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Pediatric surgical patients are a population at risk of intravenous (IV) opioids with nonopioid IV analgesics.
inadequate pain management. The American Society Ketorolac and acetaminophen are the 2 nonopioid IV
of Anesthesiologists’ 2012 Practice Guidelines for analgesics currently available for use in the United
Acute Pain Management in the Perioperative Set- States. This article provides a review of the literature
ting recommend a multimodal approach as the most of IV ketorolac and IV acetaminophen regarding their
effective way to prevent and treat pain in children. A pharmacology, analgesic efficacy, limitations, and
multimodal approach entails the use of 2 or more anal- practical considerations, with a focus on patients 16
gesic medications that act by different mechanisms, years of age and younger.
to maximally target a variety of pain receptors and
reduce the potential for side effects. One method for Keywords: Acetaminophen, anesthesia, ketorolac,
incorporating a multimodal approach is to augment multimodal analgesia, pediatric.
T
he historic undertreatment of pain in the pedi- Administration (FDA) approval in 1989. Overall, it has
atric population is a problem that anesthesia a well-established safety profile, but concerns have been
providers are challenged to eliminate. In the raised regarding the potential to exacerbate hemorrhage.
American Society of Anesthesiologists’ (ASA’s) Acetaminophen (Tylenol) has been a mainstay of pain
2012 Practice Guidelines for Acute Pain Man- management for more than 50 years and is currently the
agement in the Perioperative Setting, pediatric patients are most prescribed analgesic and antipyretic in children.5
identified as a subpopulation at risk of inadequate pain The parenteral formulation achieved FDA approval in
control and requiring additional analgesic consideration.1 2010, but has been safely used in Europe for more than
The Practice Guidelines recommend a proactive approach 20 years in adults and children.6,7
to pain management with analgesic therapy based on age This article will review and compare IV ketorolac and
and weight, and embracing a multimodal approach.1 A IV acetaminophen regarding their pharmacologic pro-
multimodal approach may be characterized by the use files, analgesic potentials alone and in conjunction with
of 2 or more analgesic medications that act by different opioids, their limitations, and considerations such as ease
mechanisms, which can be administered via the same or of administration and cost. It will provide a summary of
different routes. It is believed that a combination of medi- each drugs’ risks and benefits, to promote a more edu-
cations optimizes analgesic efficacy while minimizing cated, individualized provision of multimodal pain man-
adverse effects of any one medication used alone.1 agement in surgical patients 16 years of age and younger.
Intravenous (IV) ketorolac and IV acetaminophen are
2 such nonopioid medications, whose administration Pharmacologic Profiles
combined with other analgesics addresses multimodal • Ketorolac. Ketorolac tromethamine is the only IV
therapy, as well as the ASA’s recommendation to initi- NSAID currently available for use in the United States. It
ate a regimen of nonsteroidal anti-inflammatory drugs is administered as a racemic mixture; the S(−) isomer is
(NSAIDs), cyclooxygenase (COX) 2–selective NSAIDS, responsible for the analgesic effects of the medication.8
or acetaminophen in pediatric surgical patients.1 Ketorolac acts at central and peripheral sites in the body.
Intravenous acetaminophen and IV ketorolac have been It inhibits COX-1 and COX-2, with a slightly increased
used successfully, both alone and in conjunction with affinity for COX-1.9 Both COX-1 and COX-2 are enzymes
opioids, to manage surgical pain in various settings that play a role in the formation of chemical mediators
around the world.2-4 Ketorolac has been widely adminis- in the body. Inhibition of these enzymes by ketorolac
tered in the United States since gaining Food and Drug primarily prevents the production of prostaglandin-2
AANA Journal
renal dysfunction, after induction 50/50 air/oxygen mixture (P=.04) but still within normal limits higher in Group K (P=.001)
coagulopathy, family • IV fentanyl 1 μg/kg given intra-op • PACU pain scores higher
history of bleeding if BP or HR increased greater than in group K (P=.003) (FLACC
disorders, required 15% above pre-op values scale)
premedication • No other sedatives or opioids given • No statistically significant
during the operation difference between groups
• NMB reversal at end with IV for sedation scores (4-point
February 2014
neostigmine 50 μg/kg and IV scale), PACU discharge
atropine 20 μg/kg times, or unplanned hospital
• Deep extubation admissions
• PACU: Rectal acetaminophen and IV
fentanyl rescue analgesics if needed
2011, Uysal • n=64 • Tonsillectomy and • PO midazolam 0.5 mg/kg given 30 • I: no statistically significant • No statistically significant
et al22 • Age 6-16 years adenoidectomy minutes before surgery difference between groups difference between groups for
www.aana.com/aanajournalonline
2010, Hong • n=63 • Ureteroneocystostomy • No premedication • I: higher incidence in group F • On both POD 1 and 2, total
et al4 • Age 6-24 months • Group FA: IV fentanyl 0.5 • Induction: IV thiopental 5 mg/kg, IV (P=.011) dose of fentanyl received
• PS I and II μg/kg and IV acetaminophen rocuronium 0.6 mg/kg by group FA was half that
• Exclusion criteria: 15 mg/kg • Maintenance: 1-4% end-tidal received by group F
kidney or liver • Group F: IV fentanyl 0.5 sevoflurane, air/oxygen mixture with • Cumulative dose of
dysfunction, required μg/kg inspired oxygen equal to 50% fentanyl over 72 hours was
premedication • Initial dose of study • IV fentanyl 1 μg/kg given to all significantly lower in group FA
medications given at patients after induction but before (P<.05)
peritoneal closure incision • Sedation scores higher in
• Post-op, all patients on group F (P=.019) (modified
PCNA pump with basal Ramsey Sedation Scale)
infusion rate, maximum • No statistically significant
duration of usage 72 hours difference in pain scores
• Group FA: IV fentanyl between groups (Children’s
www.aana.com/aanajournalonline
0.25 μg/kg/hr and IV Hospital of Eastern Ontario
acetaminophen 1.5 μg/kg/hr Pain Scale)
• Group F: IV fentanyl 0.25 • Parent satisfaction scores
μg/kg/hr higher in group FA (P=.02)
(4-point scale)
2010, Hong • n=55 • Unilateral inguinal hernia • No premedication • I: higher incidence in group C • Lower total consumption
et al4 • Age 1-5 years repair • Induction: inhalation of 8% (P=.016) of fentanyl, fewer patients
• Exclusion • Group KA: IV ketorolac 1 sevoflurane in oxygen, IV atracurium • III: no occurrence in either group received rescue fentanyl in
criteria: kidney or mg/kg and IV acetaminophen 0.5 mg/kg PACU in group KA (P=.001
liver dysfunction, 20 mg/kg • Maintenance: 1-4% sevoflurane, for both)
hemorrhagic • Group C: control, IV saline air/oxygen mixture with inspired • Higher pain scores on arrival
diathesis, asthma, • Study drug given one time oxygen equal to 50% to PACU in group C (P=.041)
history of long- after induction • IV fentanyl 1 μg/kg given to all (Wong-Baker FACES Scale)
term analgesic patients after induction but before • Higher incidence of sedation
use, required incision in PACU in group C (P=.023)
premedication • No other opioids given intra-op (modified Ramsey Sedation
AANA Journal
• Awake extubation Scale)
• PACU: IV fentanyl rescue analgesic • No statistically significant
if needed difference in time to discharge
between groups
2007, • n=40 • Dental restorations • PO midazolam 0.5 mg/kg given 30 • I: no statistically significant • Lower PACU pain scores in
Alhashemi, • Age 3-16 years • Group A: IV acetaminophen minutes before surgery difference between groups group Me (P=.012) (OPS)
Daghistani2 • PS I and II 15 mg/kg • Induction: sevoflurane inhalation or • III, IV: no occurrence in either group • Increased incidence of
February 2014
• Exclusion criteria: • Group Me: IM meperidine IV propofol 2-3 mg/kg sedation in PACU in group Me
planned extractions, 1 mg/kg • Maintenance: sevoflurane, oxygen/ (P=.0130) (Ramsey Sedation
developmental delay, • Study drug given one time nitrous oxide mixture Score)
renal insufficiency, after induction • IV fentanyl 1 μg/kg given to all • Group A achieved Aldrete
neurologic patients immediately after induction score of 10 and readiness for
dysfunction • No other intra-op analgesics, local discharge faster than group
anesthetics, or anti-emetics given Me (P=.009)
57
continues on page 58
continued from page 57
58
Surgical procedure Postop adverse effects
Year of analgesic I: PONV II: Bleeding III:
publication/ comparisons Respiratory Depression IV:
Authors Demographics and dosages Anesthetic management Pulse Oximetry Values Results
2007, Lynn • n= 37 • Craniectomy, other • No details of anesthetic • II, IV: no statistically significant • No statistically significant
et al12 • Age 6-18 months neurosurgery, general, management provided difference among groups difference in morphine
• Patients admitted plastic, urologic, and cardiac • No statistically significant difference consumption between groups
after surgery surgical procedures in BUN, creatinine, AST, ALT, or urine • Authors suggest this was
AANA Journal
• Exclusion criteria: • Group P: IV placebo analysis results among groups possibly due to a reluctance
< 36 weeks gestation • Group K0.5: IV ketorolac 0.5 to wean medication based
at birth, history of mg/kg on satisfactory pain scores
GI bleed, hepatic or • Group K1: IV ketorolac 1 mg/ (FLACC scale) and lack of
renal impairment, kg adverse effects
coagulopathy in • Study drug given one time
patient or family on POD 1
February 2014
member • All patients placed on
continuous infusion of IV
morphine at 5-30 μg/kg/hr
2006, • n=80 • Tonsillectomy • PO midazolam 0.5 mg/kg given 30 • I, II, III, IV: no statistically significant • No statistically significant
Alhashemi, • Age 3-16 years • Group A: IV acetaminophen minutes before surgery differences between groups difference in pain scores
Daghistani21 • PS I and II 15 mg/kg • Induction: sevoflurane inhalation or between groups (OPS)
• Exclusion criteria: • Group Me: IM meperidine IV propofol 2-3 mg/kg • Group A had a greater
www.aana.com/aanajournalonline
1995, Rusy • n=50 • Tonsillectomy with or • No premedication • II: higher incidence in group K • No significant difference in
et al24 • Age 2-15 years without adenoidectomy • Induction: halothane inhalation in (P=.025) pain scores between groups
• PS I and II • Group K: IV ketorolac 1 mg/kg oxygen/nitrous oxide mixture, IV • 8/25 patients in group K required (OPS)
• Exclusion criteria: • Group A: rectal atracurium 0.5 mg/kg additional measures to achieve • Majority of patients in both
renal dysfunction, acetaminophen 35 mg/kg • Maintenance: 70/30 nitrous oxide/ hemostasis groups required additional
egg allergy, bleeding • Study drug given given oxygen mixture, IV propofol 75-300 • 1/25 patients in group A required analgesia in PACU
disorders, family once various times μg/kg/min additional measures
history of bleeding intraoperatively • No opioids given pre- or intra-op
disorders • NMB reversal at end with IV
neostigmine 0.05 mg/kg and IV
glycopyrrolate 0.01 mg/kg
• Awake extubation
• PACU: IV morphine rescue
analgesic if needed
www.aana.com/aanajournalonline
1994, Morrison, • n= 60 • Strabismus surgery • General inhalational anesthesia or • I: 2 occurrences each in group A • Lower pain scores in group
Repkaa23 • Age 13-18 years • Group A: PO local periocular anesthesia and group I, no occurrence in group K K compared with group A and
• Exclusion criteria: acetaminophen 650 mg Intra-op sedation and IV analgesia • II: no statistically significant group I (P=.001) (VAS)
history of peptic • Group I: PO ibuprofen 600 “held constant” (p.916) regardless difference among groups • 63% group K required no
ulcer disease, mg of anesthetic type additional pain medication,
platelet disorders, • Group K: IV ketorolac 60 mg • No additional details given 100% group I and 80% group
sensitivity to NSAIDs, administered at the end of regarding induction or maintenance A required additional
>3 previous eye surgery, plus PO placebo • IV droperidol 75 μg/kg analgesics (P= .0001)
surgeries • PO medications given one administered to all patients before • No statistically significant
time in PACU 35-40 minutes surgery for PONV prophylaxis difference in sedation scores
after surgery completed • PACU: PO acetaminophen with among groups (VAS)
and without oxycodone rescue
analgesic if needed
Table. Studies Evaluating the Postoperative Analgesic Efficacy of IV Ketorolac and IV Acetaminophen in Common Pediatric Procedures
Abbreviations: n, number of study participants; PS, physical status; IV, intravenous; BP, blood pressure; HR, heart rate; NMB, neuromuscular blockade; PACU, post anesthesia care unit;
FLACC, face legs activity cry consolability; PO, per os/by mouth; PAED, pediatric anesthesia emergence delirium; PCNA, parent/nurse-controlled analgesia; POD, postoperative day;
AANA Journal
OPS, objective pain scale; PONV, postoperative nausea and vomiting; NSAIDs, non-steroidal anti-inflammatory drugs; VAS, visual analog scale.
a Study enrolled teenagers and adult subjects
February 2014
Vol. 82, No. 1
59
limited analgesic efficacy above 30 mg with an increased Seven studies from the anesthesia, pediatric, and surgi-
risk of side effects.10 cal (specifically ear, nose, and throat) literature link IV
In the second study, rectal acetaminophen was found ketorolac administration with the potential for increased
to be equally effective to IV ketorolac in pediatric patients hemorrhage. All of the studies examined hemorrhage or
undergoing tonsillectomy.24 Neither agent was found to coagulopathy as one of the primary outcome measures.
be sufficient as a solo analgesic, because both groups Of these 7 studies, 2 indicated negligible increased risk
required additional morphine in the PACU. Increased of hemorrhage12,29 and 5 demonstrated some degree of
bleeding occurred in the patients receiving ketorolac. coagulopathy.7,11,24,30,31
• Combined Ketorolac-Acetaminophen Clinical Trials. Several studies highlighted the safety of ketorolac and
One study (see Table) examined the efficacy of a combina- the lack of adverse bleeding effects.12,29 A double-blind,
tion of IV acetaminophen and IV ketorolac on total fen- placebo-controlled study involving 37 patients 6 to 18
tanyl requirements in pediatric patients undergoing ingui- months of age demonstrated no association between ke-
nal hernia repair.25 The authors reported reduced fentanyl torolac administration and bleeding.12 The details of this
consumption, improved satisfaction scores, less vomiting, study can be found in the Table. Similarly, a retrospective
and less sedation in the acetaminophen-ketorolac group review of 310 pediatric patients’ medical records found
vs the saline control group. Also, no adverse effects in the no significant difference in frequency of postoperative
acetaminophen-ketorolac group were reported. hemorrhage between patients receiving a 1-time dose
of IV ketorolac in the normal dose range (ie, 0.5-1 mg/
Limitations kg) compared with patients who did not receive ketoro-
• Ketorolac. The analgesic effect of ketorolac is derived lac (2.3% for ketorolac group vs 3.1% for nonketorolac
from the drug’s ability to inhibit prostaglandin synthesis, group, P = 0.71).29
which is also the primary source of the drug’s limitations. Five studies were identified that suggested an associa-
Like other NSAIDs, ketorolac is responsible for 2 catego- tion between ketorolac and bleeding,7,11,24,30,31 including
ries of side effects, those that are predictable and caused a frequently cited article from 1995, which was one of the
by the inhibition of prostaglandins, and those that are un- first studies to demonstrate the adverse hemostatic effects
predictable and caused for unknown reasons. Numerous of ketorolac in pediatric patients.24 In this study, addition-
studies demonstrate that NSAIDs’ suppression of prosta- al hemostatic measures (eg, packing with phenylephrine)
glandin synthesis can result in gastrointestinal ulcerations were required more frequently in the ketorolac group than
and erosions, nephrotoxicity, and abnormal bleeding.26-28 the acetaminophen group (8 vs 1, P = .012). Furthermore,
However, most of these studies did not focus on pediatric measured blood loss was found to be greater in patients
patients, nor did they test short-term intraoperative use of who received ketorolac than those who did not (3 ± 2
IV ketorolac. mL/kg vs 1 ± 1 mL/kg, P = .025). Although the blood loss
• Side Effects. The most troublesome side effect of ke- in the ketorolac group was deemed clinically significant
torolac is the potential for hemorrhage due to blockade because it required extra time and work for the otolaryn-
of the COX-1 system. A 2001 comprehensive review of gologist to correct (the study labeled the bleeding “nui-
the risks and benefits of NSAID use in children speci- sance bleeding”), there were no effects on hemodynamic
fied that ketorolac has been studied primarily in children compromise or patient morbidity.24 Details of the study
older than 1 year of age undergoing minor surgeries such appear in the Table. Similarly, a randomized, prospec-
as tonsillectomy, strabismus correction, myringotomy, tive, placebo-controlled study of 90 children undergoing
hernia repair, and dental work.26 The studies reviewed elective general, orthopedic, or genitourinary procedures
include IV ketorolac administered preoperatively or found that compared with bleeding times before adminis-
postoperatively as a single dose ranging from 0.5 to 1.5 tration of a single dose of 0.75 mg/kg intramuscular (IM)
mg/kg. Although many studies found no increased risk ketorolac, bleeding times at 180 minutes after study drug
of hemorrhage after ketorolac administration, several administration increased 53 ± 75 seconds (P = .006).30
described a correlation between ketorolac administra- The ketorolac groups’ mean bleeding time was still within
tion and postoperative hemorrhage. The authors of the the normal range and no bleeding problems or adverse
review article recommended that during surgeries with effects occurred during the study. Likewise, a chart review
the potential for substantial blood loss, such as tonsil- of 258 adult and pediatric patients undergoing tonsillecto-
lectomy, ketorolac may be administered, 0.5 to 1.5 mg/ my with or without adenoidectomy reported an increased
kg, postoperatively after hemostasis has been achieved. incidence of postoperative hemorrhage, operationalized as
Only a handful of studies have examined the use of ke- an unquantified amount of bleeding requiring surgical or
torolac in children undergoing orthopedic, genitourinary, medical intervention, in patients treated with periopera-
cardiac, or reconstructive surgeries, but notably there are tive IV ketorolac: 10.1% in the ketorolac group vs 2.2% in
no reports of any increase in bleeding complications in the narcotic analgesia group.31
these more extensive procedures.26 In addition to the 3 studies discussed in the previous
T
he AANA needs photos of CRNAs giving anesthesia for use in
periodicals, brochures, Nurse Anesthetists Week materials, on the
website, and for other purposes. Photos can be of any type of procedure
in any type of setting. Please send photos on a CD to Christopher Bettin,
Senior Director, Communications, AANA, 222 S. Prospect Ave., Park Ridge, IL
60068, or by using www.yousendit.com, www.dropbox.com or any similar
web based electronic delivery system.
Photo Tips
1. Photos should be high quality, high-resolution (300 pixels per inch).
Photos taken with cell phones generally are not high-enough quality for
publication.
2. Providers in photos must follow practice guidelines, that is, wear masks,
caps, appropriate eye protection, and remove jewelry.
3. It’s best if you center the key elements of the photo (for easier cropping to
fit space needs).
4. Avoid overly graphic images or procedures.
5. Obtain signed photo releases from all those in the photo.