Ketorolac Use in Cardiovascular

Surgery
Presenter: Miley Nikirk, PharmD
IU Health PGY1 Pharmacy Resident

Research Mentor: Shelley Porter, PharmD, BCCCP

IU Health Critical Care Specialist

I have no actual or potential conflicts of interest in this

presentation.
 Ketorolac
Non-selective non-steroidal anti-inflammatory drug (NSAID)
Inhibition of COX-1 receptors decreases activation of thromboxane A2
Inhibition of COX-2 prevents the formation of prostacyclin
Contraindicated in cerebrovascular bleeding, history of peptic ulcer disease,
recent gastrointestinal (GI) bleeding or perforation
FDA black box warning for cardiovascular thrombotic events such as
myocardial infarction and stroke

Ketorolac Tromethamine IV, IM Injection Package Insert; Bedford Laboratories: 2009.

Nussmeier et al. N. Engl. J. Med. 2005, 352, 1081–1091.
Howard et al. Pharmacy. 2016, 4(3), 22.
Learning Assessment Question #1

Which of the following is a black box warning of ketorolac?

A. Hyperkalemia
B. Myocardial infarction
C. Hepatic impairment
D. CNS effects
Learning Assessment Question #1

Which of the following is a black box warning of ketorolac?

A. Hyperkalemia
B. Myocardial infarction
C. Hepatic impairment
D. CNS effects
 Ketorolac in Cardiovascular Surgery
Short-term use of ketorolac post-operatively
Two propensity-matched studies found ketorolac intermittent infusion at
15 – 30 mg every 6 hours was associated with decreased mortality and
improved graft patency in postoperative CABG
Retrospective cohort found no difference in mortality, myocardial
infarction or bleeding in ketorolac continuous infusion vs no ketorolac

Engoren et al. J. Cardiothorac. Vasc. Anesth. 2007, 21, 820–826.

Engoren et al. Ann. Thorac. Surg. 2001, 92, 603–609.
 Enhanced Recovery After Surgery
Enhanced recovery after surgery (ERAS) is an evidence-based process used
as a resource for institutions to implement
Reduce cost complications, length of stay, expedite recovery after surgery,
minimize pain postoperatively
Reduce opioid consumption
First ERAS study done in cardiac surgery patients did not include ketorolac
IU Health ERAS protocol in cardiovascular surgery does not include
ketorolac

.
Williams et al. The Journal of Thoracic and Cardiovascular Surgery. 2019, 157(5), 1881–1888.
 IU Health Methodist Hospital Cardiac Surgery ERAS
Tylenol 650 mg orally every 6 hours
Lidoderm patches
Gabapentin 100 mg orally three times per day
Tramadol 50 mg every 6 hours as needed for mild pain
Oxycodone 5 mg every 4 hours as needed for moderate pain
IV dilaudid or fentanyl as needed for severe/breakthrough pain until chest
tubes removed

.
Learning Assessment Question #2

Which of the following is a possible benefit of using ketorolac post

cardiovascular surgery?

A. Improve cardiovascular outcomes

B. Decrease gastrointestinal bleeding
C. Reduce opioid use
D. Reduce renal injuries
Learning Assessment Question #2

Which of the following is a possible benefit of using ketorolac post

cardiovascular surgery?

A. Improve cardiovascular outcomes

B. Decrease gastrointestinal bleeding
C. Reduce opioid use
D. Reduce renal injuries
Study Objective

Assess the efficacy of ketorolac for pain management in

non-emergency cardiovascular surgery patients

10
Primary and Secondary Outcomes

Opioid utilization over 72 hours postoperatively

measured by morphine milligram equivalents (MME)

Pain scores (average over 72 hours) Gastrointestinal (GI) bleed

Acute kidney injury (AKI) Total length of stay (LOS)

Clinically significant bleeding event (TIMI criteria)

11
Methods
 Retrospective chart review of patients at IU Health Methodist Hospital
from January 1, 2020 to September 15, 2020
Inclusion Criteria Exclusion Criteria
• Age ≥ 18 years • Pregnant women
• Non-emergent cardiovascular surgery that required a • Incarceration
sternotomy
• Cardiovascular surgery ERAS protocol
• Serum creatinine (SCr) measurement within 48 hours
of admission

12
 Statistics Plan

Power Calculation

• A mean value of total morphine milligram equivalents within 72 hours in

patients not receiving ketorolac of 90 MME (30 MME/day) is being used
• An expected 20% decrease in patients receiving ketorolac (72 MME) with a
standard deviation of 25 MME
• For a power of 80% and alpha level of 0.05, sample size required is
calculated to be approximately 60

Data Analysis

• Microsoft Excel (version 16.40)

Williams et al. The Journal of Thoracic and Cardiovascular Surgery 2019, 157(5), 1881–1888.
Ready et al. Anesthesiology 1994, 80, 1277–1286.
Etches et al. Anesth. Analg. 1995, 81, 1175–1180.
Statistics Plan
MME within 72 hours postoperative
(per 24 hours)
Mann-Whitney U test

Ketorolac group No ketorolac group

Continuous data
T-test or
Mann-Whitney U test

Categorical data
Chi-square test or
Fisher’s Exact test 14
Patient Selection 232 patients
identified: ERAS
protocol 1 patient did not meet
inclusion criteria
231 patients included

80 patients selected

Ketorolac group No ketorolac group

31 patients (38.8%) 49 patients (61.3%) 15
Baseline Characteristics

Ketorolac No ketorolac P-value

(n=31) (n=49)
Age, years 56 (38.3-63.5) 63 (53.5-70) 0.001
Male sex, n (%) 22 (73.3) 32 (65.3) 0.598
Weight, kg 89.5 (77.2-101.3) 88.3 (72.5-103.3) 0.449
SCr, mg/dL 0.94 (0.81-1.01) 0.94 (0.76-1.09) 0.266
Hemoglobin, g/dL 11.8 (10.6-13.3) 12.6 (11.2-13.7) 0.321
Platelets 225 (187-321) 222 (171-263) 0.177

* all continuous variables are reported as median (interquartile range)

16
 Baseline Characteristics (cont.)
Ketorolac No ketorolac P-value
(n=31) (n=49)
Comorbidities
Chronic kidney disease 1 (3.2) 9 (18.4) 0.046
Diabetes 6 (19.4) 24 (49.0) 0.008
History of GI bleed 0 (0) 4 (8.2) 0.103
History of myocardial
infarction 5 (16.1) 12 (24.5) 0.373
History of stroke 2 (6.5) 4 (8.2) 0.777
Prior opioid use
Illicit 7 (23.3) 2 (6.5) 0.003
Prescription 1 (2.0) 3 (6.1) 0.953

* all categorical data represented as number of patients, n (incidence %)

17
 Baseline Characteristics (cont.)

Ketorolac No ketorolac P-value

(n=31) (n=49)
Types of non-emergent cardiovascular surgery
Aortic ascending aneurysm 4 (12.9) 2 (4.1) 0.144
Aortic valve replacement 7 (22.6) 19 (38.8) 0.132
Coronary artery bypass graft 12 (38.7) 22 (44.9) 0.585
Mitral valve
replacement/repair 7 (22.6) 5 (10.2) 0.131
Other 10 (32.3) 18 (36.7) 0.683
* all categorical data represented as number of patients, n (incidence %)

18
 Ketorolac Dosing

Ketorolac
(n=31)
Ketorolac dose (mg/day) 56.0 (36.1-59.9)
Ketorolac total (mg) 120 (60-225)
Ketorolac frequency
As needed 7 (22.6)
Scheduled 28 (90.3)
* all continuous variables are reported as median (interquartile range)

19
 Primary & Secondary Outcomes
Ketorolac No ketorolac P-value
(n=31) (n=49)
Primary outcomes
MME per day 108 (34.3-132.5) 34.6 (22.1-57.9) 0.006
Secondary outcomes
Pain scores 4.3 (2.9-5.7) 3.5 (2.1-4.8) 0.118
AKI*, n (%) 3 (9.7) 7 (14.3) 0.544
Total length of stay (days) 6 (5.0-9.0) 7 (5.0-9.0) 0.702
GI bleed, n (%) 0 0 --
Clinically significant bleeding
event (TIMI criteria), n (%) 0 1 (2.0) 0.423

* all continuous variables are reported as median (interquartile range). AKI defined as KDIGO Stage 1 criteria or
new start RRT 20
Discussion
Ketorolac group received statistically significantly more MME
Possible sampling bias
⎻Ketorolac more likely to be used in more severe pain
⎻Illicit drug users were more likely to receive ketorolac
Heterogeneity of non-emergent cardiovascular surgeries
No statistically significant difference in bleeding events or acute kidney
injury in ketorolac group
Strengths and Limitations
Strengths
Baseline pain management medications similar
Addresses ketorolac utilization in ERAS protocols
Did not see increase adverse events

Limitations
Single center, retrospective chart review
Possible sampling bias
Did not look at opioids received in operating room
Conclusions
 MME within 72 hours of non-emergent cardiovascular surgery were
significantly greater in patients who received ketorolac than patients who
did not receive ketorolac

Additional studies are needed to assess for the potential role of ketorolac in
cardiovascular surgery patients and ERAS protocols
Exclude illicit drug users
Only include illicit drug users
References
1. Bedford Laboratories. Ketorolac Tromethamine IV, IM Injection Package Insert; Bedford
Laboratories: Bedford, OH, USA, 2009.
2. Nussmeier, N.A.; Whelton, A.A.; Brown, M.T.; Langford, R.M.; Hoeft, A.; Parlow, J.L.; Boyce,
S.W.; Verburg, K.M. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac
surgery. N. Engl. J. Med. 2005, 352, 1081–1091.
3. Howard, M., Warhurst, R., & Sheehan, C. (2016). Safety of Continuous Infusion Ketorolac in
Postoperative Coronary Artery Bypass Graft Surgery Patients. Pharmacy, 4(3), 22.
4. Engoren, M.C.; Habib, R.H.; Zacharias, A.; Dooner, J.; Schwann, T.A.; Riordan, C.J.; Durham,
S.J.; Shah, A. Postoperative analgesia with ketorolac is associated with decreased mortality after
isolated coronary artery bypass graft surgery in patients already receiving aspirin: A propensity-
matched study. J. Cardiothorac. Vasc. Anesth. 2007, 21, 820–826.
5. Engoren, M.; Hadaway, J.; Schwann, T.A.; Habib, R.H. Ketorolac improves graft patency after
coronary artery bypass grafting: A propensity-matched analysis. Ann. Thorac. Surg. 2001, 92, 603–
609.
6. Williams, J. B., McConnell, G., Allender, J. E., Woltz, P., Kane, K., Smith, P. K., Engelman, D. T.,
& Bradford, W. T. (2019). One-year results from the first US-based enhanced recovery after cardiac
surgery (ERAS Cardiac) program. The Journal of Thoracic and Cardiovascular Surgery, 157(5), 24

1881–1888.
Ketorolac Use in Cardiovascular
Surgery
Presenter: Miley Nikirk, PharmD
IU Health PGY1 Pharmacy Resident

Research Mentor: Shelley Porter, PharmD, BCCCP

IU Health Critical Care Specialist