Homework #8

This is HCS class, please answer all of the questions. Please use simple words and easy English

A Double-Blind
Evaluation
of Ketorolac Tromethamine
Versus Acetaminophen
in Pediatric Tonsillectomy:
Analgesia
and Bleeding
Lynn M. Rusy, MD, Constance S. Houck, MD, Lorna J. Sullivan, RN, Laurie
Dwight T. Jones, MD, Trevor J. McGill, MD, and Charles B. Berde, MD
Departments
of Anaesthesia
and Otolaryngology,
Children’s
Downloaded from https://journals.lww.com/anesthesia-analgesia by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3n4/ufkX3x2e4pOdG1WcI42hGvqSM7mrQrzfp+qftGgyv/TckawHmQA== on 10/26/2018
The study was designed to compare intravenous
ketorolac to rectal acetaminophen
for analgesia and
bleeding
in pediatric patients undergoing
tonsillectomy. We studied 50 patients, aged 2-15 yr undergoing tonsillectomy
with or without adenoidectomy.
In a randomized,
prospective
double-blind
fashion,
patients were assigned to receive either ketorolac (1
mg/kg) or rectal acetaminophen
(35 mg/kg). Bleeding was evaluated by measuring intraoperative
blood
loss and noting extra measures required
to obtain
hemostasis. Bleeding times were also measured before and during surgery. Pain was evaluated using a
standard objective pain score for the first 3 h. Persistent pain was treated with morphine,
acetaminophen, and codeine and recorded for 24 h. Blood for
determination
of acetaminophen
levels was drawn at
20 and 40 min after the administration
of study drugs.
everal analgesic trials have found ketorolac to be
either as effective or more effective for relief of
moderate to severe pain than morphine (l-3).
Moreover, it is associated with less sedation, respiratory depression, and nausea than opioid analgesics
(4). Clinical trials have shown its efficacy in children
and adults, and its pharmacokinetics have been established for children as young as 4 yr of age (5-6). Side
effects have been rare in pediatric patients treated
with ketorolac perioperatively.
A clinical study at
Children’s Hospital in Boston showed no serious adverse reactions in administration to more than 380
patients (7).
S
This work was supported
by CHMC,
Anesthesia
Foundation
at
Boston Children’s
Hospital.
Presented
in part at the American
Academy
of Pediatrics,
Anesthesia Division,
April 1994.
Accepted
for publication
August
18, 1994.
Address
correspondence
and reprint
requests to Lynn M. Rusy,
MD, Children’s
Hospital
of Wisconsin
Anesthesia
Department,
9000
West Wisconsin
Avenue,
PO Box 1997, Milwaukee,.WI
53201.
Hospital,
Anesth
Analg
1995;80:226-9
MD,
Boston, Massachusetts
Pain scores were not significantly
different between
the ketorolac and acetaminophen
groups. The majority of patients in both groups required
additional
opioid in the postoperative
period. Acetaminophen
levels were all less than the therapeutic range. Intraoperative bleeding times were normal in all patients,
but blood loss was significantly
higher in the ketorolac group (2.67 mL/kg) compared to the acetaminophen group (1.44 mL/kg),
P = 0.025. Significantly
more measures to achieve hemostasis were required
in the ketorolac group (P = 0.012). We conclude that
ketorolac is no more effective than high-dose rectal
acetaminophen
for analgesia in the patient undergoing tonsillectomy.
Hemostasis during tonsillectomy
was significantly
more difficult to achieve in patients
receiving ketorolac.
(Anesth Analg 1995;80:226-9)
Concern about the use of ketorolac for patients undergoing tonsillectomy has revolved around its effect
on platelet aggregation and clinical bleeding (8). Postoperative bleeding has been reported in up to 3% of
patients undergoing tonsillectomy (9). In a study of
healthy adults, ketorolac produced a prolongation of
the bleeding time but no clinical bleeding was noted
(10). However, one case of hemorrhage after intramuscular ketorolac (11) and three other casesof postoperative gastrointestinal bleeding in adult patients have
been reported (12). Bean et al. (13) reported a study of
86 pediatric patients that showed significant (P = 0.04)
increases in bleeding times 180 min after the administration of ketorolac (13). The manufacturer of ketorolac warns that postoperative hematomas and other
signs of wound bleeding have been reported with the
perioperative use of ketorolac. The purpose of this
study was to compare the analgesic effectiveness of
intravenous (IV) ketorolac (1 mg/kg) with rectal acetaminophen (35 mg/kg) for patients undergoing tonsillectomy and to evaluate the effects of ketorolac on
clinical bleeding.
01995
226
A. Ohlms,
by the International
Anesthesia
Research
Society
0003-2999/95/$5.00
ANESTH
ANALG
1995;80:226-9
Methods
Fifty healthy ASA physical status I or II patients, aged
2-15 yr who were scheduled to undergo tonsillectomy
with or without
adenoidectomy
were enrolled in the
study. This study was approved by our committee on
clinical investigation
and written,
informed consent
was obtained from each child’s parent. Indications for
tonsillectomy
included obstructive
adenotonsillar
hypertrophy
(30 patients), obstructive
sleep apnea (17
patients), and recurrent tonsillitis (3 patients). Patients
were excluded who had known renal dysfunction,
egg
allergy, bleeding disorder,
or a family history of a
bleeding diathesis. All patients enrolled in this study
had normal coagulation indices, including prothrombin time, partial thromboplastin
time, hematocrit,
platelet count, and bleeding time preoperatively.
These tests are a standard part of the preoperative
preparation
for tonsillectomy
at this institution
and
were obtained at the preoperative
visit.
No premeditation
was administered.
All patients
received a standard anesthetic consisting of an inhalation induction with 02, N,O, and halothane. Anesthesia was maintained with N,O and 0, in a 70/30
ratio and IV propofol
(75-300 pkg-ismin-‘).
Atracurium (0.5 mg/kg)
was administered
to facilitate tracheal intubation and reversal of neuromuscular
blockage was accomplished
with neostigmine (0.05 mg/kg)
and glycopyrrolate
(0.01 mg/kg).
The tracheas of all
patients were extubated after the return of spontaneous respiration
and eye opening. No opioids were
administered
either pre- or intraoperatively.
Patients were randomized
to receive either ketorolac 1 .O mg/kg IV (Group I) or rectal acetaminophen
35
mg/kg (Group II) after IV placement. Acetaminophen
suppositories
(120 mg or 650 mg) were used, and
pieces were weighed to accurately approximate
the
calculated dose. There were 25 patients in each group.
Those receiving ketorolac (Group I> had a simulated
rectal examination
at the time of the IV drug administration.
Group II patients received IV saline after
placement of the IV catheter. Bleeding times were
performed
by one investigator
blinded to the treatment group 20 min after the IV study drug was administered.
Bleeding times were measured with the
standard template scalpel blade technique. Blood for
determination
of acetaminophen levels were drawn in
all patients at 20 and 40 min after drug administration.
Levels were measured in an Abbott TDX using fluorescent polarization
immune assay.
All operations
were performed
by one of three
surgeons
using a standardized
surgical technique.
The 50 patients were divided
equally among the
surgeons. The adenoids were removed under direct
vision using a curette. Hemostasis
was maintained
with nasopharyngeal
packs, placed for 5 min. Each
KETOROLAC
PEDIATRIC
ANESTHESIA
RUSY ET AL.
OR ACETAMINOPHEN
IN TONSILLECTOMY
227
tonsil was removed using electrocautery
alternating
between
“cutting”
and “coagulation”
modes. After
tonsil removal, bleeding sites were cauterized
and
packed with gauze. Persistent bleeding in either bed
was treated with additional
hemostatic
means, including
higher electrocautery
settings,
additional
packing with neosynephrine,
use of oxymetazoline
hydrochloride
spray, and microfibrillar
collagen hemostat. Additional
hemostatic measures necessary to
control surgical bleeding were prospectively
recorded
on patient data forms. Blood loss was measured in
calibrated suction canisters.
Pain was evaluated using an objective pain score
(OF’S) recorded by two observers who were unaware
of the treatment. The pain score used was developed
at Children’s
National Medical Center and takes into
account blood pressure, crying, agitation, movement,
and verbal report (14). The first OPS score was performed immediately upon emergence from anesthesia
and then 30 min, 1 h, 2 h, and 3 h postoperatively.
Morphine
sulfate IV was given in a dose of 0.05
mg/kg and pain scores reassessed every 5 min until a
score of less than five was achieved. Once the child
was able to tolerate oral fluids, pain was treated with
acetaminophen
with or without
codeine on an asneeded basis by the ward nurse. Six hours (two halflives) were allowed to pass before more acetaminophen was given after the rectal dose in the operating
room. Cumulative
morphine, acetaminophen,
and codeine doses were recorded for the first 24 h.
Requirements
for one or more additional hemostatic
measures were coded as binary data (yes or no) and
compared using a two-tailed
Fisher’s exact test. Operative blood loss (mL/kg)
was compared by an unpaired t-test. The difference in bleeding times (between pre- and intraoperative
values) for each group
were compared separately
by the Wilcoxon
signed
rank test. OPS scores were compared between groups
for each time period by a Mann-Whitney
U-test. The
amount (mg/kg)
of morphine,
acetaminophen,
and
codeine required to treat pain were compared statistically by an unpaired t-test. P values < 0.05 were considered significant. Results There was no difference in ASA status or mean age between the two groups. OF’S scores immediately and at 30 min, 1 h, and 3 h did not differ between groups (Table 1). OPS scores at 2 h were statistically lower in the ketorolac group but the clinical significance of this isolated finding is minimal because the median score is < 1 for each group. The blood acetaminophen levels were all below therapeutic range. Most 20-min levels were undetectable or < 2 mg/L and the highest level at 40 min was 7.3 mg/L. Therapeutic range is lo-25 228 PEDIATRIC KETOROLAC Table 1. Objective ANESTHESIA RUSY OR ACETAMINOPHEN ET AL. IN TONSILLECTOMY ANESTH ANALG 1995;80:226-9 Pain Score Values Group Immediate 30 min lh 2h 3h (2.7:-g) (l-22.25) (OL (O”1, (Ok (3225) 0.814 (l-32.25) 0.604 cos 0.363 (O& 0.006 (OL 0.337 Ketorolac Acetaminophen P value Values are median scores with 25th and 75th percentile in parentheses. mg/L and toxic range is > 120 mg/L. The majority of
patients in both groups required additional morphine
or codeine and the amounts did not differ significantly
between the two groups (Table 2). Additional acetaminophen administered to Group II (acetaminophen)
was significantly higher than that given to Group I
(ketorolac). Measured blood loss was significantly
more (P = 0.025) in the ketorolac group compared to
the acetaminophen group (Table 2). Bleeding times
increased between pre- and intraoperative tests in
both groups. No intraoperative bleeding times were
increased above normal (2-8 min) in either group
(Table 3). Eight of 25 patients (32%) who received
ketorolac required extra measures to obtain hemostasis versus only one of the patients (4%) who received
acetaminophen, P = 0.0124 (Table 2). No patient in
either group required reoperation for postoperative
bleeding.
Discussion
In this study, IV ketorolac given intraoperatively to
patients undergoing tonsillectomy was associated
with more difficulty obtaining hemostasis and did not
demonstrate improved analgesia compared to rectal
acetaminophen. Intraoperative bleeding times significantly increased in the patients who received ketorolac but were still within the normal range. Nevertheless, a greater number of additional methods were
needed to obtain a bloodless field in patients receiving
ketorolac versus those receiving acetaminophen. This
is the first report of increased clinical bleeding in the
pediatric surgical patient after ketorolac use and probably indicates that platelet function was not normal.
Although there was no demonstrable patient morbidity as a result of the additional clinical bleeding in the
ketorolac group, extra neosynephrine packing requires additional surgical time and synthetic collagen
is quite expensive (approximately $200 at this institution). This surgical bleeding, while not associated with
hemodynamic compromise or patient morbidity, is
considered “nuisance” bleeding by otolaryngologists.
Although no patient returned to the operating room
for control of bleeding in this study, in a larger series
of patients, reoperation for persistent bleeding might
be shown to be more common when ketorolac is used.
Table 2. Additional
Morphine,
Acetaminophen,
Codeine Required and Blood Loss
Ketorolac
Additional
morphine
(mg/ kg)
Additional
acetaminophen
(mgkg)
Additional
codeine
(mg/kg)
EBL (mL/kg)
Extra hemostatic
measures (n)
Values are mean
EBL = estimated
Table
Acetaminophen
0.12 + 0.14
0.83
35 + 17
45 -c 14
0.02
1.5 +
2-cl
0.14
l&l
1
0.025
0.0124
Preoperative
BT (min)
Intraoperative
BT (mix-r)
P
(325)
@-YO,
(3Y5)
(32
1.2
2 SD.
blood loss.
Times
Ketorolac
0.01
Acetaminophen
Values are median
BT = Ivy template
P value
0.11 2 0.12
3?2
8
3. Bleeding
Group
and
0.42
with 25th and 75th
bleeding
time.
percentiles
in parentheses.
This possibility would have to be tested in a series of
hundreds of patients given a reoperative rate for
bleeding of 2% to 4% (9).
More importantly, acetaminophen 35 mg/kg rectally produced similar analgesia postoperatively as
ketorolac 1 mg/kg. This dose of acetaminophen was
chosen based on the study by Gaudreault et al. (15)
who showed that rectal dosing of 20 mg/kg resulted
in subtherapeutic plasma concentrations. Acetaminophen levels in this study were all well below therapeutic ranges despite the higher dose (35 mg/kg).
Gaudreault et al. (15) and Nahata et al. (16) showed
that rectal acetaminophen results in erratic absorption.
There are limited pharmacokinetic data regarding the
absorption of rectal acetaminophen suppositories, and
it appears that higher doses than are currently recommended may be more effective for analgesia (17). Gaudreault et al. (15) also showed that administration of
ANESTH
ANALG
1995;80:226-9
KETOROLAC
acetaminophen solution resulted in peak concentrations at 120 min. Our levels were drawn at 20 and 40
min because the operative procedures were brief. The
highest level we found at 40 min was 7.3 mg/L. If the
peak levels were twice what we found at 40 min, they
would still be below the therapeutic range of lo-25
mg/L. Our data therefore indicate that higher rectal
doses do not result in toxic levels of acetaminophen at
40 min. Additional studies are required to determine
the true peak levels of this dose of rectal acetaminophen. It should be pointed out that there is a significant cost difference between ketorolac and acetaminophen. At this institution, one 60-mg dose of ketorolac
costs $5.85 and a single rectal suppository of 650 mg of
acetaminophen costs 15 cents.
Neither acetaminophen nor ketorolac at the doses
given were sufficient to provide complete analgesia,
as most patients required morphine supplementation
in the recovery room and acetaminophen with codeine
on the wards. Both groups needed statistically similar
amounts of additional morphine and codeine to treat
persistent pain. The acetaminophen group required
statistically more acetaminophen for analgesia on the
ward. This finding could be explained by the half-lives
of the study drugs: 4.5 h for ketorolac and 2.5 h for
acetaminophen (18). Patients receiving acetaminophen
might therefore require supplemental analgesia
sooner and more frequently than those receiving ketorolac. Acetaminophen does not have the additional
antiinflammatory effect of ketorolac.
In patients with documented sleep apnea, where
potent opioids are best avoided, perhaps a single large
dose of inexpensive rectal acetaminophen supplemented with codeine may provide sufficient analgesia
with less risk of IV opioid-induced respiratory depression. The results of our study demonstrate that ketorolac increased bleeding in patients undergoing tonsillectomy. Acetaminophen, with no effect on platelet
function, is an equally effective analgesic in this group
of pediatric patients.
The authors would like to thank Dr. Robert
Palmisano
for their help with computer
Thanks also to Minna Levine for assistance
Wilder and Dr. Barbara
formatting
and review.
with statistical
analysis.
PEDIATRIC
ANESTHESIA
RUSY ET AL.
OR ACETAMINOPHEN
IN TONSILLECTOMY
229
References
1. Yee JP, Koshiver
MS, Allbon
C, et al. Comparison
of intramuscular ketorolac
tromethamine
and morphine
sulfate for analgesia of pain after major surgery.
Pharmacotherapy
1986;6:253-61.
2. O’Hara
D, Fragen RJ, Kinzer
M, et al. Ketorolac
tromethamine
as compared
with morphine
sulfate for treating
postoperative
pain. Clin Pharmacol
Ther 1987;41(5):556-61.
3. Olkkola
KT, Maunuksela
EL. The pharmacokinetics
of postoperative
intravenous
ketorolac
tromethamine
in children.
Br J
Clin Pharmacol
1991;31:182-4.
4. Bravo LJ, Mattie H, Spierdijk
J, et al. The effects on ventilation
of
ketorolac
in comparison
with morphine.
Eur J Clin Pharmacol
1988;35:491-4.
5. Watcha MF, Jones MB, Lagueruela
RG, et al. Comparison
of
ketorolac
and morphine
as adjuvants
during
pediatric
surgery.
Anesthesiology
1992;76:368-72.
6. Maunuksela
EL, Kokki
H, Bullingham
RE. Comparison
of intravenous
ketorolac
with morphine
for postoperative
pain in
children.
Clin Pharmacol
Ther 1992;52:436-43.
7. Houck CS, Wilder RT, McDermott
J, et al. Intravenous
ketorolac
in children
following
surgery:
safety and cost savings with a
unit dosing system. Anesthesiology
1993;79:1139A.
8. Roe RL, Bruno JJ, Ellis DJ. Effects of a new nonsteroidal
antiinflammatory
agent on platelet function
in male and female subjects. Clin Pharmacol
Ther 1981;29:277.
9. Handler
SD, Miler L, Richmond
KH, et al. Post-tonsillectomy
hemorrhage:incidence,
prevention
and management.
Laryngoscope 1986;96:1243-7.
10. Conrad
KA, Fagan TC, Mackie
MJ, et al. Effects of ketorolac
tromethamine
on hemostasis
in volunteers.
Clin Pharmacol
Ther 1988;43(3):542-7.
11. O’Leary
M, Martin
P, McLean
AS. Oliguria
and haemorrhage
after intramuscular
injection
of ketorolac
tromethamine.
Med J
Aust 1993;158(10):719-20.
12. Steinberg
RB, Tessier EG. Gastrointestinal
bleeding
after administration
of ketorolac.
Anesthesiology
1993;79:1146.
13. Bean JD, Hunt R, Custer MD. Effects of ketorolac
on postoperative analgesia
and bleeding
time in children.
Anesthesiology
1993;79:1190A.
14. Hannallah
RS, Broadman
LM, Belman AB, et al. Comparison
of
caudal and ilioinguinal/iliohypogastric
nerve blocks for control
of post orchidopexy
pain in pediatric
ambulatory
surgery.
Anesthesiology
1987;66:832-4.
15. Gaudreault
P, Guay
J, Nicol J, et al. Pharmacokinetics
and
clinical efficacy of intrarectal
solution
of acetaminophen.
Can J
Anaesth
1988;35:149-52.
16. Nahata DE, Durell DE, Powell DA, et al. Pharmacokinetics
of
ibuprofen
in febrile children.
Eur J Clin Pharmacol
1991;40:
427-S.
17. Hopkins
CS, Underhill
S, Booker
PD. Pharmacokinetics
of
paracetamol
after cardiac surgery.
Arch Dis Child 1990;65(9):
971-6.
18. Rumack
BH. Chemical
and drug poisoning.
In: Berhrman
RE,
Vaughan
VC III, eds. Nelson
textbook
of pediatrics.
Philadelphia:
WB Saunders,
1983:1788-g.
HCS 418: Statistics for Health Professions
Homework #8
Directions: Use the following study by Rusy et al. (1995) and use this study to answer the
following questions (the PDF of the article is uploaded).
Rusy, L. M., Houck, C. S., Sullivan, L. J., Ohlms, L. A., Jones, D. T., McGill, T. J., & Berde, C.
B. (1995). A double-blind evaluation of ketorolac tromethamine versus acetaminophen in
pediatric tonsillectomy: Analgesia and bleeding. Anesthesia and Analgesia, 80, 226-229.
Retrieved from
1. Who/what is the population in this study?
2. What was the purpose of the study?
3. What is the independent variable(s) in this study? What is the level of measurement?
4. What are the dependent variables in this study? What is their level of measurement?
5. What is the level of significance () that the researchers have determined? How would you put
this into words?
6. Write a null hypothesis
7. Write a non-directional alternative hypothesis.
8. Write a directional alternative hypothesis. Remember to consider the introduction to the study
on page 226 for background information.
9. The researchers conducted an unpaired t-test, which is the same an independent samples t-test.
Were they correct in conducting this statistical test? Why or why not?
10. What is the critical value of t that we would compare the t statistic to for a) the nondirectional alternative hypothesis and b) the alternative directional hypothesis? How did you
determine this?
11. Is there a difference in the operative blood loss (or EBL = estimated blood loss) between the
ketorolac and acetaminophen groups? Explain your answer.
12. The t statistic for operative blood loss (or EBL = estimated blood loss) is 4.474. Are the
results statistically significant? How do you know? What does statistical significance mean?
1 of 4
13. Should the researchers accept or reject the null hypothesis? Explain your answer.
14. How would we put the results into words?
2 of 4
HCS 418: Statistics for Health Professions
Homework #8
Directions: Use the following study by Rusy et al. (1995) and use this study to answer the
following questions (the PDF of the article is uploaded).
Rusy, L. M., Houck, C. S., Sullivan, L. J., Ohlms, L. A., Jones, D. T., McGill, T. J., & Berde, C.
B. (1995). A double-blind evaluation of ketorolac tromethamine versus acetaminophen in
pediatric tonsillectomy: Analgesia and bleeding. Anesthesia and Analgesia, 80, 226-229.
Retrieved from
1. Who/what is the population in this study?
2. What was the purpose of the study?
3. What is the independent variable(s) in this study? What is the level of measurement?
4. What are the dependent variables in this study? What is their level of measurement?
5. What is the level of significance () that the researchers have determined? How would you put
this into words?
6. Write a null hypothesis
7. Write a non-directional alternative hypothesis.
8. Write a directional alternative hypothesis. Remember to consider the introduction to the study
on page 226 for background information.
9. The researchers conducted an unpaired t-test, which is the same an independent samples t-test.
Were they correct in conducting this statistical test? Why or why not?
10. What is the critical value of t that we would compare the t statistic to for a) the nondirectional alternative hypothesis and b) the alternative directional hypothesis? How did you
determine this?
11. Is there a difference in the operative blood loss (or EBL = estimated blood loss) between the
ketorolac and acetaminophen groups? Explain your answer.
12. The t statistic for operative blood loss (or EBL = estimated blood loss) is 4.474. Are the
results statistically significant? How do you know? What does statistical significance mean?
1 of 4
13. Should the researchers accept or reject the null hypothesis? Explain your answer.
14. How would we put the results into words?
2 of 4
A Double-Blind
Evaluation
of Ketorolac Tromethamine
Versus Acetaminophen
in Pediatric Tonsillectomy:
Analgesia
and Bleeding
Lynn M. Rusy, MD, Constance S. Houck, MD, Lorna J. Sullivan, RN, Laurie
Dwight T. Jones, MD, Trevor J. McGill, MD, and Charles B. Berde, MD
Departments
of Anaesthesia
and Otolaryngology,
Children’s
Downloaded from https://journals.lww.com/anesthesia-analgesia by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3n4/ufkX3x2e4pOdG1WcI42hGvqSM7mrQrzfp+qftGgyv/TckawHmQA== on 10/26/2018
The study was designed to compare intravenous
ketorolac to rectal acetaminophen
for analgesia and
bleeding
in pediatric patients undergoing
tonsillectomy. We studied 50 patients, aged 2-15 yr undergoing tonsillectomy
with or without adenoidectomy.
In a randomized,
prospective
double-blind
fashion,
patients were assigned to receive either ketorolac (1
mg/kg) or rectal acetaminophen
(35 mg/kg). Bleeding was evaluated by measuring intraoperative
blood
loss and noting extra measures required
to obtain
hemostasis. Bleeding times were also measured before and during surgery. Pain was evaluated using a
standard objective pain score for the first 3 h. Persistent pain was treated with morphine,
acetaminophen, and codeine and recorded for 24 h. Blood for
determination
of acetaminophen
levels was drawn at
20 and 40 min after the administration
of study drugs.
everal analgesic trials have found ketorolac to be
either as effective or more effective for relief of
moderate to severe pain than morphine (l-3).
Moreover, it is associated with less sedation, respiratory depression, and nausea than opioid analgesics
(4). Clinical trials have shown its efficacy in children
and adults, and its pharmacokinetics have been established for children as young as 4 yr of age (5-6). Side
effects have been rare in pediatric patients treated
with ketorolac perioperatively.
A clinical study at
Children’s Hospital in Boston showed no serious adverse reactions in administration to more than 380
patients (7).
S
This work was supported
by CHMC,
Anesthesia
Foundation
at
Boston Children’s
Hospital.
Presented
in part at the American
Academy
of Pediatrics,
Anesthesia Division,
April 1994.
Accepted
for publication
August
18, 1994.
Address
correspondence
and reprint
requests to Lynn M. Rusy,
MD, Children’s
Hospital
of Wisconsin
Anesthesia
Department,
9000
West Wisconsin
Avenue,
PO Box 1997, Milwaukee,.WI
53201.
Hospital,
Anesth
Analg
1995;80:226-9
MD,
Boston, Massachusetts
Pain scores were not significantly
different between
the ketorolac and acetaminophen
groups. The majority of patients in both groups required
additional
opioid in the postoperative
period. Acetaminophen
levels were all less than the therapeutic range. Intraoperative bleeding times were normal in all patients,
but blood loss was significantly
higher in the ketorolac group (2.67 mL/kg) compared to the acetaminophen group (1.44 mL/kg),
P = 0.025. Significantly
more measures to achieve hemostasis were required
in the ketorolac group (P = 0.012). We conclude that
ketorolac is no more effective than high-dose rectal
acetaminophen
for analgesia in the patient undergoing tonsillectomy.
Hemostasis during tonsillectomy
was significantly
more difficult to achieve in patients
receiving ketorolac.
(Anesth Analg 1995;80:226-9)
Concern about the use of ketorolac for patients undergoing tonsillectomy has revolved around its effect
on platelet aggregation and clinical bleeding (8). Postoperative bleeding has been reported in up to 3% of
patients undergoing tonsillectomy (9). In a study of
healthy adults, ketorolac produced a prolongation of
the bleeding time but no clinical bleeding was noted
(10). However, one case of hemorrhage after intramuscular ketorolac (11) and three other casesof postoperative gastrointestinal bleeding in adult patients have
been reported (12). Bean et al. (13) reported a study of
86 pediatric patients that showed significant (P = 0.04)
increases in bleeding times 180 min after the administration of ketorolac (13). The manufacturer of ketorolac warns that postoperative hematomas and other
signs of wound bleeding have been reported with the
perioperative use of ketorolac. The purpose of this
study was to compare the analgesic effectiveness of
intravenous (IV) ketorolac (1 mg/kg) with rectal acetaminophen (35 mg/kg) for patients undergoing tonsillectomy and to evaluate the effects of ketorolac on
clinical bleeding.
01995
226
A. Ohlms,
by the International
Anesthesia
Research
Society
0003-2999/95/$5.00
ANESTH
ANALG
1995;80:226-9
Methods
Fifty healthy ASA physical status I or II patients, aged
2-15 yr who were scheduled to undergo tonsillectomy
with or without
adenoidectomy
were enrolled in the
study. This study was approved by our committee on
clinical investigation
and written,
informed consent
was obtained from each child’s parent. Indications for
tonsillectomy
included obstructive
adenotonsillar
hypertrophy
(30 patients), obstructive
sleep apnea (17
patients), and recurrent tonsillitis (3 patients). Patients
were excluded who had known renal dysfunction,
egg
allergy, bleeding disorder,
or a family history of a
bleeding diathesis. All patients enrolled in this study
had normal coagulation indices, including prothrombin time, partial thromboplastin
time, hematocrit,
platelet count, and bleeding time preoperatively.
These tests are a standard part of the preoperative
preparation
for tonsillectomy
at this institution
and
were obtained at the preoperative
visit.
No premeditation
was administered.
All patients
received a standard anesthetic consisting of an inhalation induction with 02, N,O, and halothane. Anesthesia was maintained with N,O and 0, in a 70/30
ratio and IV propofol
(75-300 pkg-ismin-‘).
Atracurium (0.5 mg/kg)
was administered
to facilitate tracheal intubation and reversal of neuromuscular
blockage was accomplished
with neostigmine (0.05 mg/kg)
and glycopyrrolate
(0.01 mg/kg).
The tracheas of all
patients were extubated after the return of spontaneous respiration
and eye opening. No opioids were
administered
either pre- or intraoperatively.
Patients were randomized
to receive either ketorolac 1 .O mg/kg IV (Group I) or rectal acetaminophen
35
mg/kg (Group II) after IV placement. Acetaminophen
suppositories
(120 mg or 650 mg) were used, and
pieces were weighed to accurately approximate
the
calculated dose. There were 25 patients in each group.
Those receiving ketorolac (Group I> had a simulated
rectal examination
at the time of the IV drug administration.
Group II patients received IV saline after
placement of the IV catheter. Bleeding times were
performed
by one investigator
blinded to the treatment group 20 min after the IV study drug was administered.
Bleeding times were measured with the
standard template scalpel blade technique. Blood for
determination
of acetaminophen levels were drawn in
all patients at 20 and 40 min after drug administration.
Levels were measured in an Abbott TDX using fluorescent polarization
immune assay.
All operations
were performed
by one of three
surgeons
using a standardized
surgical technique.
The 50 patients were divided
equally among the
surgeons. The adenoids were removed under direct
vision using a curette. Hemostasis
was maintained
with nasopharyngeal
packs, placed for 5 min. Each
KETOROLAC
PEDIATRIC
ANESTHESIA
RUSY ET AL.
OR ACETAMINOPHEN
IN TONSILLECTOMY
227
tonsil was removed using electrocautery
alternating
between
“cutting”
and “coagulation”
modes. After
tonsil removal, bleeding sites were cauterized
and
packed with gauze. Persistent bleeding in either bed
was treated with additional
hemostatic
means, including
higher electrocautery
settings,
additional
packing with neosynephrine,
use of oxymetazoline
hydrochloride
spray, and microfibrillar
collagen hemostat. Additional
hemostatic measures necessary to
control surgical bleeding were prospectively
recorded
on patient data forms. Blood loss was measured in
calibrated suction canisters.
Pain was evaluated using an objective pain score
(OF’S) recorded by two observers who were unaware
of the treatment. The pain score used was developed
at Children’s
National Medical Center and takes into
account blood pressure, crying, agitation, movement,
and verbal report (14). The first OPS score was performed immediately upon emergence from anesthesia
and then 30 min, 1 h, 2 h, and 3 h postoperatively.
Morphine
sulfate IV was given in a dose of 0.05
mg/kg and pain scores reassessed every 5 min until a
score of less than five was achieved. Once the child
was able to tolerate oral fluids, pain was treated with
acetaminophen
with or without
codeine on an asneeded basis by the ward nurse. Six hours (two halflives) were allowed to pass before more acetaminophen was given after the rectal dose in the operating
room. Cumulative
morphine, acetaminophen,
and codeine doses were recorded for the first 24 h.
Requirements
for one or more additional hemostatic
measures were coded as binary data (yes or no) and
compared using a two-tailed
Fisher’s exact test. Operative blood loss (mL/kg)
was compared by an unpaired t-test. The difference in bleeding times (between pre- and intraoperative
values) for each group
were compared separately
by the Wilcoxon
signed
rank test. OPS scores were compared between groups
for each time period by a Mann-Whitney
U-test. The
amount (mg/kg)
of morphine,
acetaminophen,
and
codeine required to treat pain were compared statistically by an unpaired t-test. P values < 0.05 were considered significant. Results There was no difference in ASA status or mean age between the two groups. OF’S scores immediately and at 30 min, 1 h, and 3 h did not differ between groups (Table 1). OPS scores at 2 h were statistically lower in the ketorolac group but the clinical significance of this isolated finding is minimal because the median score is < 1 for each group. The blood acetaminophen levels were all below therapeutic range. Most 20-min levels were undetectable or < 2 mg/L and the highest level at 40 min was 7.3 mg/L. Therapeutic range is lo-25 228 PEDIATRIC KETOROLAC Table 1. Objective ANESTHESIA RUSY OR ACETAMINOPHEN ET AL. IN TONSILLECTOMY ANESTH ANALG 1995;80:226-9 Pain Score Values Group Immediate 30 min lh 2h 3h (2.7:-g) (l-22.25) (OL (O”1, (Ok (3225) 0.814 (l-32.25) 0.604 cos 0.363 (O& 0.006 (OL 0.337 Ketorolac Acetaminophen P value Values are median scores with 25th and 75th percentile in parentheses. mg/L and toxic range is > 120 mg/L. The majority of
patients in both groups required additional morphine
or codeine and the amounts did not differ significantly
between the two groups (Table 2). Additional acetaminophen administered to Group II (acetaminophen)
was significantly higher than that given to Group I
(ketorolac). Measured blood loss was significantly
more (P = 0.025) in the ketorolac group compared to
the acetaminophen group (Table 2). Bleeding times
increased between pre- and intraoperative tests in
both groups. No intraoperative bleeding times were
increased above normal (2-8 min) in either group
(Table 3). Eight of 25 patients (32%) who received
ketorolac required extra measures to obtain hemostasis versus only one of the patients (4%) who received
acetaminophen, P = 0.0124 (Table 2). No patient in
either group required reoperation for postoperative
bleeding.
Discussion
In this study, IV ketorolac given intraoperatively to
patients undergoing tonsillectomy was associated
with more difficulty obtaining hemostasis and did not
demonstrate improved analgesia compared to rectal
acetaminophen. Intraoperative bleeding times significantly increased in the patients who received ketorolac but were still within the normal range. Nevertheless, a greater number of additional methods were
needed to obtain a bloodless field in patients receiving
ketorolac versus those receiving acetaminophen. This
is the first report of increased clinical bleeding in the
pediatric surgical patient after ketorolac use and probably indicates that platelet function was not normal.
Although there was no demonstrable patient morbidity as a result of the additional clinical bleeding in the
ketorolac group, extra neosynephrine packing requires additional surgical time and synthetic collagen
is quite expensive (approximately $200 at this institution). This surgical bleeding, while not associated with
hemodynamic compromise or patient morbidity, is
considered “nuisance” bleeding by otolaryngologists.
Although no patient returned to the operating room
for control of bleeding in this study, in a larger series
of patients, reoperation for persistent bleeding might
be shown to be more common when ketorolac is used.
Table 2. Additional
Morphine,
Acetaminophen,
Codeine Required and Blood Loss
Ketorolac
Additional
morphine
(mg/ kg)
Additional
acetaminophen
(mgkg)
Additional
codeine
(mg/kg)
EBL (mL/kg)
Extra hemostatic
measures (n)
Values are mean
EBL = estimated
Table
Acetaminophen
0.12 + 0.14
0.83
35 + 17
45 -c 14
0.02
1.5 +
2-cl
0.14
l&l
1
0.025
0.0124
Preoperative
BT (min)
Intraoperative
BT (mix-r)
P
(325)
@-YO,
(3Y5)
(32
1.2
2 SD.
blood loss.
Times
Ketorolac
0.01
Acetaminophen
Values are median
BT = Ivy template
P value
0.11 2 0.12
3?2
8
3. Bleeding
Group
and
0.42
with 25th and 75th
bleeding
time.
percentiles
in parentheses.
This possibility would have to be tested in a series of
hundreds of patients given a reoperative rate for
bleeding of 2% to 4% (9).
More importantly, acetaminophen 35 mg/kg rectally produced similar analgesia postoperatively as
ketorolac 1 mg/kg. This dose of acetaminophen was
chosen based on the study by Gaudreault et al. (15)
who showed that rectal dosing of 20 mg/kg resulted
in subtherapeutic plasma concentrations. Acetaminophen levels in this study were all well below therapeutic ranges despite the higher dose (35 mg/kg).
Gaudreault et al. (15) and Nahata et al. (16) showed
that rectal acetaminophen results in erratic absorption.
There are limited pharmacokinetic data regarding the
absorption of rectal acetaminophen suppositories, and
it appears that higher doses than are currently recommended may be more effective for analgesia (17). Gaudreault et al. (15) also showed that administration of
ANESTH
ANALG
1995;80:226-9
KETOROLAC
acetaminophen solution resulted in peak concentrations at 120 min. Our levels were drawn at 20 and 40
min because the operative procedures were brief. The
highest level we found at 40 min was 7.3 mg/L. If the
peak levels were twice what we found at 40 min, they
would still be below the therapeutic range of lo-25
mg/L. Our data therefore indicate that higher rectal
doses do not result in toxic levels of acetaminophen at
40 min. Additional studies are required to determine
the true peak levels of this dose of rectal acetaminophen. It should be pointed out that there is a significant cost difference between ketorolac and acetaminophen. At this institution, one 60-mg dose of ketorolac
costs $5.85 and a single rectal suppository of 650 mg of
acetaminophen costs 15 cents.
Neither acetaminophen nor ketorolac at the doses
given were sufficient to provide complete analgesia,
as most patients required morphine supplementation
in the recovery room and acetaminophen with codeine
on the wards. Both groups needed statistically similar
amounts of additional morphine and codeine to treat
persistent pain. The acetaminophen group required
statistically more acetaminophen for analgesia on the
ward. This finding could be explained by the half-lives
of the study drugs: 4.5 h for ketorolac and 2.5 h for
acetaminophen (18). Patients receiving acetaminophen
might therefore require supplemental analgesia
sooner and more frequently than those receiving ketorolac. Acetaminophen does not have the additional
antiinflammatory effect of ketorolac.
In patients with documented sleep apnea, where
potent opioids are best avoided, perhaps a single large
dose of inexpensive rectal acetaminophen supplemented with codeine may provide sufficient analgesia
with less risk of IV opioid-induced respiratory depression. The results of our study demonstrate that ketorolac increased bleeding in patients undergoing tonsillectomy. Acetaminophen, with no effect on platelet
function, is an equally effective analgesic in this group
of pediatric patients.
The authors would like to thank Dr. Robert
Palmisano
for their help with computer
Thanks also to Minna Levine for assistance
Wilder and Dr. Barbara
formatting
and review.
with statistical
analysis.
PEDIATRIC
ANESTHESIA
RUSY ET AL.
OR ACETAMINOPHEN
IN TONSILLECTOMY
229
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