stimulation have b e e n noted in several recent
studies. 12q6 Systematic laboratory and clinical
Acute, Episodic Pain versus Established
studies of neonatal pain support (1) a physiolog-
or Chronic Pain
ical increased sensitivity to pain in neonates, (2)
p r o l o n g e d hyperalgesia after acute painful stim- The low pain threshold in preterm neonates is
uli in p r e t e r m neonates, perhaps leading to es- accentuated by an increased excitability of noci-
tablished pain, (3) a possibility that the acute ceptive neurons in the dorsal h o r n of the spinal
physiological responses to painful stimuli may cord after exposure to any painful stimulus
cause or e x t e n d early 1VH or ischemia leading to (windup phenomenon).20,27 This sensory hyper-
periventricular leucomalacia (PVL), and (4) sensitivity is caused by m a r k e d increases in the
preliminary associations between the neurobe- excitability and the receptive area of neurons
 Practical Analgesia and Sedation 419

Table 1. A Practical Approach to Procedural Pain

Procedure Issues Suggested Approach
Relatively Minor Procedures
Heel prick Good technique Autolet/tenderfoot device
Good heel perfusion Avoid EMLA, caused by vasoconstriction

Venous and arterial EMLA

puncture
Suprapubic aspiration EMLA
Insertion of nasogastric tube Discomfort/gag Slow insertion
Vagal reflex
Handling for radiograph Extra morphine for ventilated babies
Moderate/Major Procedures
Lumbar puncture Skin, ligaments, dura EMLA and lignocaine infiltration
Stress of restraint Midazolam/morphine if ventilated
Chest drain Skin, muscle, pleural pain, Ventilate
pain with respiratory Morphine bolus and infusion
movements Lignocaine infiltration
Periosteum on ribs

Ventricular tap Skin, dura EMLA

Midazolam/morphine if ventilated
Elective intubation Discomfort/gag/cough Midazolam/morphine bolus ?short acting
Vagal reflex muscle relaxant

Endotracheal suction Discomfort/gag/cough Morphine or midazolam bolus

Vagal reflex, hypoxia
Retinopathy of prematurity Discomfort/restraint Ventilation
Treatment for retinopathy Eyeball pain Morphine loading and infusion or
Vagal reflex inhaled anaesthetic
Pancuronium
Atropine

located in the substantia gelatinosa of the dorsal pain or discomfort have greater biological and
horn. These changes are mediated by N-methyl- clinical importance for critically-ill preterm ne-
D-asparate and tachykinin receptor activity above onates.
and below the spinal level innervating the area
of tissue damage. 2~ Compared with the adult
Procedural Pain
rat, the duration of excitability was prolonged in
neonatal rats, and tactile stimuli in the region of Babies in NICUs are subjected to frequent inva-
hyperalgesia produced an activation of pain sive and potentially noxious procedures. 12-16
pathways, pain-mediated behavior, and the phys- Korones 14 d o c u m e n t e d 70 nonsocial episodes of
iological responses to pain. Thus, for prolonged handling in one baby in 24 hours, and Barker
periods after a painful stimulus, preterm neo- and Rutter 1~ recorded 488 invasive procedures
nates may experience other, non-noxious stim- during the hospital stay of one preterm infant.
uli (handling, physical examination, nursing Most handling procedures in small and sick ba-
procedures) that cause heightened activity in bies probably lead to stress, and if not con-
nociceptive pathways, leading to the systemic trolled, may cause cumulative harm.
physiological responses to stress. 3~Prolonged ac- Some procedures including heel prick, blood-
tivity in the nociceptive pathways may be per- letting 3s and vascular cannulation (arterial and
ceived as chronic noxious stimulation (classified venous), suprapubic aspiration, chest drain in-
as chronic pain or discomfort).al.a2 Despite the sertion, and ventricular tap are known to pro-
current research focus on acute pain, chronic duce pain and stress. Other procedures such as
420 Menon, Anand, and Mclntosh

Table 2. Nonpharmacological Approaches for avoided for heel prick, because the associated
Analgesia/Sedation vasoconstriction may prolong the duration of
Environmental changes and distraction the p r o c e d u r e and make it more stressful, s9
Decrease stimulation EMLA cream needs to be applied 60 minutes
Decrease light, noise, handling before the procedure. T h e r e is conflicting infor-
Swaddle, use pacifier mation about whether it helps in lumbar punc-
Changes in position, look for pressure sores
tures, 47'48 and no information in relation to su-
Touch, music, soothing voice
Holding, rocking, rubbing, kangaroo care prapubic aspiration of urine. With lumbar
Hydrotherapy, sponging punctures, the pain related to puncturing the
Physical therapy, occupational therapy dura probably justifies infiltration with a local
Transcutaneous Electrical Nerve Stimulation anesthetic, especially because this does not ap-
pear to make the p r o c e d u r e any more difficult. 49

handling for nursing procedures, 34 radiographs,

Systemic Analgesia
weighing, ultrasound scans, intubation, physio-
therapy, 35 oral and endotracheal suction, ~6 in- Systemic analgesic drugs may be given pre-emp-
sertion o f nasogastric tubes, 37 and treatment for tively as background cover for babies in intensive
retinopathy o f prematurity lead to distress and care, a n d / o r given in anticipation of a specific
discomfort (Table 1). p r o c e d u r e (Table 3). Background cover alone is
not likely to provide adequate analgesia for pain-
ful events, but bolus doses are more likely to lead
Nonpharmacologieal Methods
to side effects because of the higher plasma
Procedural pain can be minimized by an effi- levels achieved. This can be minimized by con-
cient training of staff using indwelling lines for trolled infusion of a bolus dose. Nurse-con-
sampling, using mechanical devices if heel stab trolled analgesia has been r e p o r t e d in other in-
is necessary, 3s-4~ and planning procedures so tensive care settings, 50 but not in the neonate.
that an analgesic approach can be considered Multiple boluses are associated with the danger
(Table 2). Comforting by a p a r e n t or other care- o f accumulation. Systemic analgesics are dis-
giver is a complex process, but clearly alters the cussed in greater detail in relation to chronic
behavioral responses to painful stimuli, and pain.
probably alters the perception of pain. 39,4a A
pacifier with sucrose solution may help with all
Persistent or Chronic Pain or Distress
m i n o r and medical procedures. 42 It has been
suggested that nursing and medical procedures Chronic pain or distress are difficult to assess in
should be batched together to allow longer pe- the newborn. Ongoing nociception may be a
riods of rest. But if the p h e n o m e n o n of wind-up feature of babies needing intensive care contrib-
or central sensitization applies to humans as in uted to by (1) intubation and ventilation, (2)
animals, this approach may be counterproduc- physical restraints and exposure, (3) the distress
tive. 43 of increased respiratory work, (4) thermal stress,
and (5) exposure to bright lights and noise. Pain
may also be persistent postoperatively, in patho-
Topical Analgesics
logical conditions causing inflammation, eg,
Local analgesic creams (eg, 5% EMLA, a mix- cellulitis, tissue infiltration o f intravenous infu-
ture of lidocaine and prilocaine) are effective in sions, osteomyelitis, necrotizing enterocolitis,
blunting the pain response to venepuncture and and meningitis.
superficial surgical procedures in children. 44 It's In situations that may be associated with per-
use in neonates may be associated with a greater sistent pain or discomfort, an attempt can be
theoretical likelihood of systemic absorption made to assess its degree and the effectiveness of
and methemoglobinaemia. Blood levels of met- treatment by using a scoring system such as the
hemoglobin do tend to be raised, but are well Premature Infant Pain Profile. 51 Subjective bed-
below the toxic range, and are not associated side assessments of pain by clinical staff often
with any clinical problems. 45,46 It should be d e p e n d on clinical experience.
 Practical Analgesia and Sedation 42 1

Table 3. Drugs Used for Systemic Analgesia

Drug Intermittent Dose Infusion Dose
Opioid analgesics
Morphine 0.05-0.1 mg/kg 0.01-0.03 mg/kg/h
Fentanyl 2-5/~g/kg 1-4/zg/kg/h
Methadone 0.05-0.2 mg/kg
Alfentanil 5-15/zg/kg 5-20/zg/kg/h
Sufentanil 0.05-0.3/zg/kg 0.05-0.2/zg/kg/h
Meperidine 0.5-1 mg/kg 0.5-4.0 mg/kg/h
Nonsteroidal anti-inflammatory drugs
Acetaminophen 10-15 mg/kg PO, 30--45 mg/kg PR
Ibuprofen 10-15 mg/kg PO, 20-25 mg/kg PR
Indomethacin 0.2-0.3 mg/kg IV
Ketorolac tromethamine 0.5 mg/kg IV, 0.5-1.0 mg/kg PO
Anesthetic agents
Ketamine 0.5-1 mg/kg IV, 2-5 mg/kg PO
Abbreviation: IV, intravenously;PO, orally; PR, rectally.

Nonpharmaeologieal Measures These attitudes have served to perpetuate com-

m o n misconceptions about neonatal pain.
Several environmental measures and behavioral If routine analgesia/sedation is to be given to
interventions may help reduce the ongoing nox- ventilated infants, it seems sensible to start ad-
ious influences of neonatal intensive care. They ministration soon after birth, before the period
include nesting, 52 kangaroo care, 53 non-nutritive o f intensive handling with its associated stress
sucking, ~4 reduction of light and noise levels, (venous and arterial cannulation, radiographs).
and providing a day-night cycle. 55 Recent studies In a recent multicenter pilot study, ventilated
have suggested that an individualized package o f preterm infants between 24 and 33 weeks gesta-
care incorporating many of these techniques tion were randomly allocated to intravenous in-
can improve short-term respiratory and long- fusions of m o r p h i n e (sedative and analgesic),
term behavioral and developmental o u t c o m e 56 midazolam (sedative), or dextrose (placebo).
(Table 2). T h e results suggest that m o r p h i n e and midazo-
lam reduce pain responses and stabilize vital
Systemic Analgesia and Sedation signs, but that m o r p h i n e (not midazolam) re-
duces the risk of death or major neurological
In many units, it is now routine practice to give morbidity (grade 3 / 4 IVH or PVL).73
a sedative/analgesic to babies who are ventilated
(Table 3). The aims are (1) to reduce distress,
(2) to facilitate the asynchrony o f spontaneous Morphine
and ventilator respirations, and (3) to prevent
physiological instability. -~7-62It is important that a Morphine is the most widely used opiate in neo-
clear distinction is made between muscle relax- natal intensive care. Neonates are particularly
ants (which produce physiological stability and sensitive to many o f the side effects for good
abolish ventilator asynchrony but have no seda- physiological reasons. However, these may be
tive or analgesic effect), pure sedatives such as avoided by loading with slowly infused boluses
the benzodiazepines (which may p r o d u c e phys- and restricting the dose and duration of contin-
iological stability but have no analgesic effect), uous infusion. In theory, a r e b o u n d increase in
and analgesics such as the opiates (which have plasma levels and late respiratory depression
sedative and analgesic effects). In the recent might occur some time after administration be-
past, it was all too c o m m o n to administer muscle cause of an enterohepatic circulation of mor-
relaxant without any sedation and it was also phine. Respiratory depression is rarely a clinical
c o m m o n in neonatal units to colloquially refer problem in babies taken off the ventilator within
to paralyzed babies as "asleep" or "waking up." 1 h o u r of stopping a m o r p h i n e infusion. 64 If it
422 Menon, Anand, and McIntosh

does occur, naloxone can be administered. In lus doses. Sufentanil, one of the most p o t e n t
p r e t e r m infants in this situation, respiratory sup- opioids, is used for deep anesthesia, and should
port should be provided for a longer period perhaps be reserved for use in ventilated neo-
rather than give naloxone because there is a risk nates tolerant to other opiates. Alfentanil, with
o f a massive r e b o u n d stress response with asso- its short duration of action, may have a role for
ciated disruption in homeostasis. Hypotension, procedural analgesia.
bradycardia, and flushing are part of the hista-
minic response to m o r p h i n e (more than other
opiates) and are associated with rapid intrave- Inflammatory Conditions
nous bolus administration. A fall in blood pres-
In conditions such as necrotizing enterocolitis,
sure, though measurable, is not clinically signif-
meningitis, and osteomyelitis, it should be as-
icant. 65 T h e histaminic effects are of concern in
sumed that pain is a feature o f the disease until
the treatment of infants with chronic lung dis-
treatment has had a chance to take effect, and
ease because of resultant airway narrowing. The
analgesia should be considered routinely. 7~
real extent of this problem is unknown. Reduc-
T h e r e are no data concerning the optimum
tion in gastrointestinal motility may delay estab-
regimen in these conditions. In necrotizing en-
lishment of enteral feeding, but gut priming
terocolitis, the most appropriate analgesia is
with small volumes o f milk is still possible. In
probably an opiate infusion because o f the po-
babies who n e e d sedation for longer-term venti-
tential severity of pain, and the contraindica-
lation, the use of o t h e r purely sedative agents
tion of enteral analgesia and nonsteroidal anti-
s h o u l d obviate some o f these problems. With-
inflammatory agents with their gastrointestinal
drawal symptoms may occur after as little as 48
and antiplatelet side effects. Concerns about
hours of m o r p h i n e infusion, but are not usually
the possible hypotensive effects of opiates in a
problematic. 64,65 These potential effects may be
potentially shocked infant can be overcome by
minimized by gradual weaning (see Suresh and
delaying administration until after initial resus-
Anand, this issue).
citation and the initiation of monitoring. The
risk of respiratory depression with opiates may
Fentanyl be no greater than that associated with the pain
and diaphragmatic splinting effect o f an acute
T h e r e is an increasing a m o u n t of data relating
abdomen.
to fentanyl, which seems to have a large thera-
peutic index. It is effective in d a m p e n i n g stress
responses at low doses. Pharmacokinetics show a Sedatives
wide individual variation in the newborn, a n d
there are late rebounds in plasma level in a large A pure sedative agent may be more appropriate
p r o p o r t i o n of babies, probably related to drug than the sedative and analgesic opiates in cer-
release from adipose tissue stores. 66 Fentanyl has tain circumstances. Sedation is indicated for
two properties that may give it a special role: (1) long-term ventilation, when the frequency o f in-
a lesser histaminic effect, that might make it vasive procedures is reduced and routine anal-
m o r e suitable for use in infants with chronic gesia is less of an issue. Sedatives are also given
lung disease, 67 and (2) a tendency to reduce when there are problems with tolerance to opi-
p u l m o n a r y vascular resistance, making it poten- ates in babies who remain ventilator d e p e n d e n t
tially useful in infants with persistent pulmonary for a p r o l o n g e d period with the n e e d for inva-
hypertension with or without underlying dia- sive intensive care. The use of a sedative in this
phragmatic hernia, 6s during extra-corporeal situation may allow weaning and discontinua-
m e m b r a n e oxygenation, and after cardiac sur- tion of opiates. Sedation may also be beneficial
gery. 69 Fentanyl and its derivatives, if given in in older babies with severe chronic lung disease
large doses rapidly, may p r o d u c e chest wall ri- who appear to be distressed by dyspnea. In this
gidity through effects o n stimulatory pathways in situation, it is important to observe closely for
the spinal cord. This occurs more frequently in the respiratory depressant effects of sedation.
full-term than in p r e t e r m neonates and is an- This approach, if used with caution, has pro-
o t h e r justification for controlled infusion o f bo- vided clinical benefit.
 Practical Analgesia and Sedation 423

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