Journal of PeriAnesthesia Nursing 38 (2023) 139−147

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Journal of PeriAnesthesia Nursing

jo urn a l h om ep ag e: ww w.j o pa n. org

Review

Utilization of Ketamine in Total Knee and Hip Joint Arthroplasty: An

Evidence-Based Review
Matthew B. Watson, RN, BSN, Blake A. Wood, RN, BSN, Tito D. Tubog, PhD, DNAP, CRNA*
Graduate Programs of Nurse Anesthesia, Texas Wesleyan University, Fort Worth, TX

A B S T R A C T

Purpose: To evaluate the efficacy of ketamine in total knee and hip arthroplasty.
Design: Evidence-based review.
Methods: Following the guidelines outlined in the PRISMA statement, a comprehensive search was conducted
using Google Scholar, PubMed, CINAHL, Cochrane Collaboration, and other grey literature. Only randomized
controlled studies and pre-appraised evidence such as systematic review and meta-analysis examining the
effects of ketamine in total knee and hip arthroplasty were included. The quality appraisal of the literature
was conducted using the proposed algorithm described in the Johns Hopkins Nursing Evidence-Based Prac-
tice Evidence Level and Quality Guide.
Findings: Three systematic reviews and meta-analyses and 2 randomized controlled trials involving 1284
patients were included in this review. The use of ketamine reduced pain scores within the 24 hours after sur-
gery. In addition, evidence suggests that patients who were treated with ketamine consumed fewer opioids
24 and 48 hours after surgery. Furthermore, ketamine reduced the incidence of postoperative nausea and
vomiting with no effects on the incidence of hallucinations and central nervous system side effects. All stud-
ies included in the review were categorized as Level I and rated Grade A implying strong confidence in the
true effects of ketamine in all outcome measures in the review.
Conclusions: The current evidence demonstrates the viability of ketamine as a safe and effective alternative to
opioids in the perioperative setting with major total joint arthroplasty surgery. Decreased pain scores and
opioid consumption up to 48 hours into the postoperative period were observed in a number of the
appraised articles.
© 2022 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.

Significant postoperative pain is a common adverse effect after
major joint arthroplasty, affecting the patient’s well-being and
decreasing patient satisfaction scores.1-3 Pain can impede rehabilita-
tion and prolong the length of hospitalization, leading to increased
morbidity and mortality.4 Providing effective analgesic management
after surgery is critical to improving patient outcomes. The traditional
usage of opioid analgesics to relieve postoperative pain has been
related to complications such as respiratory depression, urinary
retention, nausea, vomiting, and constipation.5 The literature sug-
gests the need to reduce reliance on opioid analgesia and use alterna-
tive methods to alleviate postoperative pain.6,7 One approach is using
non-opioid analgesics for effective pain relief.7 Ketamine, an N-
methyl-D-aspartate (NMDA) receptor antagonist, provides analgesia
without respiratory depression or other opioid-related complica-
tions.8-10
Conflict of Interest: None to report.
* Address correspondence to Tito D. Tubog, Texas Wesleyan University, 1000 Wes-
leyan St, Fort Worth, TX 76105.
E-mail address: tdtubog@txwes.edu (T.D. Tubog).
At low doses, ketamine has been reported to relieve postoperative
pain and reduce the consumption rate of opiates.11 In a review con-
ducted by Brinck et al11 patients receiving perioperative ketamine
reported a pain reduction score of 5/100 mm on the visual analog
scale (VAS) 24 hours after surgery. Similarly, total opioid consump-
tion was significantly lower by 8 mg morphine equivalents.11 In addi-
tion to pain scores and opioid consumption reduction, ketamine
prolongs the time to the first dosage of analgesics.11
In 2019, approximately 2 million total hip and knee surgeries
were performed in the United States.12 Many of these patients expe-
rience moderate to severe postoperative pain despite treatment with
traditional pain management strategies.13,14 Several reviews and
meta-analyses have examined ketamine for use in many orthopedic
cases and have found it to provide good analgesia while reducing
postoperative opioid consumption.11,15,16 In total knee or hip arthro-
plasty, the use of ketamine may provide optimal postoperative pain
management and improve clinical outcomes. Therefore, this evi-
dence-based review was conducted to critically evaluate the benefits
of low-dose ketamine in total knee and hip arthroplasty.

https://doi.org/10.1016/j.jopan.2022.04.019
1089-9472/© 2022 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.
M.B. Watson et al.
Methods
The PICO question that guided the search was: Does ketamine
improve postoperative pain management in patients undergoing knee or
hip arthroplasty? The reporting of this systematic review of evidence
followed the recommended process described in the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement.17
Search Strategy
Two independent researchers (MW, BW) performed a compre-
hensive electronic search between February and March 2021 using
Google Scholar, PubMed, CINAHL, and Cochrane Collaboration data-
bases. Other databases such as clinicaltrials.gov and professional
organizations’ abstract repositories were also searched to obtain pub-
lished and unpublished clinical trial results and professional poster
presentations to minimize publication bias. The key search terms
ketamine, orthopedic, hip arthroplasty, knee arthroplasty, postoperative
pain, and joint arthroplasty were used alone or combined using
appropriate Boolean operators.
The titles and abstracts were examined for inclusion by two
authors separately. Any disagreements were resolved via consensus
discussion between the authors.
Selection Process
Articles considered for inclusion in this review were: (1) random-
ized controlled trials (RCT) comparing ketamine to placebo, no keta-
mine or active control, (2) pre-appraised studies such as systematic
review and meta-analysis papers examining ketamine and placebo,
no ketamine or active control, (3) patients have undergone orthope-
dic surgery such as total knee and hip arthroplasty regardless of anes-
thetic techniques, and (4) studies published within 10 years in
scholarly, peer-reviewed academic journals. The RCTs included in
meta-analysis papers were not appraised individually to take advan-
tage of the Level 1 pre-appraised evidence. Instead, we examined the
meta-analysis in which the findings of the trials were evaluated. Case
reports, observational studies, expert opinions, and editorials were
excluded from this review.
Data Abstraction
The authors individually extracted data from included studies
using a previously piloted template. The data extracted were the fol-
lowing: patient demographics, American Society of Anesthesiologists'
Physical Status Classification, the number of participants, anesthesia
techniques, the amount, route, and timing of ketamine. In addition,
we abstracted the primary and secondary outcomes for the current
review. Disagreements or any discrepancies in data collection were
resolved through discussion until a consensus was reached.
Outcome Measures
The primary outcome was pain scores in the postoperative set-
ting. Pain scores of each study were examined at various time points
after surgery. Pain scores value reported using VAS and numeric rat-
ing scale (NRS) were converted to an 11-point scale (0 = no pain and
10 = worst pain) for consistency in data analysis. Pain scores were
assessed at 6, 12, 24, and 48 hours after surgery. If pain score was not
recorded in the time points specified in this review, those reported
close to the time point were used for analysis.
The secondary outcomes for this evidence-based review were
total opioid consumption, time to first administration of analgesic or
rescue analgesia, and complications of ketamine. The total opioid
140
Journal of PeriAnesthesia Nursing 38 (2023) 139−147
consumption was evaluated at 24 and 48 hours postoperatively. This
review assessed various adverse effects of ketamine, including hallu-
cination, sedation, and the incidence of postoperative nausea and
vomiting (PONV).
Quality Assessment
Two authors assessed the quality of the evidence independently.
The quality appraisal of the literature was conducted using the pro-
posed algorithm described in the Johns Hopkins Nursing Evidence-
Based Practice Evidence (JHNEBP) Level and Quality Guide.18 The evi-
dence level was rated using Level I-V (see footnotes Tables 1 and 2),
and quality ratings A = high quality, B = good quality, or C = low qual-
ity with major flaws were assigned. Disagreements were resolved by
consensus with a third author.
Results
After the initial electronic database search, 930 articles were iden-
tified, with 643 remaining after removing duplicate results. Further
screening of the identified article titles and abstracts left a remaining
22 articles. Of those, 17 did not meet the inclusion criteria. Eventu-
ally, 5 studies were included in this review: 3 systematic reviews
with meta-analysis19-21 and 2 RCTs.22,23 The search strategy and the
selection process are presented in Figure 1.
Study Characteristics
A total of 1284 patients were included in this review between all
studies (Tables 1-3). All 3 systematic reviews and meta-analysis stud-
ies19-21 pooled a total of 22 RCTs24-45 involving 1161 patients
(Table 3), with the remaining participants enrolled in 2 RCTS22,23 not
included in the meta-analysis. All patients underwent total knee or
hip arthroplasty under general or regional anesthesia.
The dose, route, and timing of ketamine administration varied
across all studies. In the 2 RCTs22,23 not included in the meta-analy-
ses, ketamine was given via an intravenous (IV) bolus of 0.05 mg/kg
followed by an infusion of 3 mcg/kg/min23 or 10 mcg/kg/min.22 The
dosages of ketamine in the 3 meta-analyses19-21 varied ranging from
an initial IV bolus of 0.05 mg/kg to 1 mg/kg (Table 3). In studies with
continuous infusion, the maintenance dose were between 2 mcg/kg/
min to as high as 120 mcg/kg/min. Ketamine was administered
through IV,22-24,28,29,32,35-38,40,41 IV PCA,26,27,30,33 epidural34,39,42-45
and intra-articular.25,31 Ketamine was given
preoperatively,34,36,37,39,42,43 intraoperatively at induction or before
surgical incision22-24,28,29,32,35,38,40,41,44 and started postopera-
tively.25-27,30,31,33,45
The assessment methodology of postoperative pain scores dif-
fered between studies. All 3 meta-analyses converted NRS and VAS
into an 11-point scale of 0 to 10, with 0 as no pain and 10 as severe
pain for analysis.19-21 In those trials not included in the meta-analy-
sis, 1 RCT23 evaluated pain scores using VAS, while 1 trial22 used the
NRS. The time points of pain assessment contrasted among the stud-
ies included in this review. Three meta-analyses evaluated pain
scores up to 48 hours after surgery.19-21 The 2 RCTs evaluated pain
scores up to 72 hours postoperatively.22,23 All opioids were converted
to morphine equivalent in all studies included in the review.19-23
The 3 systematic reviews used the Cochrane Risk of Bias tool to
appraise the bias concerns of the trials included in the meta-analy-
sis.19-21 One systematic review and meta-analysis20 presented a fun-
nel plot showing symmetrical configuration, suggesting no potential
publication bias in all included RCTs in the review. In the same
review, Begg's correlation test corroborated no possible risk of publi-
cation bias.20 All 3 reviews conducted the I2 statistic to detect hetero-
geneity across studies in the meta-analysis.19-21 An I2 statistic of
 M.B. Watson et al.
Table 1
The Characteristics of Systematic Review and Meta-Analysis Examining the Efficacy and Safety of Ketamine in Joint Arthroplasty

Studies N Type of Evidence Primary Outcomes Secondary Outcomes

Level* Qualityy Findings I2 Findings I2

19
Wang et al 21 RCT (n = 1145) I A VAS 6 hrs 42% 24-hr morphine consumption 95%
MD, −1.45; 95% CI, −1.71 to 1.18; P < .00001 MD, −17.58; 95% CI, −29.07 to −6.10; P = .003
VAS 12 hrs 91% 48-hr morphine consumption MD, −16.82; 95% 94%
MD, −1.55; 95% CI, −2.28 to −0.82; P < .0001 CI, −27.75 to −5.89; P = .003
VAS 24 hrs 90%
MD, −0.78; 95% CI, −1.25 to −0.31; P = .001
VAS 48 hrs 92%
MD, −0.74; 95% CI, −1.26 to −0.22; P = .006
20 z
Xu et al 10 RCT I A IV Ketamine 50% IV Ketamine 95%
(n = 577) VAS 0-8 hrs 24-hr morphine consumption
MD, −1.21; 95% CI, −1.45 to −0.98; P < .00001 MD, −17.76; 95% CI, −31.25 to −4.27; P = .01
IV Ketamine 0% IV Ketamine 0%
VAS 8-24 hrs 48-hr morphine consumption
MD, −0.48; 95% CI, −1.13 to 0.17; P = .14 MD, −21.79; 95% CI, −25.46 to −18.11; P < .00001
Intraarticular Ketamine 0% Intraarticular Ketamine 0%
VAS 0-8 hrs 24-hr morphine consumption
MD, −0.12; 95% CI, −0.51 to 0.26; P = .52 MD, −0.40; 95% CI, −1.83 to 1.03; P .58

Intraarticular Ketamine 0% Intraarticular Ketamine 0%

VAS 8-24 hrs 48-hr morphine consumption
MD −0.49; 95% CI, −0.70 to −0.29; P < .00001 MD, −4.10; 95% CI, −4.10; 95% CI, −5.85 to −2.35;
P < .00001

Epidural Ketamine NA Psychotic and gastric effects did not differ Unable to
141

VAS 8-24 hrs calculatex

MD, −2.10; 95% CI, −3.30 to 0.90; P = .0006
Li et al21 6 RCT{ I A VAS 6 hrs 0% 24-hr morphine consumption 98%
(n = 244) WMD, −0.296; 95% CI, −0.488 to −0.104; P = .003 WMD, 17.402; 95% CI: 34.006 to 0.798;
P = .040
VAS 12 hrs 0% 48-hr morphine consumption 97%
WMD, 0.304; 95% CI: 0.491 to 0.117; P = .001 WMD, 19.963; 95% CI: 34.056 to 5.871;
P = .005
VAS 24 hrs 71% Length of hospital stay (days) 0%
WMD, 0.252; 95% CI: 0.404 to 0.101; P = .001 WMD, 0.070; 95% CI: 0.314 to 0.453; P = .722
VAS 48 hrs 80%
WMD, 0.007; 95% CI: 0.131 to 0.116; P = .911
CI, confidence interval; I2, statistic assessing heterogeneity of the studies; IV, intravenous; MD, mean difference; VAS, visual analog score; WMD, weighted mean difference.

Journal of PeriAnesthesia Nursing 38 (2023) 139−147

* Johns Hopkins Nursing Evidence-Based Practice Model Evidence Level. Level I: RCT, systematic review of RCTs, with or without meta-analysis; Level II: Quasi-experimental study; Level III: Non-experimental study; Level IV: Opinion
of respected authorities and/or nationally recognized expert committees/consensus panels based on scientific evidence; Level V: Based on experiential and non-research evidence.
y
Johns Hopkins Nursing Evidence-Based Practice Model Quality Rating. A, high quality; B, good quality; C, low quality or major flaws.
z
Only one RCT analyzed in this meta-analysis was not included in the meta-analysis by Wang et al.19
x
Unable to calculate heterogeneity. One RCT was included in this analysis.
{
All RCTs included in the meta-analyses were also pooled in 2 other meta-analyses by Wang et al19 and Xu et al.20
M.B. Watson et al. Journal of PeriAnesthesia Nursing 38 (2023) 139−147

* Johns Hopkins Nursing Evidence-Based Practice Model Evidence Level. Level I: RCT, systematic review of RCTs, with or without meta-analysis; Level II: Quasi-experimental study; Level III: Non-experimental study; Level IV: Opinion
>50% was considered substantial heterogeneity. The I2 statistic dif-

VAS at rest and during movement 24, 48 and 72-

hrs postoperative, opioid consumption, rescue
fered for both primary and secondary outcomes on the reviews
VAS 24, 48 and 72-hrs postoperative, opioid (Table 1). One systematic review20 explored the causes of heteroge-

mediation use, ketamine adverse effects

neity. However, the review authors failed to identify factors affecting
the variations between the studies. The authors of the 2 RCTs22,23
conducted a power analysis (a = 0.05, b = 0.2) to determine the sam-
ple size for the outcomes measured.
consumption, TUG

Outcome Measures
Outcome Measures

Pain Scores
All 5 studies evaluated pain scores at various time points after sur-
gery.19-23 The most common time frames presented in individual
studies were 6, 12, 24, and 48 hours after surgery.
of respected authorities and/or nationally recognized expert committees/consensus panels based on scientific evidence; Level V: Based on experiential and non-research evidence.

6-12 Hours. Two meta-analyses estimated the pain scores within

6 hours after surgery.19,21 Wang et al19 pooled 5 RCTs consisting of
259 patients and reported a significant reduction in the pain score of
patients treated with ketamine by an average of 1.45 on a pain scale
At induction

At induction

of 0 to 10 (MD, −1.45; 95% CI, −1.71 to −1.18; P < .0001). Similarly,

Timing

another meta-analysis21 reported a lower pain score in patients with

ketamine (MD −0.296; 95% CI, −0.488 to −0.014). In the same review,
The Characteristics of Randomized Controlled Trials not Included in the Meta-Analysis Examining the Efficacy and Safety of Ketamine in Joint Arthroplasty

patients given ketamine experienced lower pain scores within

12 hours after surgery (P = .003).21
0.5 mg/kg bolus followed by

0.5 mg/kg bolus followed by

10 mcg/kg/min infusion

3 mcg/kg/min infusion

24 Hours. The effects of ketamine were observed 24 hours after sur-

gery in the 3 reviews19-21 and 2 RCTs.22,23 The highest pain score dif-
Johns Hopkins Nursing Evidence-Based Practice Model Quality Rating. A, high quality; B, good quality; C, low quality or major flaws.

ference was reported in a meta-analysis of 13 trials composed of 732

patients.19 The authors in the review reported a difference of 0.78
lower in pain intensity in patients with ketamine (P = .001).19 Two
Ketamine

other reviews20,21 corroborated the reduction in pain scores within

Dose

24 hours after surgery. Conversely, reports from the 2 RCTs showed

conflicting outcomes.22,23 One RCT22 reported no difference in pain
IV, intravenous; kg, kilogram; mcg, microgram; mg, milligram; TUG, timed to Up and Go; VAS, visual analog score.

intensity in patients with ketamine. The other RCTs evaluated the

effect of ketamine in patients undergoing bilateral knee arthro-
plasty.23 With bilateral knee arthroplasty, it has been suggested that
patients experience more pain in the second knee operation.23 In this
Route

RCT, the authors reported no difference in pain score at rest in the

first knee operation compared to placebo.23 However, outcomes in
IV

IV

the study23 showed a significant difference in pain score on the sec-

ond knee operated with patients treated with ketamine having more
Ketamine (n = 24)

Ketamine (n = 40)

pain by an average of 0.930 at rest and during movement.

Placebo (n = 25)

Placebo (n = 31)

48 Hours. Two meta-analyses19,21 and 2 RCTs22,23 examined the

effects of ketamine 48 hours after surgery. Two RCTs suggested that
ketamine did not reduce pain scores within the first 48 hours.22,23
N

However, 2 reviews19,21 estimated a statistically significant difference

in pain scores reduction ranging between 0.00721 and 0.7419 on a 0 to
y

10 pain scale.
Quality Rating
Evidence Type

Opioid Consumption
A

All studies reported opioid consumption at 24 and 48 hours after

surgery.19-23 Three systematic reviews and meta-analyses reported a
significant difference in the 24 and 48-hour morphine equivalent
Level*

consumption.19-21. The average morphine equivalent used in patients

I

with ketamine is lower by 17 mg within 24 hours19,21 and 20 mg

within 48 hours after surgery.20,21 Conversely, the 2 RCTs showed no
significant difference in the 24-hour opioid consumption.22,23
Susan Paulin et al22
RCT Country

Time to First Rescue Analgesia

Koh et al23
Korea
Table 2

India

There were limited data on time to first rescue of analgesia. In our

review, only 1 study23 reported this outcome and suggested no
y

142
M.B. Watson et al.
Figure 1. PRISMA search flow.
difference in the number of rescue medications in patients receiving
ketamine compared to placebo.
Adverse Effects
Adverse effects such as hallucinations and sedation were eval-
uated in the studies included in this review. The incidence of hal-
lucinations and central nervous system (CNS) side effects were
reported in two reviews. Xu and colleagues20 pooled 3 RCTs con-
sisting of 286 patients and concluded that there is no difference
in the incidence of psychotic adverse effects in patients given IV
ketamine compared to placebo. Similarly, 1 review19 examined 2
RCTs and concluded that the use of ketamine did not cause seda-
tion postoperatively.
Postoperative Nausea and Vomiting
There were conflicting findings regarding the effects of keta-
mine on the incidence of PONV. However, in a most recent
review published in 2020, Wang et al19 reported that the
143
Journal of PeriAnesthesia Nursing 38 (2023) 139−147
incidence of PONV was lower in the ketamine group (OR = 0.54,
95%, CI: 0.37 to 0.77, P = .0008). In contrast, another review21
reported no significant difference in the incidence of PONV
between groups. The possible explanation for the contrasting out-
comes between the 2 reviews was the number of RCTs included
in the analysis. In the meta-analysis conducted by Wang and col-
leagues,19 a total of 13 RCTs were pooled, while there were only
4 RCTs analyzed in a much earlier review.21
Quality Assessment
We rated the quality of the evidence using the JHNEBP model. All
studies19-23 included in this review were categorized as Level I and
rated Grade A. The authors in the 2 RCTs22,23 not included in the sys-
tematic review and meta-analysis papers minimized study bias by
using sound random sequence generation, adequate concealment of
allocations before trial assignment, and blinded the participants and
the study outcomes assessors. All three systematic reviews and
meta-analyses adhered to universally acceptable reporting guidelines
(PRISMA and Cochrane Guidelines).19-21
 M.B. Watson et al.
Table 3
Summary of Randomized Controlled Trials Examining the Efficacy and Safety of Ketamine in Joint Arthroplasty Included in Systematic Review and Meta-Analysis

RCT N Surgery Ketamine Outcomes

Route Dose Timing
Tan24 91 IV 69 mg at 6 mcg/kg/min In OR until skin closure VAS POD 0 to 2 wk, opioid
TKA consumption POD 0 and POD 1
25
Zhang 44 Intra-articular 2 mg/kg Postoperative VAS at 2-48 hrs; 24 and 48-hr opioid
TKA consumption; time of ambulation,
LOS; adverse effects of ketamine
Ji26 50 IV PCA 2 mg/kg, bolus 0.5 mL with lockout Postoperative VAS at 6, 12, 24 and 48 hrs;
TKA interval 15 min complications
27
Liu 90 IV PCA 1 mg/mL, bolus 2 mL with lockout Postoperative VAS at 6, 12, 24 and 48 hrs; adverse
TKA interval 60 min effects of ketamine
28
Cengiz 60 IV 6 mcg/kg/min In OR until skin closure VAS at 6, 12 and 24 hrs; 24 and 48-hr
TKA opioid consumption; complication
29
Martinez 72 IV 0.5 mg/kg then maintained at 3 mcg/ At induction until skin closure VAS at rest and on movement, 48-hrs
THA kg/hr infusion morphine consumption
30
Chen 60 IV PCA 0.4 mg/mL, bolus 2 mL with lockout Postoperative 48-hrs opioid consumption
TKA interval 6 min
Guar
a Sobrinho 31
39 Intra-articular 0.25 mg/kg Postoperative VAS at 6, 12 and 24 hrs;
TKA complications
32
Zhao 40 IV 1 mg/kg bolus, then 1mg/kg/hr In OR VAS at 12 and 24 hrs; adverse effects
TKA infusion of ketamine
33
Wang 90 IV PCA 1-2 mg/mL, bolus 0.5 mL with lockout Postoperative VAS at 24 and 48 hrs; 48-hrs
THA interval 15 min morphine consumption
34
Zhai 60 Epidural 30 mg Preoperative VAS at 6, 12, 24 and 48 hrs; 24 and
THA 48-hr opioid consumption
35
Aveline 49 IV 0.2 mg/kg bolus, then maintained at In OR until 48 hrs postoperative VAS at 6, 12, 24 and 48 hrs; 24 and
144

TKA 120 mcg/kg/h infusion during 48-hr opioid opioid consumption,

surgery and 60 mcg/kg/h for 48 hrs complications
after surgery
Cagla Ozbakis Akkurt36 40 IV 0.15 mg/kg Preoperative 24-hr opioid consumption
TKA
37
Perrin 12 IV 0.5 mg/kg bolus, then at 4 mg/kg/min Preoperative until intraoperative VAS at 6, 12, 24 and 48 hrs; 24-hr
TKA infusion during the surgery opioid consumption; LOS
rand
Reme 38
154 IV 0.5 mg/kg bolus, then maintained at 2 In OR until 48 hrs postoperative VAS at 24 and 48 hrs; 24-hr opioid
THA mcg/kg/min infusion for 48 hrs consumption
after surgery.
Liu39 20 Epidural 0.6 mg/kg Preoperative VAS at 6, 12, 24 and 48 hrs; adverse
THA effects of ketamine
40
Wang 40 IV 0.05 mg/kg bolus, then at 3 mcg/kg/ In OR until 48 hrs postoperative Unable to locate RCT
TKA min infusion during surgery and 1.5
mcg/kg/min for 48 hrs after surgery

Journal of PeriAnesthesia Nursing 38 (2023) 139−147

Adam41 40 IV 0.5 mg/kg bolus, then at 3 mcg/kg/ In OR until 48 hrs postoperative VAS 6, 12 and 24 hrs; 48-hr opioid
TKA min infusion during surgery and 1.5 consumption
mcg/kg/min for 48 hrs after surgery
Lauretti42 27 Epidural 0.1 mg/kg Preoperative VAS 24 hrs; 48-hr opioid
TKA consumption
43
Ma 30 Epidural 0.5 mg/kg Preoperative VAS at 24 and 48 hrs
TKA
44
Himmelseher et al 37 Epidural 0.25 mg/kg Before incision Adverse effects of ketamine
TKA
45
Wong et al 16 Epidural 10 mg/kg Postoperative VAS at rest and activity POD 1-3;
TKA, THA meperidine requirements; patient
satisfaction scores and adverse
effects (drowsiness, PONV, pruritus
and CNS responses)
CNS, central nervous system; hr, hour; hrs, hours; kg, kilogram; LOS, length of stay; mcg, microgram; mg, milligram; min, minute; mL, milliliter; NR, non-reported; OR, operating room; PCA, patient controlled analgesia; POD, postopera-
tive day; PONV, postoperative nausea and vomiting; RCT, randomized controlled trial; THA, total hip arthroplasty; TKA, total knee arthroplasty.
M.B. Watson et al.
Discussion
The overall findings of our review suggested that patients under-
going total joint arthroplasty treated with ketamine reported lower
pain scores postoperatively. In addition, a reduction in morphine
equivalent consumption was observed up to 48 hours following sur-
gery. This evidence-based review also showed the opioid-sparing
effect of ketamine. Adverse side effects secondary to opioids, such as
PONV, were significantly lower in patients treated with ketamine.
Clinical presentations such as sedation and hallucination were not
different when treated with ketamine.
A primary challenge for patients undergoing total joint arthro-
plasty surgery is adequate postoperative pain control. Inadequate
postoperative pain management provokes stress responses causing
pulmonary, immunological, and metabolic dysfunction.4,46 Managing
postoperative pain using a single modality such as opioids has been
declining in recent decades because of new drugs, improved drug
delivery methods, and a much greater understanding of the pain
pathway.47-49 Opioids have numerous side effects, including seda-
tion, respiratory depression, and postoperative nausea and vomiting,
leading to decreased patient safety and satisfaction.50 However,
despite advancements in pain management strategies, suboptimal
pain control remained a problem in the postoperative setting.51 In
the US, data suggest that patients undergoing orthopedic surgery
such as knee or hip arthroplasty report severe pain despite
treatment.13,14 Greater than 80% of patients report inadequate pain
control resulting in slower recovery, increased complication rates,
extended length of hospital stays, and decreased patient
satisfaction.4,51 In addition, suboptimal postoperative pain control
may lead to opioid tolerance and opioid dependency.
The opioid crisis in the US is becoming a national health emer-
gency. The latest data show that the opioid problem results in the
deaths of 128 people a day and an estimated economic cost of 78.5
billion dollars a year.50 One of the causes of the opioid epidemic is
believed to be exposure to opioids in the perioperative setting result-
ing in an increased number of prescriptions to treat chronic postoper-
ative pain.52-55 As the opioid crisis worsens, a multimodal analgesic
approach is quickly becoming a priority as the need to reduce opioid
consumption becomes both a legislative and practical focus of care.
Decreasing the prescription rate and utilization of opioids is one
approach to reducing opioid exposure.
A multimodal approach in pain management has been recom-
mended as it provides pain relief, improves the quality of life, and
decreases opioid dependency, thus aiding in fighting the opioid epi-
demic. Multimodal analgesia is administering 2 or more pharmaco-
logical agents or using 2 or more analgesia techniques with a
different mechanism of action to reduce pain by targeting different
pain pathways.56 The goal of multimodal analgesia is to provide syn-
ergistic effects from 2 or more modalities to manage pain effectively.
Enhanced recovery after surgery (ERAS) programs include multi-
modal analgesia strategies in their initiatives. In ERAS protocols spe-
cifically for orthopedic surgery, a combination of minimal opioid and
optimized non-opioid techniques have improved patient outcomes,
including improvement in patient pain scores, overall opioid con-
sumption, length of stay, and patient satisfaction.57,58 One non-opioid
medication extensively examined in joint arthroplasty surgical cases
is ketamine.
Ketamine has been shown to affect pain modulation, anti-toler-
ance, anti-allodynia, and anti-hyperalgesia.9,59 Sub-dissociative dos-
ages of ketamine have been reported to reduce intraoperative and
postoperative consumption of opioids.8 The reduction in opioid con-
sumption leads to a reduction in complications from the side effects
of opioids and a better outcome in the postoperative setting.
Ketamine is a phencyclidine-derived dissociative anesthetic that
works predominantly by antagonism of N-methyl-D-aspartate
145
Journal of PeriAnesthesia Nursing 38 (2023) 139−147
10
(NMDA) receptors. The NMDA receptors exert nociception through
the post-synaptic nerve ending on the second-order neuron in the
spinal cord's dorsal horn in response to painful stimuli.10 With pain-
ful stimulation, the first-order neuron releases glutamate to bind to
NMDA receptors on the second-order neuron. This binding results in
conformational changes to the receptors allowing the increased
influx of calcium and, with prolonged stimulation, causes the devel-
opment of central sensitization. Central sensitization leads to the
upregulation of the nervous system into a high reactivity state, lead-
ing to chronic pain syndrome.10 Additional central sensitization
effects include opioid tolerance and opioid-induced hyperalgesia
through the NMDA receptor.10
Ketamine works by antagonizing the NMDA receptor, thus block-
ing the subsequent centrally mediated pain processes reducing acute
pain and preventing chronic pain. Ketamine has additional effects on
pain processing. Additionally, mu receptor activation has been
observed.60 Dissociation of the thalamocortical region responsible for
pain-sensing and perception is another property. Lastly, ketamine is
noted to have antidepressant and anti-inflammatory effects, enhanc-
ing exogenous opioid use, making it a unique medication to use in
pain management.61
Using the Johns Hopkins EBP model, the overall quality of the evi-
dence was considered high because of sufficient effect sizes and rea-
sonably consistent findings. Our review showed a consistent and
sound reduction in pain scores in the early postoperative period until
48 hours after surgery in patients undergoing total joint arthroplasty
receiving perioperative ketamine. In addition, our findings were simi-
lar to earlier studies examining the efficacy of perioperative ketamine
in other orthopedic surgeries such as shoulder, knee arthroscopy and
spine cases.15,16,62,63 Furthermore, pain scores were markedly
reduced in the first 6 hours postoperative, with pain score differences
as high as −1.45.19 We also observed that pain scores differences
gradually diminish 24 to 48 hours after surgery. One possible expla-
nation for this progressive reduction in pain scores was the duration
of action of ketamine which is at least 45 minutes.64
Opioid consumption within the 24- and 48-hour periods is com-
parable with earlier studies examined in a previous meta-analysis.65
In the current review, we noted a reduction in 24-hour morphine
consumption averaging 17 mg and, at 48-hours, a reduction of 20mg
in patients who received perioperative ketamine. With reduced opi-
oid consumption, opioid side effects were expected to be minimal.
Evidence also showed that the incidence of sedation and other CNS
effects were not significantly different in the ketamine group com-
pared to the control or placebo.
Several limitations were identified in this review. First, the varia-
tions in the dosing regimen, timing, and routes of ketamine adminis-
tration may have affected the overall pain scores. Second, different
anesthetic modality choices, such as the choice between general or
regional anesthesia for joint arthroplasty, could have affected the
overall effect of ketamine on pain scores and opioid consumption.
Third, all 3 meta-analyses acknowledged substantial heterogeneity in
their estimates; however, factors affecting the effect sizes were not
uncovered despite sensitivity and sub-group analyses. Last, this
review did not appraise the RCTs included in the 3 SRs independently
due to reliance on the previous appraisal done by the authors of the
systematic reviews and meta-analyses.
Further research is needed to define the most suitable ketamine
dosage for postoperative pain management. This may include dose-
finding studies evaluating the effective dose in 50% and 95% of
patients for total joint arthroplasty under general or regional anes-
thesia. Since chronic pain is becoming a common sequela after total
joint arthroplasty,66 further studies should examine the efficacy of
ketamine on chronic pain management postoperatively. Additionally,
studies are needed to investigate the appropriate dosage for obese
patients with a BMI above 30, where an adjusted or ideal body weight
M.B. Watson et al.
may be utilized. Last, research on intra-articular and neuraxial keta-
mine administration is needed as the use of regional anesthesia in
total joint arthroplasty is becoming common.67
Conclusion
Ketamine is a common component of ERAS protocols. This litera-
ture review demonstrates the viability of ketamine as a safe and
effective alternative to opioids in the perioperative setting with
major total joint arthroplasty surgery. Decreased pain scores and opi-
oid consumption up to 48 hours into the postoperative period were
observed in a number of the appraised articles. Although ketamine
reduced the incidence of PONV, ketamine showed no adverse effects
in the postoperative period.
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