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DOI: 10.1542/neo.14-1-e222013;14;e22Neoreviews

Dennis E. Mayock and Christine A. GleasonPain and Sedation in the NICU

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Painand Sedation in the NICUDennis E. Mayock, MD,

Christine A. Gleason, MD

Author Disclosure

Drs Mayock and

Gleason have

disclosed no financial

relationships relevant

to this article. This

commentary does

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Practice Gaps

1. Many neonates do not receive adequate sedation for procedures in the NICU.2. There is no evidence to guide appropriate sedation during extracorporeal life support.

3. The risks of some sedatives may outweigh their potential benefits.

4. Nonpharmacologic methods of sedation need further evaluation.

AbstractRecognition and treatment of procedural pain and discomfort in the neonate remain

a challenge. Procedural sedation and control of pain and discomfort are frequently man-

aged together, often by using the same intervention. Therefore, although this article

focuses on sedation, separating sedation from pain control is not always possible or wise.

Despite signicant progress in the understanding of human neurodevelopment, phar-

macology, and more careful attention to how we care for sick infants, we still have muchto learn. Protecting and comforting our fragile patients requires us to use poorly val-idated tools to assess and intervene to minimize distress, often applying data derived

from adult patients to infants. Ourrst priority should be to minimize pain and distress.

Further exploration of nonpharmacologic methods of procedural pain and distress con-

trol are needed. When pharmacologic intervention is necessary for procedural pain con-

trol and sedation, we need to use the least amount of drug that controls the pain and

distress for the shortest period of time. As newer techniques and medications are intro-

duced to clinical practice, we must demonstrate that such additions achieve their goal of

sedation or pain control, and are safe over the lifetimes of our patients. Clinicians should

identify appropriately the need for and use of sedatives and analgesics in the neonate.

Objectives After completing this article, readers should be able to:

1. Understand the challenges of using pain scores to assess the need for, and response

to, neonatal sedation.

2. Describe the uses of sedation for facilitation of neonatal procedures.

3. Discuss pharmacologic approaches to neonatal sedation.

4. Discuss nonpharmacologic approaches to neonatal comfort care.

IntroductionAdvances in neonatology have signicantly improved morbidity and mortality, but pain, dis-

comfort, and stress remain sad realities for infants in the NICU. Assessing, managing, and

trying to limit these clinical realities while providing optimal care for critically ill neonates

is challenging and increasingly controversial. Fortunately, there has been considerable research

and much clinical dialogue aimed at developing best clinical

practices in this problematic area.

Sedation can be dened as the reduction of irritability or

agitation, usually by administration of sedative drugs. In the

NICU, sedation is used both to facilitate care (by limiting

movement/agitation) and to minimize pain, discomfort, and

stress during procedures and intensive care. Appropriate identi-

cation of the need for and use of sedatives and analgesics, based

on the best available evidence, should be cliniciansobjective.

Abbreviations:

EMCO: extracorporeal membrane oxygenation

EMLA: eutectic mixture of local anesthetics

M3G: morphine-3-glucuronide

M6G: morphine-6-glucuronide

Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.

Article pharmacology

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Assessment of Neonatal Sedation: PainScoresMore than 40 infant pain scales have been developed,

most often for use in clinical trials to assess treatment ef-

cacy; few have been validated for general clinical use for

acute pain assessment. These pain scores are also fre-

quently used to assess adequacy of sedation, even though

they were not developed for this purpose nor were they

designed or validated for assessment of chronic pain or

discomfort associated with mechanical ventilatory sup-

port, or for use in paralyzed or neurologically compro-

mised infants. The American Academy of Pediatrics

(AAP) and the American Academy of Pediatric Dentistry

have recently published an update on pediatric sedation,

which recommends using a carefully staged process toplan for and carry out sedation for diagnostic and thera-

peutic procedures (Cot et al, 2006).

Sedation can be categorized according to the level of

consciousness, effect on protective airway reexes, pa-

tency of the airway, and response to stimulation. The

level of sedation can progress from conscious sedation

to deep sedation to general anesthesia (Table 1).

The optimal approach to sedation management should

include reducing the frequency of painful procedures and

environmental stressors, facilitating developmentally ap-

propriate care, determining the best technique to mini-

mize the pain and stress associated with procedures,delegating responsibility for pain/sedation assessment

and treatment to the bedside nursing staff, and using a bal-

anced multimodal approach to procedural sedation

(Allegaert et al, 2009).

Sedation for Mechanical VentilationUse of mechanical ventilation in neonates who have re-

spiratory failure is a common practice. In the past, seda-

tion (most often with opiates) was frequently used in

pediatric and adult ICU patients who required mechan-

ical ventilation. Extrapolation of evidence from early

studies in nonneonatal patients led to frequent use of opi-

ate sedation in neonates during mechanical ventilation,

with limited information as to safety and efcacy. How-

ever, in the past decade, use of pharmacologic sedation in

the adult ICU has been signicantly reduced because of

concerns regarding adverse cognitive outcomes and lon-

ger duration of ventilator support. These concerns have

led to a rethinking of this practice in both pediatric

and neonatal ICUs. The following discussion is a histor-ical review of this issue.

Mechanical ventilation in neonates is associated with an

increase in hormonal stress responses, including increased

cortisol and catecholamine levels. In the past, infants who

appeared uncomfortable while on ventilatory support

demonstrated asynchronous respiratory effort (ghting

the ventilator), compromised gas exchange, and altered

stress responses. Clinical studies from the 1990s demon-

strated that opiate treatment prevented these adverse ef-

fects and reversed the previously described hormonal

stress changes. Opiate sedation decreased stress scores in

ventilated newborns. In ventilated term infants, the sever-ity of respiratory failure as assessed by using the oxygena-

tion index directly correlated with the need for analgesia

and sedation. More recently, with the introduction of sur-

factant replacement therapy and synchronized ventilatory

Table 1. Levels of Sedation According to the American Academy of Pediatrics

CategoryMinimal Sedation(Anxiolysis)

Moderate (Conscious)Sedation Deep Sedation General Anesthesia

Level ofconsciousness

Minimally depressedconsciousness

State of depressedconsciousness

State of depressedconsciousness or

unconsciousness

State ofunconsciousness

Protective airwayreflexes

Protective airwayreflexes maintained

Protective airwayreflexes maintained

Partial or complete lossof protective airwayreflexes

Complete loss ofprotective airwayreflexes

Airway patency Maintainedindependently andcontinuously

Maintainedindependently andcontinuously

Inability to maintainairway independently

Inability to maintainairwayindependently

Response tostimulation

Responds to physicalstimulation or verbalcommand

Responds to physicalstimulation or verbalcommandpurposefully

Cannot be easilyaroused but respondspurposefully torepeated verbal orpainful stimulation

Unable to respondpurposefully topainful physical orrepeated verbalstimulation

Source: American Academy of Pediatrics; American Academy of Pediatric Dentistry; Cot CJ; Wilson S; Work Group on Sedation. Guidelines for monitoringand management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics. 2006; 118(6):25872602

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technology, many of these previous problems with infants

ghting the ventilator have been eliminated. Further-

more, clinical trials have shown that preemptive narcotic

use in ventilated infants may actually have detrimental ef-

fects. A small randomized trial of routine morphine infu-

sion in ventilated preterm infants concluded that morphine

lacked a measurable analgesic effectand there was ab-

sence of a benecial effect on poor neurological outcome.

The larger clinical trial which followed (NEOPAIN, pub-

lished in 2004) reported no benecial effect of preemptive

morphine infusions in ventilated preterm infants and an in-

creased incidence of severe intraventricular hemorrhage in

27- to 29-week gestational age preterm infants. Indeed,

additional bolus doses of morphine resulted in worse respi-

ratory outcomes and longer requirement for ventilatorysupport. These controlled clinical trials provide no evi-

dence that routine narcotic sedation during mechanical

ventilatory support in neonates is benecial. One approach

to this dilemma has been to minimize the use of ventilatory

support as much as possible.

A recentCochrane Reviewsarticle evaluated the effects

of preemptive opioid sedation on pain scales, duration of

mechanical ventilation, mortality, growth, and develop-

ment in neonates requiring mechanical ventilation (Bell

et al, 2008). The authors found no differences in mortality,duration of mechanical ventilation, or short- and long-

term neurodevelopmental outcomes. However, very pre-term infants given morphine took longer to achieve full

enteral feeding. If morphine sedation prolongs time to full

enteral feeds, we should expect an increase in the risk

of complications related to the use of venous lines (blood-

stream infections) and parenteral nutrition (cholestasis).

Indeed, the duration of morphine use was a strong predic-

tor for development of severe necrotizing enterocolitis.

The overall conclusion of the Cochrane Reviewsarticle re-

garding use of sedation during mechanical ventilation was

that there is insufcient evidence to recommend routine

use of opioids in mechanically ventilated newborns.

Sedation for ProceduresInfants undergoing intensive care endure many painful

procedures, often several times each day. Although

new pharmacologic and nonpharmacologic treatment

strategies have been developed to decrease or eliminate

some of this pain and stress, we have a long way to go

in developing evidence-based best practices.

Blood Sampling and MonitoringHeel sticks are routinely performed to obtain blood samples

in neonates. The most appropriate method for relieving

pain from a heel stick has yet to be determined. EMLA (eu-

tectic mixture of local anesthetics; 2.5% lidocaine and 2.5%

prilocaine) does not relieve the pain of a heel lance. Neo-

nates experiencing venipuncture had lower pain scores than

those who underwent heel stick. In neonates, venipuncture

should be used preferentially over heel stick.

The pain of arterial puncture can be decreased by in-

ltrating the site with 0.1 to 0.2 mL of 0.5% or 1% lido-

caine using the smallest-gauge needle possible. Buffering

the lidocaine with sodium bicarbonate is recommended

to decrease the burning caused by lidocaine. EMLA

may reduce the pain of arterial puncture.

Endotracheal Intubation

The use of premedication to minimize the pain and stressof endotracheal intubation benets the neonate. How-

ever, concerns about rapid medication availability, ability

to maintain the airway, and the ability to provide ongoing

ventilatory support have caused controversy. Premedica-

tions typically include atropine, narcotics for sedation,

and muscle relaxants. Atropine abolishes vagal bradycar-

dia. Narcotics attenuate the increases in arterial blood

pressure. Muscle relaxants attenuate the increases in in-

tracranial pressure. Combination treatment decreases

time and number of attempts needed to intubate the

infant.

When one is considering the use of medications for in-tubation, several questions need to be asked:

Does the infant have adequate vascular access?

What is the urgency of intubation need?

Is the infant known to have a difcult airway?

When was the last feeding?

Can the infant be preoxygenated while avoiding gastric

distension?

If the decision is made to use medications for intuba-

tion, typical dosages include:

Atropine 0.02 mg/kg fast intravenous (IV) push

Fentanyl 2 mg/kg slow IV push (over at least 5minutes)

Vecuronium 0.1 mg/kg IV push

Alternative muscle relaxants may include succinylcholine

1 to 2 mg/kg IV push or rocuronium 1 mg/kg IV push.

Propofol has been used as a premedication for intuba-

tion. As a single agent, it is easier and faster to prepare

compared with a preparation of three separate drugs.

Propofol is a hypnotic agent without anesthetic proper-

ties. However, propofol is painful when injected into

small veins, and extremely painful if it extravasates. A ma-

jor advantage is continued spontaneous breathing during

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the intubation procedure. The dose is 2.5 mg/kg intra-

venously; this dose might need to be repeated. Concerns

with the use of propofol for intubation in neonates in-

clude minimal published experience in neonates, uncer-

tain pharmacokinetics and duration of action, restricted

availability in some institutions, and incompatibility with

peripherally inserted central catheter lines.

CircumcisionThe 2012 AAP Technical Report on Male Circumcision

recommends that analgesia be provided to infants under-

going circumcision. EMLA cream, dorsal penile nerve

block, and subcutaneous ring block are all possible op-

tions. The AAP reports that subcutaneous ring block

may provide the best analgesia and has published a video-tape demonstrating the use of local anesthesia for this

procedure. Subcutaneous ring block is more effective

than EMLA or dorsal penile nerve block. Dorsal penile

nerve block is more effective than EMLA.

EMLA is superior to placebo for pain relief during cir-

cumcision. An effective method for applying EMLA in

preparation for circumcision is to apply one third of

the dose to the lower abdomen, extend the penis upward

gently, pressing it against the abdomen, and then apply

the remainder of the dose to an occlusive dressing placed

over the penis. The dressing is taped to the abdomen so

the cream surrounds the penis and is left on for 60 to 90

minutes. Another method is to apply the cream and then

place plastic wrap around the penis in a tube-like fashion

to help direct the urine stream out and away from the

cream.

Acetaminophen is ineffective for the management of

acute pain associated with the circumcision procedure

but may provide some analgesia in the postoperative

period.

Other Invasive ProceduresPlacement of a central venous catheter requires topical

anesthesia with EMLA or inltration of the skin with li-docaine. In addition, a parenteral opioid such as mor-

phine or fentanyl is typically used. Consideration

should also be given to regional blocks for central line

placement if anesthesia expertise is available for this

method.

The pain of a lumbar puncture is compounded by

both the needle puncture and the distress caused by

the body position required for the procedure. EMLA

has been shown to decrease the pain of lumbar puncture

in children. Sedatives are generally not recommended.Chest tube insertion is painful and requires an intrave-

nous opioid, adequate local analgesia (lidocaine), or both.

Sedation for Imaging ProceduresImaging of neonates in the NICU typically includes rou-

tine diagnostic radiographs and ultrasound examinations,

including echocardiograms. Sedation is rarely required

for these procedures. More detailed imaging requires spe-

cialized scanning such as computed tomography or mag-

netic resonance imaging. Although they provide more

specic diagnostic and predictive information, such imag-

ing usually requires transportation of the infant from the

NICU to distant facilities. For high-quality computed to-

mography and magnetic resonance imaging, sedation is

often considered to minimize artifacts from patient

movement. Sedation in these circumstances can add sub-

stantial risk and cost to the procedure. Various ap-

proaches to avoid the use of sedation have beenemployed. Sleep promotion is often used, with scanning

scheduled soon after a feeding (30 minutes), use of im-

mobilization (swaddling) and restraint devices, and ad-

ministration of sucrose drops before and during the

scanning. Use of paciers during magnetic resonance im-

aging scanning, while often calming to the infant, can add

motion artifact.

Sedation During Therapeutic HypothermiaTherapeutic hypothermia is used increasingly for neuro-

protection in newborns who have neonatal encephalop-

athy. Shivering is an uncommon nding in neonates,but it has been described frequently in infants undergo-

ing therapeutic hypothermia and is an adverse effect that

counteracts the physiologic intent of this intervention.

Morphine sedation is usually adequate to minimize shiv-

ering. Dexmedetomidine, clonidine, meperidine, and

propofol have been used for this purpose in adults. Ben-

zodiazepines should be avoided because they can mask

seizure activity. Pharmacologic neuromuscular blocking

agents are not used unless the patient has uncontrollable

shivering or generalized clonus that cannot be controlled

with other sedatives or anticonvulsants.

Sedation During Extracorporeal Life SupportSedation and analgesia are frequently needed during ex-

tracorporeal life support (also known as extracorporeal

membrane oxygenation [ECMO]) to prevent cannula

displacement with body movement. Muscle relaxants

are also often used. No controlled trials have been pub-

lished to provide guidance. It is important to understandthat multiple factors inuence drug pharmacokinetics

during ECMO and that prediction of appropriate dosing

is not possible.

Factors leading to need for increased drug doses:

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Increased volume of distribution from ECMO circuit

priming volume

Binding/sequestration of drugs in oxygenator/other

circuit components

Hemoltration of small molecules

Factors leading to need for decreased drug doses:

Renal and hepatic injury decreasing drug clearance

Immature organ function in neonates

Active drug metabolites

Sedatives such as midazolam and opiates such as fen-

tanyl are commonly used. However, achieving the de-

sired effect of these medications frequently results in

substantial dose escalation, requiring prolonged periodsof slow drug weaning to avoid abstinence symptoms.

Dexmedetomidine may be useful as a short-term adjunct

for ECMO sedation.

Pharmacologic Sedative InterventionsThe expected severity of the discomfort, its etiology,

available administration routes, and potential adverse ef-

fects should all be considered when selecting a sedative

for a planned procedure. Once medication administration

has begun, careful monitoring for these effects can de-crease potential adverse events. A key component of ef-

fective sedation management is ongoing assessmentduring and after an intervention or procedure. It is im-

portant to be prepared to rescue the infant if needed from

a deeper level of sedation than originally planned.

Nonopioid AnalgesicsNONSTEROIDAL ANTI-INFLAMMATORY DRUGS. Non-

steroidal anti-inammatory drugs (eg, indomethacin,

ibuprofen) inhibit prostaglandin synthesis by inhibiting

the action of cyclooxygenase enzymes. These agents have

many physiologic effects, including sleep cycle disruption,

increased risk of pulmonary hypertension, cerebral blood

ow alterations, decreased glomerular ltration rate, al-teration in thermoregulatory control, and changes in

platelet function. Moreover, development of the central

nervous, cardiovascular, and renal systems are all depen-

dent on prostaglandins. These drugs have been used fre-

quently in the NICU for pharmacologic closure of

a patent ductus arteriosus, and aside from effects on renal

and perhaps mesenteric circulation (which are difcult to

separate from the patent ductus arteriosus), no clear-cut

adverse effects have been reported. However, there is no

robust evidence that they have analgesic efcacy in infantsaged less than 3 months, thus limiting their use in

neonates.

ACETAMINOPHEN. Acetaminophen is the most widely

administered analgesic in patients of all ages despite little

evidence of efcacy in infants less than 3 months of age.

Acetaminophen inhibits the activity of cyclooxygenase in

the central nervous system, decreasing the production of

prostaglandins and peripherally blocking pain impulse

generation. Neonates are able to form the metabolite that

results in hepatocellular damage; however, it is inappro-

priate to withhold acetaminophen in newborns because

of concerns of liver toxicity. The immaturity of the new-

borns cytochrome P-450 system may actually decrease

the potential for toxicity by reducing production of toxic

metabolites.

Current recommendations call for less frequent oral

dosing (every 8 to 12 hours in preterm and term neo-nates) because of slower clearance times and for higher

rectal dosing due to decreased absorption. Oral dosages

for acetaminophen are 10 mg/kg per dose every 6 to 8

hours for preterm neonates and 12.5 mg/kg per dose ev-

ery 4 to 6 hours for term infants. The maximum recom-

mended daily dose is 75 mg/kg for infants, 60 mg/kg for

term and preterm neonates greater than 32 to 34 weekspostconceptual age, and 40 mg/kg per day for preterm

neonates 28 to 32 weekspostconceptual age.

Rectally administered acetaminophen has a longerhalf-life, but absorption is highly variable because it is de-

pendent on the individual infant and placement of thesuppository. It should also be noted that the drug may

not be uniformly distributed throughout the suppository

and therefore should be divided lengthwise if a partial

dose is desired. The analgesic effect of acetaminophen

may be additive when the agent is administered with

opioids; coadministration may enable a decrease in the

opioid dose and in corresponding opioid adverse effects.

However, demonstration of this potential benet awaits

further study.

OPIOID ANALGESICS. Opioids are believed to be the

most effective sedative and analgesic for control of mod-erate to severe pain in patients of all ages. There is a wide

range of interpatient pharmacokinetic variability. Opioid

dosing depends on the severity of the anticipated proce-

dural pain as well as the age and clinical condition of the

infant. Opioids should be used in infants younger than

age 2 months in a monitored setting only. Some clinicians

propose a more conservative recommendation, restrict-

ing use of opioids to monitored settings for any infant

younger than age 6 months.

MORPHINE. Morphine remains the gold standard for

procedural pain management in neonates despite lack

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of proven efcacy in many circumstances. Morphine is

metabolized in the liver by uridine diphosphate glucuro-

nyltransferase into two active metabolites: morphine-6-

glucuronide (M6G), a potent opiate receptor agonist,

and a second metabolite, morphine-3-glucuronide (M3G),

a potent opiate receptor antagonist. Both metabolites

and some unchanged morphine are excreted in the urine.

The predominant metabolite in preterm and term neo-

nates is M3G. Because of slow renal excretion, the me-

tabolites can accumulate substantially over time. There

is a potential for late respiratory depression due to a de-

layed release of morphine from less well-perfused tissues

and the sedating properties of the M6G metabolite.

Because the predominant metabolite of morphine in

infants is M3G, a potent opiate receptor antagonist,one should consider using the lowest dose possible to

achieve the needed sedation. As we escalate the morphine

doses, we are also increasing the levels of M3G and po-

tentially interfering with our goal of adequate sedation.

Doses as low as 1 to 5 mg/kg per hour can provide ad-

equate sedation/analgesia, minimizing the risk of accu-

mulation of high M3G levels with that metabolites

prolonged half-life.

Clearance or elimination of morphine and other

opioids is prolonged in infants because of the immaturityof the cytochrome P-450 system. The rate of elimination

and clearance of morphine in infants aged 6 months andolder approaches that of adults. Chronologic age seems

to be a better indicator of opioid metabolism in infants

than gestational age.

Infants are at greater risk for opioid-associated respi-

ratory depression because of their immature respiratory

center responses to hypoxia and hypercarbia. Further-

more, there is an increase in unbound or free morphine

and M6G available to reach the brain as a result of

the reduced concentration of albumin and a1-acid

glycoproteins.

Dosing recommendations currently reect the wide

range of interpatient pharmacokinetic variability. Previ-ously, a 0.03 mg/kg bolus of IV morphine was suggested

as a starting dose in nonventilated infants (Acute Pain

Management Guideline Panel, 1992) whereas 0.05 to

0.1 mg/kg of IV morphine was recommended as an ap-

propriate starting dose in ventilated infants. Recently,

much lower doses have been recommended (0.0250.05 mg/kg as a bolus dose or 15 mg/kg per hour as

a continuous infusion). Titration to the desired clinical

effect is required in adjusting both the dose and the fre-

quency of administration. Furthermore, it is important tocontinually assess need and responses. As we further ex-

plore the use of morphine for analgesia and sedation in

neonates, it is becoming concerning that some of the risks

may outweigh any potential benets.

FENTANYL. Fentanyl is 80 to 100 times more potent

than morphine and causes less histamine release, making

it a more appropriate analgesic/anesthetic choice for in-

fants who have hypovolemia, hemodynamic instability, or

congenital heart disease. Another potential clinical advan-

tage of fentanyl is its ability to reduce pulmonary vascular

resistance, which can be of benet for infants who have

undergone cardiac surgery, have persistent pulmonary hy-

pertension, or need ECMO. Bolus doses of fentanyl must

be administered slowly over a minimum of 5 minutes to

avoid chest wall rigidity, a serious adverse effect observed

after rapid infusion. Chest wall rigidity, which can resultin difculty or inability to ventilate, can be treated with nal-

oxone or a muscle relaxant such as pancuronium or vecuro-

nium. Recommended bolus doses are 1 to 2 mg/kg by

slow IV infusion. Continuous infusion dosing should start

at low levels (12 mg/kg per hour) and titrate to effect.

Fentanyl is highly lipophilic. It has a quick onset and

relative short duration of action. Because of this short du-

ration of action, fentanyl is typically used as a continuous

infusion for sedation and postoperative pain control. In

infants age 3 to 12 months, total body clearance of fen-tanyl is greater than that of older children, and the elim-

ination half-life is longer owing to its increased volume ofdistribution. Fentanyl has a prolonged elimination half-

life in infants who have increased abdominal pressure.

Due to tachyphylaxis, continuous infusions of fentanyl

are frequently increased to maintain constant levels of se-

dation and pain management. Infusion dosing can reach

substantial levels requiring prolonged withdrawal.

A rebound transient increase in plasma fentanyl levels

is a phenomenon known to occur after discontinuation of

therapy in neonates. It is a result of fentanyls accumula-

tion in fatty tissues, which may prolong its effects after

continued use. Therefore, caution must be exercised in

the use of repeated doses or a continuous infusion.

ORAL OPIOIDS. Oral methadone can be used to wean

infants from long-term opioid use, although there are

limited data on its efcacy and pharmacokinetics in this

population. The respiratory depressant effect of metha-

done is longer than its analgesic effect. Methadone is me-

tabolized very slowly via hepatic N-methylation resulting

in accumulation in the body, and its half-life is very long

(16 to 25 hours) in neonates.

Codeine has been prescribed at 0.5 to 1 mg/kg orallyevery 4 hours as needed. Scarce data are available to rec-

ommend use of codeine in neonates. Most pharmacies

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supply acetaminophen and codeine in a set formula con-

sisting of acetaminophen 120 mg and codeine phosphate

12 mg per 5 mL with 7% ethanol. The dose prescribed is

limited by both the appropriate dose of codeine and the

safe dose of acetaminophen. This combination is not rec-

ommended in neonates.

Oxycodone is not recommended in neonates because

no data are available for dosing guidelines. The liquid

form is not universally available.

BENZODIAZEPINES. Benzodiazepines such as loreza-

pam and midzaolam are sedatives that activate

g-aminobutyric acid receptors and should not be used in

place of an appropriate pain medication because this classof medication has no analgesic effect. Benzodiazepines

can be administered to decrease irritability and agitation

in infants and to provide sedation for procedures. In ven-

tilated infants, benzodiazepines can help avoid hypoxia

and hypercarbia from breathing out of sync with the

ventilator, although, as noted previously, this is not as

much of a problem today as it was in the past. When given

as continuous infusions, dosing often escalates rapidly to

maintain apparent sedation, resulting in the need for pro-

longed weaning. These medications have been associated

with abnormal neurologic movements in both preterm

and term infants. In rats, prenatal exposure to diazepam

results in long-term functional decits and atypical be-

haviors, and exposure of 7-day-old mice to diazepam in-

duces widespread cortical and subcortical apoptosis.

Midazolam potentiates pain behavior, sensitizes cutane-

ous reexes, and has no sedative effect in newborn rats.

Whether these data can be extrapolated to human infants

is unknown, but clinicians have reason to be concerned

and should use these drugs with caution in the NICU.

DEXMEDETOMIDINE. Dexmedetomidine is a potent

relatively selective a2-adrenergic receptor agonist indi-

cated for the short-term sedation of patients in ICU set-tings, especially those receiving mechanical ventilatory

support. It is administered by either bolus doses for short

procedural sedation (13 mg/kg) or by continuous IV in-

fusion (0.250.6 mg/kg per hour). Because dexmedeto-

midine does not produce signicant respiratory

depression, it has been used for procedural interventions

in spontaneously breathing infants. As neonatologists be-

come more familiar with dexmedetomidine, its use may

increase. However, short- and long-term safety and effec-

tiveness need to be assessed in human infants becausepreliminary work in a neonatal rodent model suggests

that it may alter brain development.

TOPICAL ANESTHETICS. EMLA cream reduces the pain

of circumcision. It must be applied 60 to 90 minutes be-

fore the procedure; longer application times provide

deeper local anesthetic penetration but may lead to tox-

icity. There is a slight risk of methemoglobinemia with

the use of EMLA cream in infants and patients who

are G6PD-decient. This rare occurrence (methemo-

globinemia) occurs when hemoglobin is oxidized by

exposure to prilocaine. EMLA should not be used in

patients who have methemoglobinemia or infants

younger than age 12 months who are also receiving

methemoglobinemia-inducing drugs, such as acetamino-

phen, sulfonamides, nitrates, phenytoin, and class I anti-

arrhythmic agents. A study of 30 preterm infants found

that a single 0.5-g dose of EMLA applied for 1 hourdid not lead to a measurable change in methemoglobin

levels. A systematic review concluded that EMLA dimin-

ishes the pain during circumcision. Limited efcacy was

noted with pain from venipuncture, arterial puncture,

and percutaneous venous line placement. EMLA did

not diminish pain from heel lancing. Oral sucrose or glu-

cose may be as effective as EMLA for venipuncture.

Nonpharmacologic Analgesic InterventionsThere are numerous nonpharmacologic interventions

available for prevention and/or relief of neonatal proce-

dural pain and stress, either as the sole method of pain

control or in combination with pharmacologic interven-

tions. Because pharmacologic analgesia and sedation

have not been proven effective and may be harmful,

these alternative methods of pain and stress relief need

to be assessed for their efcacy and safety. As clearly

stated by Golianu et al (2007), These therapies may

optimize the homeostatic mechanisms of the infant,

thereby mitigating some of the adverse consequences

of untreated pain, as well as facilitating healthy physio-

logic adaptions to stress. However, widespread adop-

tion of specic interventions is not consistent.

Following are summaries of currently available informa-tion on selected interventions:

Breastfeeding reduces the physiologic and behavioral

responses to acute procedural pain and stress in neo-

nates and has been recommended as the rst line of

treatment.

Nonnutritive sucking using paciers reduces pain re-

sponses to heel prick, injections, venipuncture, and cir-

cumcision procedures.

Infant massage decreases plasma cortisol and catechol-amine levels in preterm infants during painful

procedures.

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Maternal skin-to-skin contact (kangaroo care) is asso-

ciated with greater physiologic stability and reduced

responses to acute procedural pain. Kangaroo care

can decrease pain scores after vitamin K injections.

Maternal rocking has been shown to diminish neonatal

distress.

Multisensory stimulation (simultaneous gentle mas-

sage, soothing vocalizations, eye contact, smelling

a perfume, and sucking on a pacier) has been associ-

ated with analgesia and calming of the infants in several

reports from one unit.

Music therapy may reduce the behavioral and physio-

logical responses to acute procedural pain.

Oral sucrose reduces pain behavior in preterm and

term infants. The mechanism of oral sucrose analgesiais not known but may be related to stimulation of en-

dogenous opioid release. Of all these methods and

techniques, oral sucrose has been the most widely

studied and used.

As more data regarding the limitations of pharmaco-

logic treatment are published, consideration of nonphar-

macologic interventions will likely become more

important and commonplace.

Long-term Consequences of Neonatal Opioid

ExposureExperimental Animal Studies

Perinatal and neonatal opioid exposure in experimental

animals is associated with both short- and long-term ad-

verse neurologic effects. These effects should make clini-

cians wonder whether the use of such medications, with

questionable benets, should continue. Perinatal narcotic

exposure restricts brain growth, induces neuronal apo-

ptosis, and alters behavioral pain responses later in life.

One area of particular concern to clinicians is the devel-

oping cerebral circulation, which is extremely vulnerable

to physiologic perturbations and drug effects. Cerebro-

vascular effects of drug exposure early in developmentmay have lifelong consequences, including increased risk

for stroke. The acute effects of exogenous narcotics, in-

cluding morphine, on the developing cerebral circulation

have been described in piglets and include modulation of

prostaglandin-induced pial artery dilation during hyp-

oxia, alteration in endothelin production, and increases

in endothelin A receptor messenger RNA expression. En-

dogenous opioids are important regulators of cerebrovas-

cular tone and angiogenesis. Exposure to morphine in

fetal sheep and neonatal rats permanently alters cerebro-vascular control mechanisms. Permanent neurobehavio-

ral and neuropathologic changes have reportedly been

found in a rodent model of neonatal stress and morphine

exposure. These animal studies demonstrated short- and

long-term effects of neonatal morphine exposure, which

is not surprising because opioid receptormediated sig-

naling likely plays a role in several aspects of early brain

development. However, the clinical relevance of these an-

imal studies regarding the long-term effects of neonatal

opioids is difcult due to species differences in timing

of brain development, the development of opiate recep-

tors and major neurotransmitter systems, and the phar-

macokinetics of administered opioids.

Clinical StudiesClinical studies addressing the short- and long-term ef-

fects of prolonged opiate use in human neonates are lim-

ited. The few that exist are contradictory and confounded

by illness severity. Reversible encephalopathicchanges

in neonates receiving long-term sedative and narcotic in-

fusions have been described. One study demonstrated no

adverse neurodevelopmental outcomes in a small group

of newborns who received morphine for a median of 5

days. A second study presented 5-year neurodevelopmen-

tal outcomes in very low birthweight infants exposed to

prolonged sedation and/or analgesia (dened as >7 days

of sedative and/or opioid drugs). Exposed very low birth-

weight infants had more severe or moderate disability at 5

years (42%) compared with those not exposed (26%). Pre-term infants (2332 weeksgestation at birth) evaluated

at 36 weekspostconceptual age in the NEOPAIN study

demonstrated neurobehavioral abnormalities if exposed

to morphine during ventilatory support.

SummaryRecognition and treatment of procedural pain and dis-

comfort in the neonate remain a challenge. There is still

much to learn about human neurodevelopment, pharma-

cology, and how to best care for sick infants. Because we

try to protect and comfort our fragile patients, and be-cause external regulatory forces have required us to doc-

ument discomfort by using poorly validated tools and to

intervene to minimize distress, we often apply what is

known from data in adult patients to infants. Our care

should minimize the risks of adverse effects of both drugs

and pain/stress on neurodevelopment. Further explora-

tion of nonpharmacologic methods of procedural pain

and distress control is needed. As newer techniques

and medications are introduced to clinical practice, we

must demonstrate that such additions achieve their goalof sedation or pain control, and also establish their safety

over the lifetime of our patients. Escalation of drug doses

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may, in fact, be adding to our problem. Better tools

are needed to help us optimize the outcomes of

infants.

Suggested ReadingAllegaert K, Veyckemans F, Tibboel D. Clinical practice: analgesia

in neonates.Eur J Pediatr. 2009;168(7):765770

Anand KJ, Hall RW, Desai N, et al; NEOPAIN Trial Investigators

Group. Effects of morphine analgesia in ventilated preterm

neonates: primary outcomes from the NEOPAIN randomisedtrial. Lancet. 2004;363(9422):16731682

Anand KJS, Anderson BJ, Holford NHG, et al; NEOPAIN TrialInvestigators Group. Morphine pharmacokinetics and pharma-

codynamics in preterm and term neonates: secondary results

from the NEOPAIN trial.Br J Anaesth. 2008;101(5):680689

Bell R, de Waal KA, Zanini R. Opioids for neonates receiving

mechanical ventilation. Cochrane Database Syst Rev. 2008;(1):CD004212

American Academy of Pediatrics; American Academy of Pediatric

Dentistry; Cot CJ, Wilson S; Work Group on Sedation.

Guidelines for monitoring and management of pediatricpatients during and after sedation for diagnostic and therapeutic

procedures: an update.Pediatrics. 2006;118(6):25872602

Golianu B, Krane E, Seybold J, Almgren C, Anand KJ. Non-

pharmacological techniques for pain management in neonates.

Semin Perinatol. 2007;31(5):318322

Mayock DE, Gleason CA. Neonatal pain and stress: assessment andmanagement. In: Gleason CA, Devaskar SU, eds.Averys Diseases

of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012:429444

Walden M, Carrier CT. Sleeping beauties: t he impact of sedation on

neonatal development. J Obstet Gynecol Neonatal Nurs. 2003;

32(3):393401

American Board of Pediatrics NeonatalPerinatal

Content Specifications

For therapeutic drugs commonly used in

the neonate (eg, opiates, methylxanthines,

barbiturates), know indications for their

use, clinical effects, pharmacokinetics,

adverse effects, and toxicity.

NeoReviewsQuizNew minimum performance level requirementsPer the 2010 revision of the American Medical Association (AMA) Physicians Recognition Award (PRA) and credit system, a minimum performance level mustbe established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete2013 NeoReviewsarticles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment,which measures achievement of the educational purpose and/or objectives of this activity.

InNeoReviews,AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on theassessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. Which of the following is true concerning sedation during mechanical ventilation?A. There are more than 40 infant scales that have been validated in mechanically ventilated infants.B. Mechanical ventilation in neonates is associated with an increase in cortisol and catecholamine levels.C. Preemptive narcotic use in ventilated infants in modern NICUs is likely to have a beneficial effect on both

short-term outcomes and long-term neurodevelopment.D. The use of narcotics will decrease the length of respiratory support needed for both preterm and term

infants on mechanical ventilation.E. Although the benefits of routine narcotic use for ventilated infants are not clear, the lack of any potential

harm tips the balance toward using morphine routinely for ventilated infants.

2. A 10-day-old, 34 weeks gestational age male is about to receive a heel stick for laboratory evaluation. Theparent asks you, Will he feel any pain with this procedure? An appropriate response may be:

A. He is too young to feel any pain. He may cry, but all babies cry, sometimes for no reason.

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B. He may feel a little prick, but this should hurt less than getting blood from his vein.

C. No, the heel is absent of nerve fibers. That is why we get blood from there.D. He may feel some pain; we may not be able to completely eliminate that pain, but we will try our best to

minimize that pain as much as possible before, during, and after the procedure.E. Yes, but we will apply a local anesthetic cream, which has been proven to eliminate pain completely for

this procedure.

3. A 41 weeks gestational age female is being placed on extracorporeal membrane oxygenation (ECMO) forrefractory persistent pulmonary hypertension. Which one of the following considerations is correct?

A. All drug doses should be increased by approximately double because the volume of distribution is doubledwith the addition of the ECMO circuit.

B. Sedation of ECMO patients should be avoided at all costs because it may cause respiratory depression.C. There is a clear consensus of sedation and analgesia practice based on clinical trials that should be standard

of care for all patients receiving ECMO.

D. Due to the complex factors that affect pharmacokinetics in a patient receiving ECMO, dosing of analgesicand sedative drugs in this patient may be difficult to predict.

E. Once the patient is off ECMO, all sedation and pain medications should be discontinued within 1 to 2 daysto speed recovery.

4. A 30 weeks gestational age male requires a peripherally inserted central catheter line for total parenteralnutrition and antibiotics. If you plan to give one medication for the procedure, which of the followingmedications and rationale are most appropriate?

A. Lorazepam would be the best choice because it will help the infant to keep still.B. A low dose of morphine can be given for the procedure with adjustment of dosing as needed, but the

patient should be monitored closely for respiratory depression.C. A eutectic mixture of local anesthetics cream placed at the site for 1 hour will be sufficient to eliminate

pain and not cause any adverse effects.

D. Fentanyl can be given as a quick push over 5 seconds and repeated twice as necessary.E. A peripherally inserted central catheter placement is a relatively minor procedure that should not require

any sedation or analgesia.

5. A 1-day-old, 32 weeks gestational age female has been receiving continuous positive airway pressure sincebirth for respiratory distress syndrome. She has increased work of breathing and oxygen requirement, and thedecision is made to intubate for mechanical ventilation. She has umbilical arterial and venous catheters inplace and is NPO (nothing by mouth). What is an appropriate choice for medications before intubation?

A. At this age, it will be most efficient and safest to intubate without any premedication.B. A combination of atropine, fentanyl, and vecuronium can be administered.C. To avoid excessive medication use, only one medication should be used (preferably atropine).D. If the first two or three attempts are unsuccessful, a dose of morphine can be given to facilitate the

procedure.

E. Because the patient has been on continuous positive airway pressure, an oral dextrose solution provided ona pacifier just before intubation should be sufficient.

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DOI: 10.1542/neo.14-1-e222013;14;e22Neoreviews

Dennis E. Mayock and Christine A. GleasonPain and Sedation in the NICU

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