International Journal of Nursing Studies 46 (2009) 624–632

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International Journal of Nursing Studies

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Utilization of analgesics, sedatives, and pain scores in infants with aprolonged hospitalization: A prospective descriptive cohort study

Denise Harrison a,b,c,d,*, Peter Loughnan b,c, Elizabeth Manias a, Linda Johnston a,b,d

a School of Nursing, The University of Melbourne, Australiab Department of Neonatology, Royal Children’s Hospital, Melbourne, Australiac Department of Paediatrics, The University of Melbourne, Australiad Critical Care & Neurosciences, Murdoch Childrens Research Institute, Australia

A R T I C L E I N F O

Article history:

Received 25 August 2008

Received in revised form 24 October 2008

Accepted 4 November 2008

Keywords:

Pain

Infant

Pain assessment

Analgesic

Hypnotic

Sedative

Neonatal intensive care unit

A B S T R A C T

Aim: Describe the utilization of analgesic and sedative medications and documentation of

pain scores in a cohort of critically ill infants in a neonatal intensive care unit.

Method: A prospective, longitudinal, cohort study of infants with a predicted length of stay

�28 days. Dosages and routes of administration of analgesic and sedative medications and

documentation of pain scores were collected on a daily basis.

Results: 55 infants were enrolled into the study. Oral sucrose was administered to all 55

infants, 51 infants (93%) were administered enteral acetaminophen and 50 (91%) infants

were administered morphine during their hospitalization. Sedatives were administered to

42 infants (76%); 36 (65%) were administered chloral hydrate and 32 (58%) were

administered intravenous midazolam. With the exception of the first week of admission,

when there was highest utilization of opioids and lower use of sucrose, acetaminophen

and sedatives, the pattern of administration of analgesic and sedative agents remained

relatively constant throughout the hospitalization. Pain scores were documented for 36

(65%) infants during their hospitalisation, however for these 36 infants, pain scores were

infrequently recorded.

Conclusion: There was substantial and varied analgesic and sedative use in this cohort of

infants, yet infrequent documentation of pain assessment scores. These practices highlight

important clinical implications for sick infants requiring careful consideration of pain and

distress management.

� 2008 Elsevier Ltd. All rights reserved.

What is already known about the topic?

� S

Ev

A

fa

d

00

d

ick infants in neonatal intensive care units are exposedto large numbers of painful procedures.

� S ystematic evaluation of effectiveness of analgesics and

sedatives using validated pain assessment tools is widely

* Corresponding author at: Centre for Nursing and the Child Health

aluative Sciences, Hospital for Sick Children, Toronto, 555 University

venue Toronto, Ontario, Canada M5G 1X8. Tel.: +1 416 946 0674;

x: +1 416 978 8222.

E-mail addresses: denise.harrison@utoronto.ca,

enisemargaretharrison@gmail.com (D. Harrison).

20-7489/$ – see front matter � 2008 Elsevier Ltd. All rights reserved.

oi:10.1016/j.ijnurstu.2008.11.001

recommended by national and international organiza-tions.

What this paper adds

� In

fants with complex health needs received substantialand varied analgesics and sedatives throughout theentire duration of a prolonged hospitalization. � T here was substantial utilization of oral sucrose in the

cohort of infants studied.

� T here was minimal documentation of pain scores,

highlighting that documented pain scores played anegligible role in determining the need for, and effec-tiveness of analgesic or sedatives.

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632 625

1. Introduction

Health professionals caring for sick infants have anethical and professional obligation to minimize pain anddistress and to utilize current evidence-based painreduction strategies. There are, however, significantknowledge gaps relating to the pharmacological manage-ment of pain and agitation in infants requiring prolongedhospitalization (Alexander and Manno, 2003; Anand et al.,2006; Bellu et al., 2005). Infants requiring prolongedhospitalization are more likely to have painful procedures(Johnston et al., 1997; Simons et al., 2003), surgery, andprolonged mechanical ventilation, which all increase thecomplexity of pain and agitation management. Highquality evidence supports the use of oral sucrose in thereduction of procedure-related pain in diverse populationsof infants (Harrison et al., 2003; Stevens et al., 2005, 2004);yet, there are knowledge gaps relating to its long-term use(Stevens et al., 2004) and potential adverse neurobeha-vioral effects of multiple doses in premature infants havebeen reported (Johnston et al., 2002).

Evidence supports selective use of intravenous mor-phine in critically ill infants, as indicated by clinicaljudgment and pain assessment (Bellu et al., 2005), butscarce knowledge exists regarding the safety and effec-tiveness for long-term management of procedural anddisease-related pain in infants with complex medicalconditions (Taddio, 2002). Acetaminophen is commonlyprescribed and administered in hospital settings to infantsdespite the dearth of high quality evidence to support itsuse in this population (Anderson et al., 1996, 1998; Aranaet al., 2001; Dawson et al., 1996; Lamb and Henry, 2004;Zuppa et al., 2005). Sedatives have been increasingly usedin the neonatal intensive care unit (NICU) to reducedistress in critically ill infants and reduce complicationsassociated with mechanical ventilation; yet, there remainsa paucity of evidence to support their efficacy and safety(Alexander and Manno, 2003; Ng et al., 2005; Walden andCarrier, 2003). In addition, although systematic evaluationof effectiveness of analgesics and sedatives using validatedpain assessment tools is widely recommended by nationaland international organizations (American Academy ofPediatrics et al., 2001; Anand and International Evidence-Based Group for Neonatal Pain, 2001; Harrison andAustralian College of Neonatal Nurses, 2006), numerouspublished reports show low utilization of pain assessmenttools in clinical practice in NICUs (Harrison et al., 2006;Lago et al., 2005; Reyes, 2003; Rohrmeister et al., 2003; vanDijk et al., 2005).

As little is known of the actual pharmacological painmanagement and sedation practices and the extent ofsystematic assessment of effectiveness of such agents usedthroughout hospitalization episodes in clinical settingssuch as the NICU, there is limited information to draw onwhen planning further pain research programs. The aim ofthis study was to determine the use of analgesics, sedativesand pain assessment scores throughout the duration of aprolonged hospitalization in a cohort of infants admitted toa tertiary referral NICU. This information could then informthe development of research initiatives aimed at improv-ing pain management in sick hospitalized infants.

2. Materials and methods

2.1. Setting and participants

This was a prospective, longitudinal cohort studyconducted in a 24-bed tertiary referral NICU within apediatric hospital in Australia. The NICU provides care forbetween 550 and 650 out-born infants annually, withmedical, surgical, genetic and metabolic conditions. Parti-cipants considered for entry into the study included infantsof all gestational and postnatal ages whose length of stay inthe NICU was predicted to be �28 days duration. Althoughthere is no national or international standard definition ofprolonged length of stay, defining at the outset the inclusioncriteria of �28 days ensured that analgesic and sedativeutilization was investigated for the neonatal period andbeyond. Data from the previous 3 years of admissions to theNICU were used to predict those infants likely to require alength of stay of 28 days or more. Eligibility was determinedfollowing admission of the infant, after considering exclu-sion criteria with the on-duty medical and nursing staff.Since this study formed part of a larger study, relating to oralsucrose effectiveness during heel lancing (Harrison et al.,2007), infants born to mothers on methadone wereexcluded, as sucrose has been shown to be ineffective inreducing pain in such newborn infants (Blass and Ciar-amitaro, 1994). Exclusion criteria also included spinal cordmalformation (myelomeningocele, sacral teratoma) andsuspected or known fructose intolerance.

Data relating to documentation of pain assessmentscores, using the Pain Assessment Tool (PAT) (Hodgkinsonet al., 1994; Spence et al., 2005) was collected on a dailybasis. The PAT is the pain assessment score used in the NICUwhere the study took place. In addition, the administrationof analgesic and sedative medications as well as majorprocedures such as surgery, and ventilation management,were prospectively collected by the first author, on a dailybasis from relevant patient medical records for all infants inthe study. Data collection occurred from admission of theinfant until their discharge from the NICU. Each datacollection day was for the 24-h period from 08:00 to 08:00 h.Data were entered into an Access (version 2003) databasethen imported into Stata 9 for statistical analysis (StataCorp,College Station, Texas, USA) (StataCorp, 2005). Descriptivedata are presented as means and standard deviations ifnormally distributed and as medians and interquartileranges if non-normally distributed.

No changes in standard practices were made for thepurposes of this study. Ethics approval for the study wasgranted by the affiliated hospital and university HumanResearch Ethics Committees.

3. Results

Data collection commenced in August 2004 and infantswere enrolled over an 11-month period until July 2005.There were 524 admissions to the NICU during this period.As shown in Fig. 1, 101 infants were predicted to have alength of stay of �28 days. Two infants were excluded and43 infants did not fulfill the criteria of a length of stay of 28days or more; 37 infants were discharged, or transferred to

Fig. 1. Participant flow.

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632626

other neonatal care settings prior to 28 days, and sixinfants died prior to 28 days of stay. Fifty-six enrolledinfants in total had a length of stay of 28 days or more. Oneinfant was removed from the study following enrollmentdue to parental request, leaving a cohort of 55 infants whofulfilled the study criteria. The accumulated data collectiondays for the cohort were 3384 days.

Thirty-four (62%) infants were male. The mediangestational age (weeks) at birth was 36 weeks (IQR 33–38 weeks). Forty-five (82%) infants were admitted with

Table 2

List of diagnoses of participating infants.

Diagnoses N = 55

Tracheo-esophageal fistula/atresia 10

Congenital heart disease and associated abnormalities 8

Necrotizing enterocolitis 8

Congenital diaphragmatic hernia 6

Gastroschisis 5

Pierre robin sequence 4

Exomphalos 2

Jejunal atresia 2

Chronic lung disease 2

Ambiguous genitalia 1

Bladder extrophy 1

Enteric neuropathy 1

Hydrocephalus 1

Multiple congenital abnormalities 1

Neonatal hepatitis 1

Prune belly syndrome, pulmonary hypoplasia 1

Renal failure 1

Table 1

Demographic characteristics of participating infants.

Infant characteristics (N = 55) Number or median % or (IQR)

Hospital stay (days) 50 (38–77)

Gender

Female 21 38

Male 34 62

Age on admission (days) 2 (1–4)

Gestational age at birth (weeks) 36 (33–38)

Corrected gestational age (weeks)

on admission

37 (33–39)

Birth-weight (g) 2607 (1511–3140)

Congenital abnormalities 45 82

Number of infants requiring

surgical procedures

45 (98 episodes) 82

major congenital abnormalities, and 45 (82%) infantsrequired 98 episodes of surgery. The median length of stayin the NICU was 50 days (interquartile range (IQR), 38–77days). Further demographic characteristics and admissiondiagnoses are presented in Tables 1 and 2 respectively.

4. Analgesic and sedation administration

A summary of all analgesic and sedative medicationsadministered including dosage, and the median number(and IQR) of days that each medication was administered,is presented in Table 3. As shown, morphine was the mostfrequently used opioid analgesic and was administered to50 of the 55 infants for a median of 11 days (IQR 5–27days). Forty-eight (87%) infants received continuousintravenous morphine infusions during the course of theirhospitalization. The median dose of intravenous morphineinfusion was 20 mg/kg/h (IQR, 16–32) and the mediannumber of days on a continuous morphine infusion for the48 infants was 11 days (IQR 5–22 days). A total of 223 bolusintravenous morphine doses in addition to the continuousmorphine infusions were administered to 42 of the 48infants. Oral morphine was administered to eight infants inthe cohort with one infant receiving oral morphine for atotal of 67 days. On the days when oral morphine wasadministered, the mean individual dose was0.22 � 0.26 mg/kg (SD) and a mean number of 4.7 � 1.5(SD) doses were given. As shown in Table 3, opioid or otherstrong analgesic medications other than morphine were usedless frequently. Thirty-two (58%) infants received one ormore intermittent doses of intravenous fentanyl intra-operatively. Enteral codeine was administered to 23 (42%)infants for a median of 3 days and ketamine was adminis-tered via a continuous intravenous infusion to five infants.

Acetaminophen was administered to 51 of the 55infants in the cohort for a median of 16 days (IQR 11–28days). The 51 infants were administered a mean of 44 � 33(SD) doses over the course of their hospitalization, rangingfrom 1 dose to 179 doses. The mean dose of enterallyadministered acetaminophen was 16 � 3 mg/kg (SD) and didnot differ whether the dose was administered orally orrectally. The route of administration of acetaminophen wasspecified as oral in 349 (34%) instances, rectal in 279 (27%)instances and was not specified on the infants’ medicationchart on 403 (39%) occasions (Table 3).

Table 3

Analgesic and sedative administration.

Medication Number of infants

receiving medication (%)

Median days on medication

(interquartile range)

Mean � SD or median

dosage (IQR)

Analgesics

Morphine (all morphine administered by all routes) 50 (91%) 11 (5–27)

Continuous intravenous infusion 48 (87%) 11 (5–22) 24.6 � 13.5 mg/kg/h

Oral morphine 8 (14%) 12 (8–15) 0.22 � 0.26 mg/kg

Codeine 23 (42%) 3 (2–6) 0.9 � 0.3 mg/kg

Ketamine: continuous infusion 2 (4%) 8 and 5 days respectively 2 mg/kg/min (1.4–4)

Intermittent doses 3 (5%) 1 (1) 4 (3–5)

Fentanyl (intra-operative only) 32 (58%) 1 (1) In operating theatre only;

doses not recorded

Clonidine 2 (4%) 9 (8–11) 4 mg/kg (1–4.75)

Tramadol (1 infant on 1 day only) 1 1

Acetaminophen (intravenous) 3 (5%) 1 (1) 9 mg/kg (8.5–10.5)

Acetaminophen (enteral) 51 (93%) 16 (11–28) 16 � 3 mg/kg

Sucrose 55 (100%) 21 (16–33) 0.4 � 0.3 mL

Sedatives

Chloral hydrate 36 (65%) 7 (2–20) 22 � 9 mg/kg

Midazolam 32 (58%) 6 (3–17)

(Midazolam continuous infusion) 30 (54%) 6 (3–17) 1.0 � 0.6 mg/kg/h

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632 627

Six infants had post-operative regional anestheticsadministered continuously via an epidural (n = 2) orextrapleural infusion (n = 4) for a median of 3 days,ranging from 2 to 4 days. Additional opiate analgesics wereadministered concurrently with the regional anesthesia toall six infants. Three infants were concurrently adminis-tered continuous intravenous morphine, two infantsreceived rectal codeine and one infant was administeredboth rectal codeine and continuous intravenous morphinepost-operatively.

Table 4

Description of surgical procedures.

Surgical procedure n

Laparotomy 16

Tracheo-oesophageal atresia/fistula repair 11

Gastroschisis repair 8

Congenital diaphragmatic hernia repair 6

Closure of stomas 6

Patent ductus arteriosus ligation 6

Bronchoscopy 5

Broviac1 catheter insertion 5

Cardiac surgery 4

Insertion nasal stents 4

Fundoplication and gastrostomy 3

Mandibular distraction 3

Tracheostomy 2

Liver biopsy 3

Thoracotomy 2

Insertion of Rickhams reservoir 2

Open bowel biopsy 2

Removal nasal stents 1

Wound repair 1

Skin biopsy 1

Pyloric stenosis repair 1

Oesophageal dilation 1

Laser eye surgery 1

Cystoscopy and inguinal hernia repair 1

Drainage of abscess 1

Bladder extrophy closure 1

Brachial artery graft 1

Total 98

There were 201 major procedures performed, includingsurgery, endotracheal intubation, insertion of centralvenous catheters and insertion of chest drains. There were98 episodes of surgery (Table 4), performed on 45 infants,with laparotomy being the most frequently performedsurgical procedure. Administration of continuous morphineinfusion for management of post-operative pain occurredfollowing 85 of the 98 episodes of surgery (87%). Of the 13procedures where no morphine was administered post-operatively, regional anesthesia and enteral codeine wereadministered on three occasions, and on the ten otheroccasions, the procedures performed were minor surgicalprocedures such as removal of nasal stents, cystoscopy,surgically placed central venous catheters, or bronchoscopy.Inhalation anesthesia (sevoflurane or isoflurane with orwithout nitrous oxide) was administered intra-operativelywithout additional opioid analgesics during these minorprocedures. There were 103 major procedures other thansurgery performed during the data collection period,including 42 endotracheal intubations occurring in theneonatal unit, 27 central venous catheter insertions (notincluding peripherally inserted central catheters) and 19chest drain insertions. For 73% of these major procedures,opioid analgesics were either already being administered, orwere given specifically for the procedure.

Oral sucrose (33%, w/v) was administered to all 55infants in the cohort. Sucrose was administered on amedian of 21 days (IQR 16–33 days). The total doses ofsucrose administered per day ranged from 0 to 11 doses foreach infant and the number of doses over the course of theinfants’ hospitalization ranged from 4 to 174, with a meanof 42 � 31 (SD) doses. The mean volume of sucrose deliveredper dose was 0.4 � 0.3 mL (SD).

5. Sedatives

Forty-two (76%) infants were administered sedativesduring their hospitalization. As shown in Table 3, chloralhydrate was administered enterally to 36 (65%) infants on

Fig. 2. Percentage of total data collection days when opioid analgesics, sedative, acetaminophen and oral sucrose were administered, as calculated over

successive weeks of hospitalization. Week 1 of hospitalization is divided into Day 1–2 and Day 3 through to 7. Data for weeks 20–26 are aggregated due to

there being only two infants remaining in the study by week 20.

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632628

a median of 7 days. The mean dose was 22 � 9 mg/kg (SD)and the mean number of doses given to the 36 infants on thedays when chloral hydrate was administered, was 2 � 1.2(SD) doses. One infant was administered chloral hydrate on140 days, 76% of days of the particular infant’s hospitaliza-tion. Intravenous midazolam was administered to 32 (58%) ofthe 55 infants in the cohort with the majority of infants(n = 24) receiving midazolam by continuous intravenousinfusion. The mean infused dose of continuous intravenousmidazolam was 1.0 � 0.6 mg/kg/h (SD). Ten infants in thecohort received continuous midazolam infusion for 14 daysor more, and one infant was administered midazolam for 89days in total, almost the infant’s entire hospital stay of 96days. Eleven infants received bolus doses of intravenousmidazolam in addition to the continuous infusion adminis-tered. Twenty-six (47%) infants received both chloral hydrateand midazolam during their hospitalization with a third ofinfants receiving the two sedatives concomitantly.

6. Pattern of analgesic and sedative administration

Fig. 2 shows the pattern of administration of opioid andother strong analgesics, sedatives, acetaminophen andsucrose over successive weeks of hospitalization. Theperiod of highest usage of opioid analgesic was duringweek 1 of hospitalization, contrasting with that ofacetaminophen, oral sucrose and sedatives. From week2, the pattern of administration of analgesic and sedativeagents remained relatively constant throughout thehospitalization. The increase in analgesic and sedativeuse per infant from week 19 is as a result of only twoinfants with complex medical conditions remaining in thestudy at this time point.

7. Analgesics, sedatives and assisted ventilation

Fifty (91%) infants required assisted ventilation duringthe course of their hospitalization. On 61% of the dayswhen assisted ventilation was being administered, opioidanalgesics, predominantly morphine, were being adminis-tered, and on one-third of days when assisted ventilation

was being administered, a combination of opioid analge-sics and sedative agents were being administered.

8. Documentation of pain assessment scores

Thirty-six of the 55 infants (65%) had pain assessmentscores documented during their hospitalization. Docu-mentation of pain scores was however, infrequent, withPAT scores documented on 159 days in total; five percentof the total 3384 data collection days. As the PAT tool wasoriginally introduced to the NICU to specifically evaluatepost-operative pain (Hodgkinson et al., 1994), the numberof PAT scores documented post-operatively was examinedfurther. In the first 48 h following the 98 episodes ofsurgery, a PAT score was documented on only 33 (34%)occasions. As the PAT score includes behaviors indicative ofpain which may be masked by high doses of morphine, andunable to be assessed in infants receiving muscle relaxants,the documentation of PAT scores in the first 48 h post-operatively when such medications were in use, wasspecifically examined. On 21 (21%) occasions where no PATscores were documented, muscle relaxants had in factbeen administered during the post-operative period, andon ten further occasions, continuous morphine was beinginfused at doses of 30 mg/kg/h or higher. Both of thesetreatments may have precluded reliable pain scoring usingthe multi-dimensional tool within the first 48 h post-operatively. However, there remained 34 episodes ofsurgery where no such medications had been administeredpost-operatively to account for the lack of documentationof PAT scores in the post-operative period.

9. Discussion

These findings add important knowledge to thecomplex issues of pain management in sick infants. Thisis the only study identified which has described analgesic,sedative and documentation of pain assessment scores indetail over the full course of a neonatal intensive carehospitalization. Results showed substantial utilization ofvaried analgesics and sedatives throughout the duration of

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632 629

a prolonged hospitalization in this cohort of infants withcomplex health needs, yet infrequent documentation ofpain scores. This highlights the negligible role thatdocumented pain scores had in determining the apparentneed for analgesic or sedatives, in evaluating effectivenessor otherwise of these medications or in making decisionsregarding weaning and cessation of analgesics or sedatives.Although numerous other studies have also reportedinfrequent utilization of pain assessment scores in clinicalpractice (Gharavi et al., 2007; Harrison et al., 2006; Lagoet al., 2005; Reyes, 2003; Rohrmeister et al., 2003; van Dijket al., 2005), this study epitomizes the ongoing large gapbetween analgesic use and documented pain assessments;which has not changed despite calls over many years tosystematically assess pain (Franck, 2002). Although thereare now over 35 pain assessment tools developed for use ininfants (Duhn and Medves, 2004), reliable assessmentremains problematic in certain populations of sick infants;especially in infants requiring assisted ventilation, infantswho are irritable or agitated, or those infants withestablished and ongoing pain (Anand et al., 2005; Franck,1987; Hummel and van Dijk, 2006). In addition, a lack ofintegration of pain assessment with decisions regardingpain management has been cited as an important factorunderpinning poor utilization of pain scores in the clinicalsetting (Franck, 2002; Hummel and van Dijk, 2006).Improving systematic evaluation of pain and distressmanagement strategies utilized is an important area offurther research.

Concomitant use of various combinations of analgesicsand sedatives was common. Although many of theanalgesic and sedative agents currently have an inade-quate evidence base to support their routine use in clinicalpractice for sick infants (Bellu et al., 2005) there is apressing need to reduce pain and agitation during ongoingepisodes of procedures and assisted ventilation. Admin-istration of opioid analgesics had, until recently, beenconsidered an important aspect of therapy for prematureand term infants requiring assisted ventilation (Anandet al., 1999; Anand and International Evidence-BasedGroup for Neonatal Pain, 2001; Larsson, 1999; Menon et al.,1998). Current evidence highlights uncertainties regardingboth the efficacy and safety of opioid analgesics inpremature and sick infants in the reduction of pain andstress during periods of assisted ventilation as well asduring invasive procedures occurring during the course ofa critical illness (Anand et al., 2004; Bellu et al., 2005;Carbajal et al., 2005; Simons and Anand, 2006). In addition,there is a dearth of research to inform long-term use ofmorphine in sick infants (Bellu et al., 2005; Taddio, 2002).

Further research examining long-term outcomes ininfants treated with morphine has been recommended(Taddio, 2002; Tibboel et al., 2005). The analgesic effect ofcodeine in neonates and infants is also debatable, due toimmaturity of the enzymes that are necessary to convertcodeine to its active metabolite morphine, which isnecessary for analgesia (Williams et al., 2002). Andersonand Palmer (2006) reported that codeine has beenremoved from some hospitals’ formularies as nearly halfof all children under 12 years of age lack the necessarymaturity of the enzyme required for morphine conversion.

Codeine is noted also to be a ‘‘weak’’ opioid, and is usuallyadministered in conjunction with other analgesics (Cun-liffe, 2001). In this cohort study, a total of 91 doses ofcodeine were administered to 23 (42%) of the infants in thiscohort within 3 days following major surgery. The actualeffectiveness of codeine administered post-operativelycould not be ascertained in this study due to the infrequentdocumentation of pain scores. However, on the majority ofdays when codeine was administered to the 23 infants,other analgesics were also used. Paracetamol was given on94% of the days when any codeine was given, and anintravenous infusion of morphine was being administeredon 11% of the days when codeine was administered.

The analgesic efficacy of enterally administered acet-aminophen in newborn and young infants has receivedlittle research attention despite being widely used in thispopulation (Anderson et al., 1996; Arana et al., 2001;Dawson et al., 1996; Lamb and Henry, 2004; Penna et al.,1993; Zuppa et al., 2005). Findings from the few efficacystudies that have included newborn and young infantshave generally shown little analgesic benefit of acetami-nophen (Bremerich et al., 2001; Howard et al., 1994; Shahet al., 1998; van Lingen et al., 2001) and there are nopublished studies examining effectiveness of prolongeduse of acetaminophen. Despite this, there was substantialuse of acetaminophen demonstrated in this study, with amean of 44 doses administered to the infants in the cohort,ranging up to 179 doses given to one infant during theperiod of hospitalization. In addition, although rectallyadministered acetaminophen is known to be erraticallyabsorbed and higher than oral doses are required toachieve adequate analgesia (Anderson et al., 1998;Bremerich et al., 2001; Hansen et al., 1999; Lin et al.,1997; van Lingen et al., 1999), this study highlighted thatthe route of acetaminophen was frequently not specifiedon the medication chart. When the route of administrationwas recorded, there were no differences in the dose ofacetaminophen prescribed whether the route was rectal ororal. These dosing practices are not in line with recom-mendations from the Consensus statement for theprevention and management of pain in the newbornwhich recommends higher rectal doses of 20–30 mg/kg(Anand and International Evidence-Based Group forNeonatal Pain, 2001). These prescribing practices havethe potential to impact upon the expected analgesic effectof acetaminophen.

Substantial utilization of oral sucrose over the durationof the infants’ hospitalization was evident in this study.This degree of utilization reported is higher than otherreports (Carbajal et al., 2008; Debillon et al., 2002; Grayet al., 2006; Harrison et al., 2006; Heaton et al., 2007;Rohrmeister et al., 2003), including the recently publishedreport by Carbajal et al. (2008), and could be attributed tothe implementation of a policy the participating NICU, in2001, endorsed by both medical and nursing staff,directing use of sucrose during painful procedures(Harrison, 2001, updated 2006). Alongside the introduc-tion of the sucrose policy, knowledge translation activitiessuch as local champions promoting the use of oral sucroseduring minor painful procedures, interactive educationalsessions, and signage in the NICU and around the hospital

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632630

using posters aimed at parents and staff were carried out.This combination of strategies encompassing local cham-pions, locally relevant and accessible policies, collaborativemedical and nursing relationships, ongoing educationalefforts and consumer involvement, has been shown tohave an effect on changing culture and behaviors(Schechter, 2006).

However, only recently, has there been research on thelong-term use of oral sucrose for management of minorprocedural pain. Reports from a small number of animalstudies have shown that either repeated doses of sugarsolutions or prolonged uninterrupted periods of sugarsolution consumption induced either sucrose or morphinetolerance (Fidler et al., 1993; Holder and Bolger, 1988;Lieblich et al., 1983). However, these effects weredemonstrated following consumption of large volumesof sweet solutions (up to 50 mL daily for up to 28 days), oruninterrupted supplies of sweet solution for three to 6 h.Such doses or duration of sucrose consumption would notconceivably be administered to any infant in a NICU.

Johnston et al. (2007, 2002) however, reported thatpremature infants, during the first week of life, whoreceived ten doses or more of sucrose over a 24 h period,were at risk for poorer neurodevelopmental scores thaninfants who received less than ten doses of sucrose per24 h. These findings serve as a reminder that cliniciansmust be cognisant of the fact that the administration ofsucrose should be limited to management of acuteprocedural pain, and caution should be exercised inadministering multiple doses.

In a similar study including premature infants, no suchsafety concerns were reported (Stevens et al., 2005). Oralsucrose used repeatedly for procedural pain in prematureinfants over a period of 1 month, was shown to have bothongoing efficacy and safety compared to water, whenadministered prior to a heel lance (Stevens et al., 2005).These results provided preliminary evidence to support therepeated use of sucrose in a population of prematureinfants over a prolonged period of time (1 month). Inaddition, a lack of any change in pain scores during heellancing, over the duration of a prolonged hospitalization, inthe same population of sick infants as included in thiscurrent descriptive study, was suggestive of ongoingeffectiveness of repeated doses of sucrose (Harrisonet al., 2007). The finding of such considerable use of oralsucrose in sick infants significantly contributes to the bodyof evidence concerning utilization of oral sucrose in theclinical setting during the multitude of painful or noxiousprocedures performed over a prolonged hospitalization.

Substantial use of sedatives was evident in this cohortof infants with a prolonged length of stay. Both chloralhydrate and midazolam were administered to the majorityof infants over the course of a prolonged hospitalization, inspite of the lack of evidence of efficacy as well as safetyconcerns regarding adverse neurological outcomes asso-ciated with the long-term use of sedatives in newborninfants (Anand et al., 2005). Midazolam, a short actingbenzodiazepine, has been increasingly used in neonatalintensive care units for sedation despite there beinginsufficient safety and efficacy data to support its routineuse in newborn infants (Anand et al., 1999; Bergman et al.,

1991; Ng et al., 2002, 2005), and there is limited research tosupport long-term use of chloral hydrate in infants.

This study highlights the complex management issuesfor these infants when there is obviously a need to reducepain and distress during ongoing episodes of proceduresand assisted ventilation, yet there is a limited evidentialbase relating to long-term use of analgesics and sedatives.However, the consequences of withholding such medica-tions in sick infants experiencing both acute and prolongedpain and distress have been well demonstrated and includeincreased risk of intra-operative and post-operativemorbidity and mortality, sensitization to pain, andincreased risk of altered neurodevelopmental and beha-vioral outcomes (Anand and Soriano, 2004). This cohortstudy highlights that further research into the safety andefficacy of most analgesic and sedative agents used inneonatal intensive care units is warranted. As a largemajority of analgesics used in the neonatal setting have notbeen labelled for use in newborns (Anand et al., 2005;Conroy and Peden, 2001; Tan et al., 2003), clinicians caringfor sick hospitalised infants need to collaborate with thepharmaceutical industry to ensure that well conductedstudies of both safety and efficacy of new and existinganalgesic and sedative agents are planned. Furtherresearch on the use of analgesic and sedative medicationsin the neonatal and infant population has been recom-mended and is currently being planned by the Interna-tional Neonatal Pain Control Group (Anand et al., 2006).However until such research becomes available, healthprofessionals caring for sick, hospitalized infants have theunenviable task of weighing up the benefits and risks ofprolonged use of analgesics and sedatives with the risksassociated with withholding such agents.

A limitation to this study is that it was conducted in asingle, tertiary neonatal referral center in a targeted cohortof infants with an expected prolonged length of stay. Theinfants were primarily born at or near term, and themajority of infants had congenital abnormalities requiringsurgery. Results for this cohort of infants with suchcomplex health needs cannot necessarily be generalized toneonatal intensive care settings which primarily care forpremature infants with medical illnesses. However, theresults have direct relevance to other tertiary referralcenters which care for sick infants with similar complexsurgical and medical needs. Furthermore, as this was astudy of utilization of analgesics, sedatives and painassessment scores, evaluation of effectiveness or adverseevents associated with the use of the analgesic andsedative agents was not studied. In addition, neither theutilization nor effectiveness of non-pharmacological painmanagement interventions was included in this study.Such systematic evaluation of utilization and effectivenessof non-pharmacological pain management interventionsas well as effectiveness and safety of long-term use ofanalgesics and sedatives in the NICU is urgently required.

10. Conclusions

Analgesic and sedative use in this cohort of infants witha length of stay �28 days, and complex health needs wassubstantial, yet there was a lack of systematic evaluation of

D. Harrison et al. / International Journal of Nursing Studies 46 (2009) 624–632 631

the effects of the medications. Most of the medicationsadministered have an inadequate evidence base to supportprolonged use in clinical practice. Further studies to linkevaluation of efficacy and safety of analgesics and sedativeagents with utilization of these agents in the long-termmanagement of sick infants are urgently required.

Acknowledgments

The authors thank Susan Donath, Clinical EpidemiologyUnit, Murdoch Childrens Research Institute, for statisticaladvice and support; Tony McConnell for assisting withdatabase development and Cheryl Evans, Charan Sanduand the pathology collection team (Royal Children’sHospital, Melbourne) for their assistance with datacollection.

Disclosure: There are no financial interests to disclose.Conflicts of interest: there are no conflicts of interest to

declare.Ethical approval: Ethics approval for the study was

granted by the School of Nursing, Human Ethics AdvisoryGroup at The University of Melbourne, Australia (HRECProject 040641), and the Royal Children’s Hospital,Melbourne, Australia granted approval for the study as aclinical audit (AUD/2001-).

Funding/Support: Dr. Harrison was supported by anAustralian Postgraduate Award and a Murdoch ChildrensResearch Institute trainee scholarship.

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