Effect of preemptive acetaminophen onpostoperative pain scores and oral fluidintake in pediatric tonsillectomy patientsMICHAEL ROMEJ, CRNA, MSTERRI VOEPEL-LEWIS, RN, MSSANDRA I. MERKEL, RN, MSPAUL I. REYNOLDS, MDAnn Arbor, MichiganPATRICK QUINN, CRNADetroit, Michigan

Postoperative pain is a significant problemthat continues to be undertreated in thepediatric population. Preemptiveadministration of analgesics has recentlyemerged as a method to enhance painmanagement associated with surgery. Thepurpose of this study was to comparepostoperative pain scores, rescue analgesicuse, and oral fluid intake in children whoreceived acetaminophen preoperatively tochildren who received postoperativeacetaminophen.

The sample consisted of 28 children,2-8 years of age, scheduled for electivetonsillectomy. Children were randomizedinto the control or the experimental groups.Anesthesia induction and maintenance werestandardized. The experimental groupreceived 15 mg/kg of oral acetaminophenpreoperatively, and the control groupreceived 20 mg/kg of rectal acetaminophenpostoperatively.

Pain was scored with the FLACC (faces,legs, activity, cry, consolability) behavioralassessment tool. Scores were significantlylower for the experimental group at30 minutes after awakening and significantlylower for the control group at 240 minutes(P<.05). Eight patients (57%) in the controlgroup and only 4 (28%) in the experimentalgroup required rescue morphine

postoperatively. Total postoperativemorphine was not significantly differentbetween groups. There were nodifferences in time to initial oral fluid intakeand total oral fluid intake postoperatively.Incidence of nausea and vomiting was highin both groups (64-78%).

These results provide evidence thatpreemptive acetaminophen mayenhance analgesia in pediatrictonsillectomy patients. Preoperativeacetaminophen is a safe, quick, andinexpensive intervention that canreadily be incorporated into anesthesiapractice.

Key words: Acetaminophen, pediatric,postoperative outcomes, preemptiveanalgesia, tonsillectomy.

IntroductionMore than three million children in the UnitedStates undergo surgery every year, many of whomwill experience significant pain. Researchers havefound, however, that children receive less analge-sia than adults for similar surgical procedures andemphasized the need for improved pain manage-ment.'-3 The use of preemptive analgesics has re-cently emerged as a potential method to improvepain management. Current literature suggests thatsensory signals arising from tissue injury during

December 1996 Vol. 64/No. 6 535

surgery can lead to increased excitability in thecentral nervous system that may contribute to hy-peralgesia postoperatively.4 5 The theoretical basisof preemptive analgesia is to prevent the develop-ment of this hyperexcitability by diminishing thebarrage of nociceptive inputs during surgery. Re-cent trials of preemptive analgesia have demon-strated lower postoperative pain scores and loweruse of postoperative analgesics, which lend sup-port to this theory."-9

Tonsillectomy is a procedure that is known tocause significant pain.'10-12 Poor pain managementin this population may contribute to the patient'sinability to drink, leading to other problems suchas volume depletion, fever, and prolonged re-covery.'1 Preemptive analgesia may help to im-prove patient outcomes and recovery in thispopulation.

The purpose of this study was to examine dif-ferences in outcomes of children who receive ace-taminophen prior to tonsillectomy and childrenwho receive this drug postoperatively. Specificquestions were:

1. Is there a difference in postoperative painscores between groups?

2. Is there a difference in postoperative anal-gesia requirements between groups?

3. Is there a difference in time to oral fluidintake and amount of oral fluid intake betweengroups?

Materials and methods* Sample. Approval for this study was granted

from the Institutional Review Board and writteninformed consent was obtained from parents. The28 children included in this study were male andfemale, aged 2 to 8 years, and were scheduled foruncomplicated tonsillectomy. Children were ex-cluded if they were known to have developmentaldelay, complicating health factors precluding theuse of opioids or acetaminophen or any other fac-tors which would interfere with pain assessmentand management.

* Design. Children were randomly assigned toeither the control or experimental groups. Eachchild received an inhalational induction with halo-thane and was maintained with oxygen, nitrousoxide, and halothane titrated to depth of anesthe-sia. All subjects received 0.1 mg/kg morphinesulfate after intravenous catheter insertion andwere endotracheally intubated. Neuromuscularblockade was accomplished at the discretion of theanesthetist, and ventilation was assisted or sponta-neous. Tonsillectomy was performed using electro-cautery excision without wound infiltration.

Subjects in the experimental group received

536

15 mg/kg oral acetaminophen 1 hour preopera-tively. Subjects in the control group received20 mg/kg rectal acetaminophen immediatelypostoperatively. These dosages of acetaminophenwere not altered from the standard dosages used atthis facility at the time of this study. These stan-dards were based on dosage recommendations inthe literature.' 3 The bioavailability of rectal ace-taminophen is 30-40% compared with 60-70% fororal, and therefore dosage recommendations forthe rectal route are higher.4-17

* Instrument. The FLACC (faces, legs, activity,cry, consolability) behavioral pain assessment toolwas used to assess children's postoperative pain inthis study (Figure 1). The FLACC tool incorpo-rates five categories of behavior. Each category isscored from 0 to 2 which provides a total scorebetween 0 and 10. This tool was developed to assesspain in young children who have difficulty in self-reporting their pain. The FLACC tool has goodinterrater reliability (r=.94; P<.001), and validityas demonstrated by significant correlations between FLACC and global ratings of pain (r=.41;P<.001) and between FLACC and the ObservationPain Scale (r=.81; P<.001).18

The FLACC scores were assigned by nurses inthe postanesthesia care unit (PACU) upon patientawakening and at the following time periods: 30,60, 90, 120, 180, and 240 minutes. Morphine sulfatewas used as the rescue analgesic for all patients.Time to administration and total dosage of rescueagent and time to and total amount of oral fluidintake were also recorded.

* End analysis. The student's t test was used toanalyze the differences between group characteris-tics, FLACC scores, analgesics, and oral fluid in-take. Chi-square was used to examine differencesin incidence of nausea and vomiting betweengroups.

ResultsThe two groups were similar with regard to

age and surgery duration (Table I). Average post-operative FLACC scores for each group were rela-tively low (Figure 2). Four patients in the controlgroup and two in the experimental group hadawakening FLACC scores of greater than 5, indicat-ing significant pain. Although pain scores gener-ally decreased throughout the recovery period,there was a small increase in scores at 180 and 240minutes for the experimental group. The FLACCscores were statistically significantly lower for theexperimental group at 30 minutes and for the con-trol group at 4 hours postoperatively (P<.05).

Eight (57%) of the patients in the control groupand four (28%) in the experimental group received

Journal of the American Association of Nurse Anesthetists

Figure 1FLACC scaleFace 0

No particularexpression or smile

0Normal positionor relaxed

0Lying quietly,normal position,moves easily

0No cry(awake or asleep)

0Content, relaxed

1Occasional grimaceor frown, withdrawn,disinterested

1Uneasy, restless,tense

1Squirming, shiftingback and forth,tense

1Moans or whimpers;occasional complaint

1Reassured by occasionaltouching, hugging or"Talking to"Distractible

Table IGroup characteristics

Control Expermientalgroup group(n=14) (n=14)

Mean age (years) 5.4 (±1.3) 6.1 (±1.7)Surgery duration

(minutes) 46.4 (±24.0) 39.4 (±13.9)

Figure 2Postoperative FLACC scores

3.5-

3-

U Control group2.5 U Experimental group

2-

1.5- 1.28

1- 0.78*

0.42*

04 I I I _ I ILAwakening 60 Minutes 120 Minutes 240 Minutes

*t test significant at P< .05

rescue analgesics. The individual dosage require-ments ranged from .02-.07 mg/kg for experimentalpatients and .03-1 mg/kg for the control group.The average morphine requirements were low for

both groups, but the average requirement for theexperimental group was less and approached sig-nificance (P=.06) (Table II). The average timefrom awakening to analgesic administration wasidentical for both groups (12.5 minutes).

The time to oral intake and total oral fluidintake was not significantly different betweengroups (Table II). Sixty-four percent of the controlgroup and 78% of the experimental group experi-enced nausea and vomiting. This difference wasnot significant.

DiscussionNonsteroidal anti-inflammatory agents and

acetaminophen are frequently used in the pediatric

Table IIPostoperative outcomes

Control Experimentalgroup group

PValues

Postoperativemorphine(mg/kg) 0.039±0.044 0.013±0.024

Average timeto initialanalgesic(minutes) 12.5±7.07 12.5±14.14

Postoperativeoral fluids (mL) 55±78 67± 73

Minutes toinitial oralintake 102±89 93.64±62

.06

1.00

.76

.45

December 1996/ Vol. 64/No. 6

2Frequent to constantfrown, clenched jaw,quivering chin

2Kicking, or legsdrawn up

2Arched, rigidor jerking

2Crying steadily,screams or sobs,frequent complaints

2Difficult to consoleor comfort

Legs

Activity

Cry

Consolability

537

population to treat mild to moderate pain. Theseagents presumably mediate analgesia by blockingprostaglandin synthesis, thereby decreasing pe-ripheral sensitization and the activation of nocicep-tors. 19 20 These is recent evidence that these agentsblock postaglandin synthesis in the central nervoussystem as well. 2

1-26 Theoretically, these agents may

act in the spinal cord to block mechanisms thatwould otherwise enhance central sensitization.Findings from several studies in adults and chil-dren have demonstrated decreased pain scores andless narcotic use postoperatively in patients whoreceived preprocedural analgesia with nonsteroi-dal anti-inflammatory drugs or acetaminophen. 27- 29

In this study, we found low postoperativeFLACC scores overall, indicating relatively goodanalgesia for both groups. This was expected sinceall patients received morphine before incision. Thegroup which received acetaminophen preopera-tively had significantly lower FLACC scores in theearly postoperative period, and fewer of these pa-tients required rescue analgesics postoperatively,lending support for the concept that preemptiveacetaminophen enhances pain relief in this popu-lation.

The FLACC scores gradually dropped duringrecovery for both groups, but the experimentalgroup's scores went up slightly toward the end oftheir stay. These trends in pain scores were ex-pected based on the kinetics of acetaminophen de-scribed in the literature. Oral administration ofacetaminophen in awake patients produces a peakplasma level in 30 to 60 minutes and has an aver-age half-life of about 2 hours.30 Experimental pa-tients in our study were therefore expected to havea preemptive analgesic effect that would producelower pain scores in the early postoperative pe-riod. The late rise in pain scores of these patientsat 240 minutes may relate to the fall in plasmalevels of acetaminophen around this time.

Rectal acetaminophen achieves peak plasmalevels between 100 and 170 minutes after adminis-tration, and the half-life is around 3.5 hours. TheFLACC scores in the control group similarly fol-low the expected kinetics of the drug. Rectal sup-positories were administered on arrival to thePACU while patients were still asleep, and thera-peutic levels would be expected around 60 to 120minutes after awakening. Pain scores droppedthroughout the PACU stay, reaching "0" at 240 min-utes, which may relate to the prolonged elimina-tion of rectal drug.

The recommended dosages of rectal acetamin-ophen remain conservative (15-20 mg/kg) despiteevidence that therapeutic levels may be difficult toachieve with this dose range. 1' 6, 7 In our study we

538

did not alter dosages from the standards utilized atthis institution. However, recent studies that com-pare rectal acetaminophen to other analgesics haveused higher dosages up to 35 mg/kg.31 In our study,patients who received 20 mg/kg rectal acetamino-phen demonstrated good clinical analgesia in com-bination with the morphine dosages administered.

The overall requirements for rescue analgesiawere low for both groups, again demonstratinggood overall analgesia. Only four of the patients inthe experimental group required rescue morphinepostoperatively compared with eight in the con-trol group. Interestingly, there was no differencebetween groups with regard to time to rescue anal-gesia. All patients who required rescue drug neededit early in the postoperative period. The differ-ence in total amount of rescue analgesia requiredby each group approached significance, with theexperimental group requiring less overall mor-phine. A larger sample may demonstrate a signifi-cant difference between groups.

There was no difference in the time to oralintake and the amount of oral intake betweengroups. Eighty percent of subjects in this studydrank during the first 4 hours postoperatively.There were only six patients who did not drink atall during this time, and of these, five experiencedpostoperative nausea and vomiting. There were nodifferences in pain scores between children whodrank and those who did not, thus, postoperativedrinking was unrelated to pain in this study.

The incidence of nausea and vomiting wasvery high in both groups. The reported incidenceof nausea and vomiting in the tonsillectomy popu-lation ranges from 30% to 80% and has been relatedto many factors including pharyngeal stimulation,swallowing of blood, and opioid administration.32-34

In studies where nausea was relatively low (30%),patients had received droperidol or phenerganpreoperatively. 33 34 The Splinter et al report foundthat tonsillectomy patients who underwent bal-anced anesthesia with sufentanil experienced sig-nificantly greater vomiting postoperatively thandid those receiving halothane, nitrous oxide, andeither morphine or meperidine. 33 In our study, pa-tients did not receive antimetics unless they expe-rienced significant nausea and emesis postopera-tively. Adding an antiemetic intraoperativelywould likely drop the incidence of this complica-tion significantly.

There were several methodological limitationsin this study design that confound these interpre-tations. Rescue analgesics were titrated by PACUnurses to analgesia effect as measured by patientbehaviors and FLACC scores. However, we did notstandardize FLACC scores for which analgesia

Journal of the American Association of Nurse Anesthetists

should be administered, nor did we standardizethe dosage increments for titration. Therefore,variations in nursing practice may have influencedthis outcome measure for both groups. Nurses werenot blinded to the timing and route of acetamino-phen administration. Therefore, the possibility ofobserver bias cannot be overlooked. Lastly, theFLACC tool may not have been the assessment toolof choice for some of the patients under study.Careful review of data found that two of the fourpatients in the experimental group who receivedrescue morphine had FLACC scores of 0 or 1 at alldata points postoperatively. It may be that thesepatients self-reported their pain but did not behav-iorally display discomfort. These particular pa-tients were 7 and 8 years old and would likely havebeen capable of self-report. Studies of behavioralpain scales suggest that children begin to mask be-havioral distress at around age 7. Utilizing a self-report measure for children who are able to do sowould strengthen pain assessment in this study.

Preoperative administration of oral acetamin-ophen provided greater pain relief than postoper-ative rectal administration in this study and re-duced the requirement of postoperative rescueopiates in tonsillectomy patients. The literature aswell as governmental guidelines (U.S. Agency forHealth Care Policy and Research) highlight theundertreatment of children's pain and emphasizethe need for improved assessment and manage-ment.35-4 Preemptive administration of analgesicsmay have implications toward enhancing painmanagement in the surgical population. Acetamin-ophen administered preoperatively is a safe, con-venient, and inexpensive intervention that may bereadily incorporated into anesthesia practice. Fur-ther study of this topic, perhaps with a double-blinded design and a larger sample size, iswarranted.

REFERENCES(1) Beyer JE, DeGood DE, Ashley LC, Russell GA. Patterns of post-operative analgesic use with adults and children following cardiac sur-gery. Pain. 1983;17:71-81.(2) Mather L, Mackie J. The incidence of postoperative pain in chil-dren. Pain. 1983;15:271-282.(3) Schechter NL, Allen DA, Hanson K. Status of pediatric pain con-trol: A comparison of hospital analgesic usage in children and adults.Pediatrics. 1986;77:11-15.(4) Howard R. Preoperative and postoperative pain control. Arch DisChild 1993;69:699-703.(5) Woolf CJ, Chong MS. Preemptive analgesia-treating postopera-tive pain by preventing the establishment of central sensitization. AnesthAnalg. 1993;77:362-379.(6) Jebeles JA, Reilly JS, Gutierrez JF, Bradley EL Jr, Kissin I. Theeffect of pre-incisional infiltration of tonsils with bupivacaine on thepain following tonsillectomy under general anesthesia. Pain. 1991 ;47:305-308.(7) Kavanagh B, Katz J, Sandler A, et al. Is postoperative pain re-

duced by preoperative multi-modal nociceptive blockade?: A random-ized, double-blind, placebo controlled study. Can J Anaesth. 1992;39:A76.(8) Tverskoy M, Cozacov C, Ayache M, Bradley EL Jr, Kissin I. Post-operative pain after inguinal herniorrhaphy with different types ofanesthesia. Anesth Analg. 1990;70:29-35.(9) Campbell WI, Kendrick R. Intravenous diclofenac sodium: Doesits administration before operation suppress postoperative pain? Anaes-thesia. 1990;45:763-766.(10) Kaufmann RK, Holman J. Pain control in children followingtonsillectomies: A retrospective study. Journal of Nursing Quality Assur-ance. 1989;3:45-53.(11) Leach J, Manning S, Schaefer S. Comparison of two methods oftonsillectomy. Laryngoscope. 1993;103:619-622.(12) Linden B, Gross C, Long T, Lazar R. Morbidity in pediatrictonsillectomy. Laryngoscope. 1990;100:120-124.(13) Shannon M, Berde CB. Pharmacologic management of pain inchildren and adolescents. Pediatr Clin North Am. 1989;36:855-871.(14) Dange SV, Shah KU, Deshpande AS, Shrori DS. Bioavailabilityof acetaminophen after rectal administration. Indian Pediatr. 1987;24:331-332.(15) Eandi M, Viano I, Ricci GS. Absolute bioavailability ofparacetamol after oral or rectal administration in healthy volunteers.Arzneimittelforschung. 1984;34:903-907.(16) Gaudreault P, Guay J, Nicol O, Duphis C. Pharmacokineticsand clinical efficacy of intrarectal solution of acetaminophen. Can JAnaesth. 1988;35:149-152.(17) Hopkins CS, Underhill S, Booker PD. Pharmacokinetics ofparacetamol after cardiac surgery. Arch Dis Child. 1990;65:971-976.(18) Merkel S, Voepel-Lewis T, Shayevitz J, Malviya S. FLACC as-sessment tool: Reliability and validation with existing tools. Abstractpresented at American Society of Anesthesiologists National Confer-ence, San Francisco, California. 1994.(19) Insel PA. Analgesic-antipyretics and anti-inflammatory agents;drugs employed in the treatment of rheumatoid arthritis and gout. In:Goodman AG, Gilman LS, Rall TW, Nies AS, Taylor P, eds. The Phar-macological Basis of Therapeutics. 8th ed. Elmsford, New York: PergamonPress. 1990:656-659.(20) McCormack K, Brune K. Dissociation between the antinocicep-tive and anti-inflammatory effects of the nonsteroidal anti-inflamma-tory drugs: A survey of their analgesic efficacy. Drugs. 1991;41:533-547.(21) Piletta P, Porchet H, Dayer P. Central analgesic effect of ace-taminophen but not of aspirin. Clin Pharmacol Ther. 1991 ;49:350-354.(22) Flower RJ, Vane JR. Inhibition of prostaglandin synthetase inbrain explains the antipyretic activity of acetaminophen. Nature.1972;240:410-411.(23) Tolman EL, Fuller BL, Marinan BA, et al. Tissue selectivity andvariability of effect of acetaminophen on arachidonic acid metabolism.Prostaglandins, Leukotrienes and Medicine. 1983;12:347-356.(24) Carlsson KH, Jurna I. Central analgesic effect of acetaminophenmanifested by depression of nociceptive activity in thalmic neurons ofthe rat. NeurosciLett. 1987;77:339-343.(25) Taiwo Y, Levine JD. Prostaglandins inhibit endogenous paincontrol mechanisms by blocking transmissions at spinal noradrenergicsynapses. JNeurosci. 1988;81:346-349.(26) Malmgrem AB. Yaksh TL. Hyperalgesia mediated by spinal glu-tamate or substance P receptor blocked by spinal cyclooxygenase inhi-bition. Science. 1992;257:1276-1279.(27) Maunuksela EL, Ryhanen P, Janhunen L. Efficacy of rectal ibu-profen in controlling postoperative pain in children. Can J Anaesth.1992;39:226-230.(28) Moore PA, John JR, Seldin EB, Stevens CM. Analgesic regimensfor third molar surgery. Pharmacologic and behavioral considerations.JADA. 1986;113:739-744.(29) Nordbladh I, Ohlander B, Bjorkman R. Analgesia in tonsillec-tomy: A double-blind study on pre- and post-operative treatment withdiclofenac. Clin Otolaryngol. 1991;16:554-558.(30) Walter-Sack I, Luckow V, Gaserle R, Weber E. The relativebioavailability of paracetamol following administration of solid andliquid oral preparations and rectal dosage forms. Arzneimittelforschung.1989;39:719-724.(31) Rusz LM, Houck CS, Sullivan LJ, et al. A double-blind evalua-tion of ketorolac tromethamine versus acetaminophen in pediatric ton-sillectomy: Analgesia and bleeding. Anesth Analg. 1995;80:226-229.

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(32) Yentis SM, Bissonnette B. P6 acupuncture and postoperative vom-iting after tonsillectomy in children. BrJ Anaesth. 1991;67:779-780.(33) Splinter WM, Rhine EJ, MacNeill HB, et al. The effect of gen-eral anaesthesia on post-tonsillectomy vomiting. Can J Anaesth.1990;37:S96.(34) Carithers JS, Williams JA, Gebhart DE. Postoperative risks ofpediatric tonsilloadenoidectomy. Laryngoscope. 1987;97:422-429.(35) Acs G, Drazner E. The incidence of postoperative pain and anal-gesic usage in children. ASDC Journal of Dentistry for Children.1992;59:48-52.(36) Quick Reference Guide for Clinicians. Acute Pain Management in In-fants, Children, and Adolescents: Operative and Medical Procedures. U.S.Department of Health and Human Services, Public Health Service,Agency for Health Care Policy and Research. AHCPR Pub. No.92-0020.(37) Fell D. Postoperative analgesia in children. Br J Anaesth.1993;70:4-5. Editorial.(38) Tyler DC, Tu A, Douthit J, Chapman CR. Toward validation ofpain measurement tools for children: A pilot study. Pain. 1993;52:301-309.(39) Tarbell SE, Cohen IT, Marsh JL. The toddler preschooler post-operative pain scale: An observational scale for measuring postopera-tive pain in children ages 1-5: Preliminary report. Pain. 1992;50:273-280.(40) Hannallah RS. Postoperative pain in the pediatric patient.Can JAnesth. 1992;39:641-642. Editorial.

(41) Zeltzer LK, Anderson CTM, Scliecter NL. Pediatric pain: Cur-rent status and new directions. Curr Probl Pediatr. 1990;20:409-486.

AUTHORSMichael Romej, CRNA, MS, received his BSN from the Univer-

sity of Michigan in 1979 and an MS in Nurse Anesthesia from Detroit-Henry Ford Hospital/University of Detroit Mercy Graduate Programof Nurse Anesthesiology, Detroit, Michigan. He is currently employedas a CRNA at St. Joseph Mercy Hospital in Ann Arbor, Michigan.

Terri Voepel-Lewis, RN, MS, received her BSN from MichiganState University and her MS in Medical-Surgical Nursing from theUniversity of Michigan in 1988. She is a clinical nurse specialist forPediatric Anesthesiology at the University of Michigan Medical Cen-ter, Ann Arbor, Michigan.

Sandra I. Merkelk RN, MS, received her BSN from the Universityof Iowa in 1966 and her MS from the University of Michigan in 1977.She is currently the clinical nurse specialist on the Pediatric Pain andSedation Service at the University of Michigan Medical Center.

Paul Reynolds, MD, is the chief of the Section of Pediatric Anes-thesiology and associate professor at the University of Michigan Medi-cal Center.

Patrick Quinn, CRNA, MS, received his MS in Anesthesia fromDetroit-Henry Ford Hospital/University of Detroit Mercy GraduateProgram of Nurse Anesthesiology. He is employed as a CRNA andclinical instructor at Henry Ford Hospital.

Journal of the American Association of Nurse Anesthetists540

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EEITAILE MUSION FOR IV AUISTRITIOU M U MMR (For Fl Prescribing Inforaion, Se Package Inmet)INIAIONSUAM USAGEDIPRIVAN I Emuksion iman I edatla-hypntic agethtanbe ued for botductionand r m intenanceanethelaas PartcOa balanced anethetc technique for inpatient and nidydtient u m nadubNand ncildren 3years atmge orolder

DIRA netbeEmulsion, when admlimmsered omrynus s a be seed to initale reed mintein moenioredanenlhneni wre (MAC) sedation during dianotic prncedures in adults. DIPRFAN Ijectble Emulsona lso beuseed for MACnedation in coepenction withinalregionedanesthesia in patients andergoing oridprnceduren. (See 015S.) DPRPANInjectable Emnuiion should only be administered tointnibated, mechanicaly amed adult eesin the Intesie CanUit (ICU)so proide continanus nedation and contol ofntstresn responses. In thinsething, DIV PAN Injectable Emulion should beadmininored only by pernons siled in the medical management nf critialy N patientm and trained n ardiovamcular resuscctatinand airay ren DIPRIVAN Injectable Emusion isnont recnmmended for obsteincs, including cesarean mactian delivres.DIPIVV NI m'Emuksian consses thre paceob, and an with other geonal anesthetic Aestthe administration of DIPAPANInjectable Emuiion may he anaociated wimh neonatal qaann. (See PRECCMTIONS.NDI In kje~ale Emlion isn otrecommnended for use in nring mothers because DIPRV hANIectable Emuion han been repored tn eemocreted in huemor mlkand the effects oforahborptionnof smaflamountsoof propofof arm ntdknown. (See PRECAUTIONS.) DIPRPAN Injectable Enudinisonot recommendedtor anenthesia in children before the apecd3years becausn safey andeffectmesn haemnotbeeen tmklsfed.OtPRtVAN Injecable Emuioin is not recommended for MAC seaion in children because safety reed eftectivenessmafoamnot beet

esalse.DPIVAN Injectable Emuinian in not recommended for pediatric ICU sedation becaase mainly aed elfecieneem reamnot been estalished.CONTRINMICAfIONSDIPRIVAN Injectable Emuinon is contraindicated in pretients with a known hypersensitivily in DIP~RAN Inctable Emulsion or itcoinponns, orrwhen geeral anesthesiasor sedation ametrindicaled.

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dg ohypotension, apne aeiway obstruction, andor maYge dusainnion. Thesecardioresmdratry effects aremWhrelrelyin occrfownrapid intiation (loading) boluses or dureg supplemental maeneance bkels es epecially inthe elderly dmkitaed, or ASA

AIiyV patients. DIPRIVAN Inectabe Emuinon should sot be coadministered through t he smne IV catheter with blood or planmabecause compatibilty has not been etablinhed. Intvitros avshown that ggregaterdte glolar componnt of the emunionvehicleonae occurred with blood/pm asem from fanrans and anina. Thedcirnical sinificance is not known.STICtT ASEPTIC TE OIWE ALTWAS RE MAITttlttEl URI G ____ItP d RII ICNECTILNE 9111131011MA

SILEUSE PARBIERAL PRODUCT W-C CONMIS 1.116% ESIIRIM EDEWAE TO RETAD THE RATE IF GROWTH IFMCROORASMS M THEVBIT OFACCtDENTAL EX I C MSCOINAMTtO. HOWEVER, DIPR2WNMNEC1NILE EMULIOMCAN STILL SUPPORT THE GROWTH OF MICROORGAISMS AITINT AN AIETIMRIAY RESVIED PRODUCT UNIDEUSP STANDARDS. ACCORIMGLY STRICTASEPTC TECIIOIIE MUST SILLRE ADItIEEITO. 0ONOT USEIF COIMIMIIIOIS SUSPECTED. DISCARD Uifi tIPttRTIONS AS IRECED WITITE REQtIRED TItMELIMITS (SEE DOSAGE MUADMItSIRAIOM, ttlttLNtG PROCEDU ).THJE tE N E -~1 REPORTS M WICH FAILURE TI USE ASEPTIC TECHNMQUEWHEN HANtILIG DtPRtVAN SUECiRILE M1.11N WAS ASSOCIATED WITHif MCRONtAL COIITAMMNAIONIOFIRE PRODUCTANU WITH FEVER, MFECTtOIVSEPStS, OTHER LUFE-ThRIEATEMI GLLESS, AN/O WNDAT.PRECAUTItONS Geeenat A lower induction dune aed a slower maintenance ate of atministration should be used in elderlydehiitated, or ASA MIVV patients. (See CLINCAL PHARMACOLOGY - tdIdktoton of Dosage.) Patiensnshould be contimmamslymntre d id, elevation of clowerrnntieunsnof inem oragents, or administration o tpn. Apnea oftenoccumringindoctionanmay persist for more thant60 seconds. ftntpreatorntsupport maybe required. Secause DIPRIIVAN lnjecable Emulsion n emsion,caution should be nonclond in patients with disorders of lipid metabolsm ouch an primary hypeefipopoteinemia, diabetic

administeredinoan epileptic patien, there may be adrskof sezure durigthe nadlsadchldrenattention shouldbe paid to minimize pain on administration of DPtIAN In tbe uo. Transientlobapain anbe minimied iftie lrgeransof the forearmoor antecukltal fomsaaare used. Pain duingintravenousin jection may alsoube reduced by prorn jecion ofIV Idocalte(1 ml nf a 1% solution). Pain on injection occurreitrequeretlyin pediric patients (45%)(whenrasmafamvin of the handwas utlizedwithout lkncasne pretreatment. W~kithducaine pretreatment or wiher antecukikiam iss were utiized, pain woo minimal (inciencelesthan 10%(and welinlerated. Vnus seqtreae (phlekitis or thruesnsis) haebeenrreported raely (<1%). In twoswelf-contmoledclinical stories using dedicated intravenous ateters, no instances of vesus seqamlee were okserved op in 14 days folowinginduction. Inra-aflenial injection in animasinot induce boa tissuetltactas. Accidental inta-arteri injecion a been reported inpahients, and, oter than pain, there were nmajr sequelse. Intentional i jection intnosubcutanenus or parivascutir tiosues ofanimals caused minhmal tissue reaction. During tire pnmdt period, themefame been are reports of local pain, awenngbisters, and/or tissue recrosis following accidental nodravrasation o DIPAPAN Injectable Emulsion. Prpeimyocininarelyincluding convulsion and opisthotonos, has occurred in temporal reltionship in cases inrwhich DIPRIIN Ijecable Emulsiorn Hasbeer administered. Clinical letures of anaphylna, which may include angiedemt, broochoupuem, erthem, and hypotension,occur aely following DIPRIVAN In'etal Emuksion administration, although usedo other druga in most instances mahes therelationhippin DIPRIVAN Injectable Emulsion uncleer. Therefhae beenrare reports ofpulmonary edemein temporal relationshipinotire adminitration of DIPRIVAN Injectable Emulsion, although a causal relatlonship i nnoown. DfPRPAN Injectable Emulsion hanovagolylic activity. Reports of bradyadit ansetole, and rarely cardiac arrest fame beer associated with DIPRIVAN InjectableEmutssoon. The inravenous administration oranticsonergcagerns ( atropine or I shoulde considerfed 50modifypotential lcesnin usgal tone dontocoocoesbt ae Ce r5 ac(S tA iNSant ho orIN neTIsuo stimul

of DIPRIVAN Injectable Emusion should be intated as acontinuous infusionand cagsinthe rateof administraion madenlowly(>5min in ordertomnmzhytnsnad avoid acute overdoseage. (Sen LIICA PHARMACOLOGY - Indlodaoton ofDoage.) Patients should be montiored for soofsaigniicard hypotenelion and/or cardiovascelar depresalon, which may be

profound. These effects aem reoponsiamein o DIPRIH Injectable Emulsion, IV fluid admiistration, and/orvasopremsor therapy. Au with other sedative mediatine, theme is wide intenpatient variabiitly n DIPAPAN Injectable Emulsionduae requirements, and these requirements may change with time. Failure in reduce lire infusion rate in patients receivingDIPRiVAN Injectable Emulsion for extnored pardoda may result innonmalsvely high blood concentrations of the drg. Thus, titrationto clinical response sod daily evaluation of sedation levelinaem important during use of DIPAPAN Injectable Emulsion Infusion forCU sedation, especially of long duration. Opiolda and paaylic ap should he discontinued aned respiraty functionr optiiedpo inwenring patiensnhoe necanialentlation. Infusions o DIPAPAN Injectable Emulion should be seuad int mataina

ght level of sedation priorino weaning patientsafrom mechanical" support Throughodt the weaning po this hindl ofsedation may be maintained in lire absence of respiratory depresslon. Bs of the rapid clearance of IDPRIVAN InjectableEmusion, abrupt discontinuatior of a patientk infosion may result in rpdaaa ofthe pw wt soitdaxeyagiio, and resostance in mechanical ventilation, mairing weaningfrm ecail ntb ~ Itstheoerecommended that administration of DIPRIVN Injectable Emulsion be continued in order in maintain a light level of sedmtionthmoughout lire weaning process until 10-15 inmates prior tnodxuhation at whimh time the infosion can be discontinued. SinceDIPRIVAN Injectable Emulsion in tonnulated in an oit-in-watnr emulion, elevations in serum hriglyceriden may occur whenDIPRIVAN Injectable Emulsion is administered for exdended periods of time. Patiensnat rish of hypedfipidemin should be monitoredfor increases n seum tlyerdes or serum itridity Administration of DIPRIVAN Injectable Emulsion should be adjusted f ho isbeing nadeq fw bod. A reduction inttte quantity of concurrently admilste red ipids is indicatedinocomrpensatefortheamsout lid inused us part of the DIPRIVAN Injectable Emuinon formulation; l ml of DIPRIVAN Injectable Emukioncontains approximately0.1 g oftfat (1.1 ikca). In patients who ar prediosned innc deficiency suchsthose withburs, diarrhea,and/or mapir sepsis, tire seed for supplemental znec should be considered during prolonged therapy with DIPRPAN InectableEmulsionEOTAni a strong chnlator o trace mtlm- incloudingziec. Caiciom dsodio m edetate too been used in gram quanitiesto treat heavy metaloardly. When used in thismannmertis possblethatuasrmuchas 10nrg of elementalnc can be lost per dayvin this mechanism. Although with DPIAN Injectable Emulsion themream so reports of decreased ziocleelsordcetioytotaled adverse events, DIPRIVAN Inectabile PI Emulson should notbemifsed forlonger than 5d), withutd zncdlaecproviding adugholdayin safely replace estimated or measured urine znec losses. At high donees (2-3 graapar day, ClA Iran been reported, on rareoccasions. to be tonic to the rendlobules. Studies-to-date. inpahuents with nonsal or knnafrwt tn fonction have notshown aay

nystolic, diastolic, and emn arterial pressures saed cardiac output During muoaitenrance of anesthesi o sedation, the ate ofDIPRIVAN Injectable Emulsion administration should be armused according inolire desired level of anestheoua or sedation and maybereducediodte presencecdfsupplemental analecgns(g duonerpod)Teocrrnam srh fptn

inhattional agents (ng, isoltrsonr, enfinnrane, adIaohs)drn atnnewt IRR netleEoor Ubeextnosivly evalosted. Thene inhaitiornal agents an also be eopected to increase tire anesthetic or sedative and cardiormoporatory

ettects of DIPRIVAN Injectasle Emulsion. OrPRIVAN Irjectable Emuteion ldnes not camse a clinclyitgnifncwnt change en onsetineensity, or duration of action of lire commonly used neromucular bhisclig agents (eg, succinylcholene and sondepolarhzingnsudrelend N signitart adverse bleractions with commonly used premediations or drags used during anesthesia or

seain( arange of muscle relaants, inhelational agents, analgesic agents, reed local anesthretic agents) havebeen observed.

Ceheee, leho", hepehreed Fe~llAnimal cacinpenicy stdies havemnotbeen performed witir propofol. Invitosandinvivo animal tests faited to show any poteeltal for reutagenicdy by pinpoint Tentsfor stutaqenicily included Use Amen

n e hamstrs ndamouemon deu s td nfme rt topaenu oe to 15i m edy(6ts thmorinsim recommended human induction dose) for 2weeks befoepmegnancy to dayl7of nnutmdid nAUshow imardfertiltyMale fertiltyinratwsotA~aected in a du nflthal study atnthoha sues upto l5 mg glday for5days.Peeegeqac 1: Reproduction studies have been perfomned n rats and rabbits at nthvensus doses of 15 m firolday (6

timseneumn irhductien dose) reedame revealed no mvidemnopied yei tilly or Hunm to the fehus due topropoll Propotul, however, tas been shown to cause matemnal deaths in rtsi andrabt and decreased su mrvival during thelactating period in dams treaed with 15 mgtirghtay (and6 times the recommended human induction dose.Th pharmacologicalactivity (anesthesia) of lire drag on the mother is probably responstil for ire adverse effects seen in the offspring. Theme am,howeve so adequatenand wel-cotroled studiesinpregnant wnmen. Becauseanimal reproduction stadies areAnotalways predictiveofhumanrresponses, thindng should be used duringpregnancy only t cauly needed.Latereeadeleee DIPRI Injectable Emulsion isnoAU recommendfed tor obstetics,ncbeding cesarean section deltveries.

DIPRIVAN Injectahle Emusion crosses th lreta and an with othrer general anesthotic agents, the administration of DIPRPNEmulsion may be associated with neonatalde .

Eloe ers: DIPR oI Ijctabebesrle EmusioninA reomnefomannrngctrsbcmeDPANnjcbhEmusio fo ben rpored n b moretd i human mi~ and Ame effects of oral aborption of all amounts of propoll ame

not known.Paihibteac: DIPRIVAN Injectable Emulsion is AUt recommendedformas in pediatric patiento for ICU or MAC sedation. In addition,

DIPRIVAN Injectable Emulsion is notrecomended for general anesthesia for children belowde age of 3years because safety andeffectiveness have AUt been established. Alhugno causal reltionhi fos foesnstablished, serious adversenevets (includingfatalities) fame been reported in chidenogiven DIPRIVANIUeta Em ~ o CU sedation. Theeevents were seen mostoftenin chidren OSEwth 'grtory tract infections given doses in excess of thmae recommended for aduts.

leeeret Adverse evensinformation's derived from contrlled ciiials and wrdwide markting eprience. In te descriptionbelow, rates of th mome cmmon events represent US/Canadim cinical study results. Less frequent events are also derived huompublicationssand mrkfeting experience in aver 8 milon patients; theeame insufficient data to support an accurate estimate of theirincidence rates. These studies were coeducted using a variely of premedicants, varying lengtho of surgica ckiagnontic procedures,and various other sesthetc/sedativeagents Most advense events were mild and tramrentbeebshie artCle$em MhiAblyThitefomo estinates of adversenavets for DIPRIVAN Injectable Emulsion include data

fromclinical tilsin general aestheiadMACseainN2889 adult pients. The r se e venrs ised below aproably causallyrelated ame thmae events in whimh Am actual incidence rain in patients hosated with DIPRAPAN Injectable Emulsion was greater thanAm compamator incidence ate in thene trials. Therefore, inhcidence ates for anesthesia and MAC sedation in aduts generallyrepresent estimates of Am ecetg of cfiik rial which appeared oe probable causal relationship. The adverse

noeecprofle from reports of 150ptinsin mthe sedation rcaltrials issilar to tprflestablished with DIPR NInjecable Emulsion dumpganesthesin aebelow). During MAC sedation clnical trials, significantmoepiratory events included cough, adds

In C iur theadvrse rn proilefromreprtsof 349 DIPRIVAN Injectable Emulsion pediatricpatentsbetweendte ages of 3 12 yarsin teU m hda anesthesaclintcal triasis similaritn th profile estalistredwithIDPRIANnjectable Emulsiodudnrganehes n adults mse Pediatric percentages [Pedso%] below).Atihough not rported asan

adversonamt in cfimal trials, anaishorquentlyosevdipdatcpaen.ICfl$eileehiYAdeti: Thefonwg estmates of adverse events include datahfom clinicalials in ICU sedation (N159)(patients.

Pro ~ ~ ~ ~ caebedncides for eation wem hdea tier e by niiua e rpotformIn ie ncuaiymbasd ~ n ppret marejrns rlaioshy ndorpoitvnmoonesto in shtances tAm preence of

cencoestant disase and concomitant Amrapy made Ame causal relationship unknown. dTherelom , icience ates for ICU sedationgenerally repreent estimeatesnof Ame percentage of clinical tri patients whimh appeared t o ve a probable causal relationship.

hrelium tear~ 1% -Preteiny CmeettRelmhii

seelsoNICAL

Central Nervous iO GY

Systeme: Movement' (Peds: 17%)Injection Site: Suming/tig

or Pain, 17.0%(Pada: 10%)

Metabohc/Nutditional Hyperlpemia'R Y (seenalso CLINICAL Aiosis

PHARMACOLOGY) DuringWenig'

Skde andAppendages: Rush (Pads: 5%)Events without an *'or % had an incidence of 1%-3%'Incidence of(events 3% in 10%

he .. a sblap 1%- P remly Ceesaty Retied

Boya hl: AnaphylacisidRactoiParinatal Disorder

Cardiovascular Prereature AtrialContractions,

Central herousmSystem: llypetonkilDystonla

Paresthesla AgtatiotDigestive: llyperalivationM meuobeea: Myalgin

RespirtoryLun FunctionSkin andAppenrages: Rushing, ProritusSpecal Senses: AmhiolUrogental: Clourfynn GremmUrine

hein ees hasbl1% - Caral Retaleelip Uebaewi

Body as aWhole: Asthena Awemness, Feer

Exremnoities Pai, Whole BodyFever, Weales

Trunk PainCardiovascular kla'oAtrial ~ dnlmnk,

Atriovnanincular Heart ARhnfehon,

CardacArrest RightECG Abonenal, Heart Failure,

Manufactured forztnec PamamatcalA uines Unit ofZeneca Inc.Wtimington, DC 19850-5437

Cardiovtscular Edema, Exrasystole, Ventriculsar(continued) Heart Block, Tachycardia

In arctonMyocardial IochensnPremature VenricularContractonso, STSemet epressin,SepraventricudarTachycardiaTachycardia,Vntricular fibrillation

Cental NervousSyte: Abnormal Drams, Chils/9hiamrin

Agitation, Amorous IttracraoidlBehavior, Assiety Hypetension,

Thasiig ht Somnolence,

Combativenes,Conhtion, Delirium,Depression, Dizziness,EmotiolLeilly

Headache, byoaMoaning, Neropathy,Opithotnon, Rigidity,Secu ure nolesc,Treesor, Twtching

Digestive: Crampang, Diarrhea, lius, LiverDry Mouth, Enlarged FunctionParotid, Nausea, Abnormal

Heaooi/ Swallowing, Vomiting

Lymphatic: Cougultiot Disorder,Leubocytusis

Injection Site: Hives/Inching, Phlebitis,RndnesslDiscnloratio

MetabolcNutritinal: Hypedmalemin, SUN Increased,

Hypedlipemlo CreatinineIncreased,

Otbphydratiot,

AcidssOsmuidyIncresed

Respiratory Bronchospasm, HyposiaBumning in Throat,CougL DyspetHiccough,Hyperventilation,Hypovuntilation,

Tachypnea, UpperSknad Arway Obstruction

Appendages: Conjunctival Rush

Draphoresis, UrticuariSpecial Sermes: Dipiopia. Ear Pain,

Eys Pain, Nystagmus,Tante Perversion,rmnnius

Urogenital: Oliguriu, Ulino Kidney FutlureRetention

Rev D006/96