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Local Infiltration Analgesia in Knee Arthroplasty

rebro Studies in Medicine 66

PER ESSVING

Local Infiltration Analgesia in Knee Arthroplasty


Per Essving, 2012

Title: Local Infiltration Analgesia in Knee Arthroplasty


Publisher: rebro University 2012
www.publications.oru.se
trycksaker@oru.se

Print: Intellecta Infolog, Kllered 02/2012

ISSN 1652-4063
ISBN 978-91-7668-855-7
Abstract
Per Essving (2012): Local Infiltration Analgesia in Knee Arthroplasty.
rebro Studies in Medicine 66.

Local infiltration analgesia (LIA) is a new technique for postoperative pain


management following knee arthroplasty. LIA involves a long-acting local
anesthetic (ropivacaine), a non-steroid anti-inflammatory drug (ketorolac)
and epinephrine infiltrated into the knee joint during surgery and injected
postoperatively via a catheter.
In the first two studies, LIA was compared with placebo in
unicompartmental (I) and total (II) knee arthroplasty. Postoperative pain
levels, morphine consumption and the incidence of side effects were lower
in the LIA groups. In addition, we found a shorter length of hospital stay in
the LIA group following unicompartmental knee arthroplasty compared
with placebo (I), while the time to home readiness was shorter in the LIA
group following total knee arthroplasty (II). In this study, we found that
the unbound venous blood concentration of ropivacaine was below system-
ic toxic blood concentrations in a sub-group of patients.
In the third study, LIA was compared with intrathecal morphine for
postoperative pain relief following total knee arthroplasty (III). Pain scores
and morphine consumption were lower, length of hospital stay was shorter
and patient satisfaction was higher in the LIA group.
In the final study, we investigated the effect of minimally invasive sur-
gery (MIS) compared with conventional surgery in unicompartmental knee
arthroplasty (IV). Both groups received LIA. We found no statistically sig-
nificant differences in postoperative pain, morphine consumption, knee
function, home readiness, hospital stay or patient satisfaction.
In conclusion, LIA provided better postoperative pain relief and earlier
mobilization than placebo, both in unicompartmental and total knee
arthroplasty. When compared to intrathecal morphine, LIA also resulted in
improved postoperative pain relief and earlier mobilization. Minimally
invasive surgery did not improve outcomes after unicompartmental knee
arthroplasty, when both groups received LIA.

Keywords: Knee arthroplasty, minimally invasive surgery, ropivacaine,


ketorolac, intrathecal morphine, local infiltration analgesia.

Per Essving, School of Health and Medical Sciences


rebro University, SE-701 82 rebro, Sweden, per.essving@orebroll.se
Contents

ABBREVIATIONS ..................................................................................... 9
LIST OF ORIGINAL PAPERS ................................................................. 11

INTRODUCTION................................................................................... 13
Local infiltration analgesia (LIA) ............................................................. 14
Minimally invasive surgery (MIS) ............................................................ 15
AIMS OF THE THESIS ........................................................................... 17
General .................................................................................................... 17
Specific aims Studies IIV...................................................................... 17
METHODS.............................................................................................. 19
Ethics ....................................................................................................... 19
Patients .................................................................................................... 19
Anesthesia ................................................................................................ 19
Study design ............................................................................................. 19
Studies I and II ..................................................................................... 20
Study III ............................................................................................... 20
Study IV ............................................................................................... 20
Surgery ..................................................................................................... 21
Studies I and IV (Unicompartmental knee arthroplasty) ...................... 21
Conventional surgery ........................................................................... 21
Minimally invasive surgery (MIS) ........................................................ 21
Studies II and III (Total knee arthroplasty) .......................................... 22
Postoperative pain management............................................................... 22
Local infiltration analgesia (LIA) ......................................................... 22
Intrathecal morphine............................................................................ 24
Rescue medication ............................................................................... 25
Outcome measurements ........................................................................... 25
Pain...................................................................................................... 25
Analgesic consumption ........................................................................ 25
Patient satisfaction............................................................................... 25
Functional outcome ............................................................................. 25
Home readiness and Length of hospital stay........................................ 25
Adverse events ..................................................................................... 26
Plasma concentrations of ropivacaine .................................................. 26
Statistics ................................................................................................... 26
RESULTS ................................................................................................. 29
Pain .......................................................................................................... 29
Morphine consumption............................................................................ 32
Home readiness, length of hospital stay ................................................... 32
Surgical outcome ...................................................................................... 33
Patient satisfaction ................................................................................... 34
Side effects................................................................................................ 34
Sub-study on ropivacaine blood concentration (II)................................... 34
DISCUSSION........................................................................................... 37
The technique........................................................................................... 37
Catheter injections ................................................................................... 38
Pain intensity and morphine consumption ............................................... 39
Knee function, patient satisfaction ........................................................... 40
Home readiness, length of hospital stay ................................................... 41
Adverse events.......................................................................................... 42
Systemic and local toxicity ....................................................................... 43
Limitations ............................................................................................... 44
Clinical implications................................................................................. 45
Future research......................................................................................... 46
CONCLUSIONS ...................................................................................... 47

SUMMARY IN SWEDISH....................................................................... 49

ACKNOWLEDGEMENTS ...................................................................... 51
REFERENCES ......................................................................................... 53
Abbreviations
EDA Epidural Anesthesia
EQ-5D EuruQol 5 Dimensions
IT Intrathecal
IV Intravenous
LA Local Anesthetic
LIA Local Infiltration Analgesia
LOS Length of Hospital Stay
MIS Minimally Invasive Surgery
NSAID Non-Steroid Anti-Inflammatory Drug
PCA Patient Controlled Analgesia
SD Standard Deviation
TUG-test Time to Up and Go test
TKA Total Knee Arthroplasty
UKA Unicompartmental Knee Arthroplasty
VAS Visual Analog Scale

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 9


List of original papers
This thesis is based on the following papers, which will be referred to by
roman numerals:

I. Essving P, Axelsson K, Kjellberg J, Wallgren O, Gupta A, Lundin A.


Reduced hospital stay, morphine consumption, and pain intensity
with local infiltration analgesia after unicompartmental knee ar-
throplasty.
Acta Orthopaedica 2009; 80:213-9

II. Essving P, Axelsson K, Kjellberg J, Wallgren O, Gupta A, Lundin A.


Reduced morphine consumption and pain intensity with local infil-
tration analgesia (LIA) following total knee arthroplasty.
Acta Orthopaedica 2010; 81:354-60

III. Essving P, Axelsson K, berg E, Spnnar H, Gupta A, Lundin A.


Local infiltration analgesia versus intrathecal morphine for postop-
erative pain management after total knee arthroplasty: a randomized
controlled trial.
Anesthesia & Analgesia 2011; 113: 926-33

IV. Essving P, Axelsson K, Otterborg L, Spnnar H, Gupta A,


Magnuson A, Lundin A.
Minimally invasive surgery did not improve outcome compared to
conventional surgery following unicompartmental knee arthroplasty
when using local infiltration analgesia.
Submitted for publication

Reprints have been made with the kind permission of the publishers.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 11


Introduction
Osteoarthritis of the knee is a common disease, characterized by progres-
sive breakdown of the articular cartilage, often resulting in pain, stiffness
and reduced function of the knee. When non-surgical management, such as
oral analgesics and physiotherapy, fail to provide sufficient relief of symp-
toms, surgery is often indicated.
There are three basic surgical options; osteotomy, unicompartmental or
total knee arthroplasty. Osteotomy involves an extra-articular correction
of the alignment in order to relieve the load from the affected part of the
knee joint and thereby reduce pain 1. This procedure is generally reserved
for the earlier stages of osteoarthritis in the younger population. Another
option is knee arthroplasty, where the diseased parts of the knee are re-
placed with artificial joint surfaces. When only one compartment of the
knee is affected, a unicompartmental arthroplasty (UKA) might be consid-
ered. UKA was first introduced in the mid 1970s and most often involves
replacement of the joint surfaces of the medial compartment. If both the
medial and the lateral parts of the joint show signs of osteoarthritis or if
the deformity is severe, a total knee arthroplasty (TKA) is recommended.
In the Swedish Knee Arthroplasty Register, TKA comprises approximately
94 % of knee arthroplasties and UKA 6 % 2. Knee arthroplasty is a suc-
cessful procedure with excellent results, both in terms of pain relief and
long-time durability 2. More than 12 000 knee replacements are performed
yearly in Sweden 2.
Early postoperative pain following knee arthroplasty is often severe 3, 4.
Poor pain control may lead to major discomfort for the patient and also
impaired early mobilization. Immobilization of the patient in bed increases
the risk of deep vein thrombosis and prolonged hospital stay may increase
the risk of nosocomial infection.
Several methods are available for pain management following knee ar-
throplasty. Peripheral nerve blocks often provide good pain relief 5-7, but
can be technically demanding and may sometimes lead to motor block of
the lower extremity, hindering early mobilization, and sometimes involves
a risk of nerve damage 8.
A simple method for postoperative pain management is opioids, admin-
istered intravenously via a patient-controlled analgesia (PCA) pump 9-11.
However, large doses of opioids are often required and the risk increases of
side effects, such as sedation, nausea, vomiting, pruritus and respiratory
depression 12. In addition, pain relief during movement is sometimes poor
13
.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 13


Epidural anesthesia (EDA) has traditionally been widely used for post-
operative pain management following knee arthroplasty 14-16. If only local
anesthetics are administered epidurally, there is risk of motor blockade and
difficulty in mobilizing the patient. Epidural anesthesia with an indwelling
catheter prolongs pain relief, but can lead to rare, but serious complica-
tions such as epidural hemorrhage, various degrees of nerve damage, men-
ingitis or epidural infection 17.
Spinal anesthesia is commonly used in knee replacement surgery 6. It has
the advantage of rapid onset of action, but has relatively short duration of
postoperative analgesia. If a small dose of opioid is added to the local
anesthetic during spinal anesthesia (intrathecal opioids), postoperative pain
relief can be enhanced and prolonged 6. Several studies have demonstrated
reduced pain intensity postoperatively and reduction in rescue analgesic
medication, at least during the first 624 postoperative hours 18-21. How-
ever, there are several disadvantages of intrathecal opioids including the
risk of side effects such as nausea, vomiting, pruritus, urinary retention and
respiratory depression, that can be troublesome for the patient and costly
for the health-care provider 22. Spinal anesthesia with intrathecal morphine
is currently one of the most common methods used in Sweden for postop-
erative pain management following knee arthroplasty 2.

Local infiltration analgesia (LIA)


The side effects and disadvantages of these traditional methods of postop-
erative pain management have led to a search for alternative techniques.
Dr. Dennis Kerr and Dr. Lawrence Kohan in Sydney, Australia, developed
a simple technique called local infiltration analgesia (LIA), which has be-
come increasingly popular during the last decade 23. The technique was
designed for the management of the acute postoperative pain phase lasting
approximately 36 hours, following hip or knee surgery. The method in-
cludes two well-defined moments, a periarticular infiltration during the
operation and intraarticular infusion via a catheter postoperatively. At the
end of the operation a mixture of local anesthetics and non-steroid anti-
inflammatory drugs (NSAIDs) is infiltrated into the soft tissue around the
surgical field by the surgeon. Before wound closure, a thin catheter is
placed intraarticularly to allow for postoperative bolus injections.
The theory behind LIA is to prevent pain at the site of its origin. This is
achived by systematically infiltrating the entire surgical site with local anes-
thetics and anti-inflammatory drugs, extending the duration of analgesia
by bolus injections via the catheter and restricting the drugs to the site of
injection using vasoconstrictors, compression bandage 24 and cooling 25.
The drugs used include a long-acting local anesthetic (ropivacaine), a di-

14 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


rectly acting non-steroid anti-inflammatory drug (ketorolac) and a vaso-
constrictor (epinephrine), which is believed to limit the absorption of the
local anesthetic (LA).
Rapid, high quality recovery from surgery and anesthesia should be the
goal following knee arthroplasty. Good pain management is central in
achieving that goal. According to Kerr and Kohan, the pain management
process begins at the preoperative visit, and proceeds through anesthesia
and surgery, during the acute postoperative phase and all the way to home
care (Kerr 2011, personal communication). LIA is known to be effective
during the acute postoperative phase and is regarded as a key enabling
technique in promoting rapid return to normal activities of daily living and
early home discharge.
In an open study of 325 patients, Kerr and Kohan reported good post-
operative pain relief and that 71 % of patients were able to leave the hospi-
tal on the first postoperative day 23. A number of studies have supported
the efficacy of LIA in TKA compared with placebo or no injections 26-29.
However, to our knowledge, no prospective randomized studies have been
conducted on unicompartmental knee arthroplasty.
To further address these questions we performed the first two studies
comparing LIA with placebo following unicompartmental (Study I) and
total (Study II) knee arthroplasty.
Several studies published in the literature compared the LIA technique to
other standard methods for postoperative pain management after TKA,
such as epidural analgesia 30-32 and femoral nerve blocks 33-36. However, no
previous study has compared LIA with intrathecal morphine. Therefore,
we conducted the third study, comparing LIA with intrathecal morphine
following TKA (Study III).

Minimally invasive surgery (MIS)


Another attempt to reduce postoperative pain and improve mobilization
has been the development of minimally invasive surgery (MIS) 37-40. Repicci
et al. introduced the mini-arthrotomy or minimally invasive surgery in
unicompartmental knee arthroplasty in the 1990s and during the proce-
dure, a limited amount of local anesthetic was infiltrated, mainly in the
anterior part of the joint 40. The procedure resulted in earlier mobilization
and shorter hospital stay than conventional surgery, in which a longer
incision was used that resulted in greater trauma. The work of Repicci et
al. influenced Kerr and Kohan in developing the LIA technique (Kerr,
2011, personal communication). In another non-randomized study, Price
found that patients undergoing UKA using MIS could be mobilized twice
as fast as conventional surgery 41. In the only randomized controlled study

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 15


comparing MIS with conventional exposure in UKA, Carlsson et al. found
shorter hospital stay in the MIS group, but no difference in postoperative
pain or range of motion of the knee 42. The use of MIS during total knee
replacements has been debated 43 and is not universally accepted.
In Sweden the MIS technique for unicompartmental knee arthroplasty
quickly became popular and today more than 50 % of UKAs are per-
formed with MIS 2. MIS is considered a more difficult technique and most
orthopedic surgeons are more familiar with the conventional exposure.
Therefore we were interested in evaluating whether MIS, compared to
conventional surgery, would reduce postoperative pain and improve mobi-
lization following UKA, when both groups received LIA (Study IV).

16 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Aims of the thesis
General
To investigate the effect of local infiltration analgesia on postoperative
pain and mobilization following knee arthroplasty.

Specific aims Studies IIV

I To evaluate whether the local infiltration analgesia (LIA) technique


would result in better postoperative analgesia and earlier mobiliza-
tion, compared to placebo, following unicompartmental knee ar-
throplasty performed with minimally invasive technique.

II To evaluate whether the local infiltration analgesia (LIA) technique


would result in better postoperative analgesia and earlier mobiliza-
tion compared to placebo, following total knee arthroplasty. To
evaluate whether the local infiltration analgesia (LIA) technique
would result in toxic blood concentrations of the local anesthetic.

III To evaluate whether the local infiltration analgesia (LIA) technique


would provide better postoperative analgesia and earlier mobiliza-
tion than intrathecal morphine following total knee arthroplasty.

IV To evaluate whether minimally invasive surgery (MIS) would result


in reduced postoperative pain and earlier mobilization, compared to
conventional surgery, following unicompartmental knee arthro-
plasty, when both groups received local infiltration analgesia (LIA).

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 17


Methods
Ethics
The Regional Ethics Committee in Uppsala, Sweden, approved the study
protocols of all four studies and the Swedish Medical Products Agency
approved the study protocols for studies I and II. All studies were con-
ducted in accordance with the Declaration of Helsinki and according to
Good Clinical Practice, and an independent body, the Clinical Research
Support Unit at rebro University Hospital, monitored studies IIII. All
studies were registered in a central online database, maintained at Clini-
calTrials.gov.

Patients
Patients scheduled for UKA (I, IV) and TKA (II, III) were screened for stu-
dy eligibility by one of the researchers participating in the study. Inclusion
criteria were: ASA physical status IIII, 2080 years (I, IV), 2085 years
(II) and 4085 years (III). Exclusion criteria were allergy or intolerance to
any of the study drugs, severe liver, heart or renal disease, bleeding disor-
der or chronic pain requiring opioid medication.

Anesthesia
All patients received diazepam 10 mg orally 1 hour before planned surgery
and all operations were performed under general anesthesia, except in stu-
dy III, where spinal anesthesia was used. General anesthesia was induced
with fentanyl 12 g/kg and propofol 12 mg/kg IV. Tracheal intubation
was performed after muscle relaxation with rocuronium 0.5 mg/kg and
anesthesia was maintained with 13% sevoflurane and 33% oxygen in
nitrous oxide.
In study III, spinal anesthesia was used and glucose-free bupivacaine
17.5 mg (3.5 mL) injected using a 27 G spinal needle at the L3/L4 or L2/L3
intervertebral space with the patient in the sitting position.

Study design
All studies were prospective, randomized, controlled trials and all but stu-
dy IV were double-blinded. Surgery was performed at the Department of
Orthopedics, rebro University Hospital, Sweden, between September
2005 and March 2011.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 19


Studies I and II
After randomization the patients were allocated to one of two groups, LIA
or Placebo, with 20 patients in each group in study I (UKA) and 24 pa-
tients in each group in study II (TKA).
In the LIA groups, the LIA-mixture was infiltrated intraoperatively into the
knee and on the following morning, injected via the knee catheter, while
the Placebo groups received no injections intraoperatively and a saline
injection via the knee catheter postoperatively.
A sub-study was first performed on 8 patients prior to the start of study
II to investigate the unbound and total venous blood concentration of
ropivacaine, the local anesthetic within the LIA-mixture.

Study III
Patients (n=50) were randomized into two groups, LIA and M (intrathecal
morphine), with 25 patients in each group. In group M, morphine 0.1 mg
(0.25 mL) was injected intrathecally, while in group LIA an equal volume
of saline (0.25 mL) was administered together with the spinal anesthetic.
Group LIA received LIA intraoperatively and then via the intraarticular
catheter on postoperative day 1 and 2, while patients in group M received
no injections intraoperatively and saline injection via the knee catheter
postoperatively.

Study IV
Patients were allocated to either group MIS or CON (conventional), with
20 patients in each group. All patients received LIA intraoperatively and an
injection via the intraarticular catheter postoperatively.

20 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Surgery

Studies I and IV (Unicompartmental knee arthroplasty)


A medial unicompartmental knee arthroplasty was performed in all pa-
tients. In study I, a minimally invasive surgery (MIS) technique was used in
all patients and in study IV, patients were randomized to either MIS or
conventional surgery. All patients received the Link Endo-Model Sled Pros-
thesis (Link Sweden AB, kersberga, Sweden) (Fig. 1).

UKA TKA

Fig. 1. X-ray images of unicompartmental (UKA) and total knee arthroplasty (TKA).

Conventional surgery
A 15- to 20-cm-long mid-line skin incision was made. A medial parapatel-
lar arthrotomy was performed from the base of the patella and continued
distally to the medial side of the tibial tuberosity. The arthrotomy was
extended proximally 510 cm into the rectus tendon of the quadriceps
muscle, in order to allow eversion and dislocation of the patella (Fig. 2).

Minimally invasive surgery (MIS)


An 8- to 10-cm-long medial parapatellar skin incision was made from the
upper medial pole of the patella and carried distally to the medial side of
the tibial tuberosity. A medial parapatellar arthrotomy was performed
from the base of the patella, leaving the muscle fibers of the vastus medialis

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 21


untouched, and continued distally to 23 cm below the joint line, to the
medial side of the tibial tuberosity. The patella was not dislocated or
everted. (Fig. 2)

Conventional MIS

Fig. 2. Surgical exposures.

Studies II and III (Total knee arthroplasty)


Total knee arthroplasty was performed through a conventional medial
para-patellar approach (Fig. 2) using AGC prostheses (Biomet, Warsaw,
IN, USA) (Fig. 1).

Postoperative pain management

Local infiltration analgesia (LIA)


During the operation, the surgeon infiltrated a mixture of ropivacaine,
ketorolac, and epinephrine systematically into all tissue that had been trau-
matized during surgery in the following way: 3050 mL of the solution
was infiltrated in the posterior capsule and the collateral ligaments after
the bone cuts had been made and before insertion of the prosthesis (Fig. 3)
The injections were performed using a systematic sequence of multiple
injections from one side to the other in order to ensure uniform distribu-
tion of the mixture of drugs. After the prosthesis had been inserted, an-
other 4060 mL was injected in the capsule incision, the quadriceps ten-
don, and the infra-patellar ligament, and around the posterior cruciate
ligament. The final 3050 mL was infiltrated into the subcutaneous tissue

22 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


before skin closure. When the conventional exposure was used, the subcu-
taneous injection was without epinephrine or ketorolac in order to avoid
possible damage of the skin blood circulation 36. In study I, a total of 200
mg ropivacaine was infiltrated during the operation, while in studies IIIV,
the dose was increased to 400 mg. In all studies 30 mg ketorolac and 0.5
mg epinephrine were injected (Table 1).

Table 1. Intraoperative LIA-mixture

Study ropivacaine ketorolac epinephrine Total volume


(mg) (mg) (mg) (mL)

I (UKA) 200 30 0.5 106


II (TKA) 400 30 0.5 166
III (TKA) 400 30 0.5 166
IV (UKA) 400 30 0.5 146 (group CON)
116 (group MIS)

Fig. 3. Local infiltration analgesia. Intraoperative infiltration.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 23


Before wound closure, a multi-hole 20-G catheter was tunneled under the
skin, the tip of the catheter was placed intraarticularly and a bacterial filter
was connected to the catheter in all patients (Fig. 4). No drains were used.
On the first postoperative morning, a bolus dose was injected via the in-
traarticular catheter. The bolus LIA mixture consisted of ropivacaine 150
mg (study I) or 200 mg (studies IIIV), ketorolac 30 mg and epinephrine
0.1 mg in a total volume of 22 mL. In study III, an additional bolus injec-
tion was administered on the second postoperative morning in an attempt
to prolong the analgesic effect.

Fig. 4. Local infiltration analgesia. Intraarticular catheter for postoperative injections.

A cooling bandage was applied for the first 6 hours postoperatively and a
compression bandage for 24 hours in all studies (IIV).

Intrathecal morphine
In study III, glucose-free bupivacaine 17.5 mg (3.5 mL) was injected in-
trathecally in all patients together with morphine 0.1 mg (0.25 mL) in
group M, or 0.25 mL of 0.9 % saline in group LIA.

24 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Rescue medication
In all studies, all patients received paracetamol 1 g orally every 6 hours. In
the recovery room, a Patient-Controlled Analgesia (PCA)-pump (Gemstar
Abbott) with IV morphine (1-mg bolus and 6-min lockout time) was con-
nected. The PCA-pump was discontinued at 24 h postoperatively in studies
I and IV and at 48 h in studies II and III, if the Visual Analogue pain Score
(VAS) 0-100 mm was < 40 mm during a 2 h period at rest. Thereafter,
patients were permitted to take paracetamol 1 g and tramadol 50100 mg
orally up to 4 times daily, as required for pain relief.

Outcome measurements

Pain
Postoperative pain intensity was assessed both at rest and on motion (60
degrees of knee flexion) using VAS.

Analgesic consumption
PCA-morphine (primary endpoint in studies II and III) and oral analgesic
consumption were recorded at different time periods postoperatively.

Patient satisfaction
The patients were asked to give a verbal rating for satisfaction with the
quality of analgesia (excellent = 4, good = 3, inadequate = 2, poor =1) dur-
ing the first, second and seventh postoperative days (IIV).

Functional outcome
Maximum degree of knee flexion and extension was assessed (IIV). In the
UKA studies (I and IV) the ability to walk with a frame 6 h postoperatively
was recorded. Time to Up and Go (TUG)-test was also assessed (IIIV).
The TUG-test involves timing the patient while they rise from an armchair,
walk three meters, turn, walk back and sit down again 44. Times < 20 s
indicate that the patient is independently mobile. The Oxford Knee Score
and EuroQol (EQ-5D) were determined (IIV). Oxford Knee Score is a
validated 12-item knee questionnaire that scores patients from 12 (best
possible) to 60 (worst possible) 45. EQ-5D is a standardized measure of
health outcome 46. It provides a single index value from 0 to 1, where 0
represents poor health and 1 represents perfect health.

Home readiness and Length of hospital stay


Time to fulfillment of discharge criteria (home readiness) was recorded in
study IIIV (primary endpoint in study IV), using the following discharge

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 25


criteria: Mild or no pain (VAS < 30 at rest) sufficiently controlled by oral
analgesics, able to walk with elbow crutches, ability to climb 8 stairs, eat
and drink normally, and no evidence of any surgical complication. Length
of hospital stay (LOS) was also recorded (day 0 = the day of operation) as
actual time to home discharge in all four studies (primary endpoint in
study I).

Adverse events
The incidence of nausea, vomiting, pruritus and sedation were recorded on
the first and second postoperative days. All complications and adverse
events were registered intra- and postoperatively and also after discharge.
Any hospital readmission during the postoperative follow-up period was
also recorded.

Plasma concentrations of ropivacaine


A sub-study of 8 patients investigating the plasma concentration of ropiva-
caine was performed prior to the start of study II. Venous blood was col-
lected postoperatively after 30, 60, 90, 120 and 180 min and just before
and after the catheter injection at 30, 60, 90, 120 and 180 min for analyses
of total and free (unbound) concentrations of ropivacaine.

Statistics
Power analyses were performed prior to the start of each study using data
from previously published studies, when available, or data from some pilot
patients for sample-size calculations. The length of hospital stay (primary
endpoint in study I) and home readiness (primary endpoint in study IV)
were analyzed using the Mann-Whitney U test.
VAS pain scores were analyzed using the Mann-Whitney U test at each
time point in studies I, II and IV. In study III, a median value for the first
48 postoperative hours was calculated as a summary measure for each
patient; the difference between the groups was then analyzed using the
Mann-Whitney U test.
The Mann-Whitney U test was used to analyze morphine consumption
in studies II (primary endpoint), I and IV, while repeated measures analysis
of variance (ANOVA) was used in study III (primary endpoint).
Patient satisfaction scores and knee function scores, including Oxford
Knee Score and EQ-5D, were also analyzed using the Mann-Whitney U
test. In study IV repeated measures analysis of variance (ANOVA) was
used to analyze knee extension and flexion.

26 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


The Bonferroni-Holm method was used to correct for multiple meas-
urements 47. Dichotomous data was analyzed using the chi-square test or
Fishers exact test, as appropriate.
A value of p < 0.05 was considered to be statistically significant. SPSS
(version 15.0 for windows, SPSS Inc., Chicago, IL) and STATA (release 11,
StataCorp., College Station, TX) were used in statistical analysis.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 27


Results
A total of 178 patients were enrolled in these four studies (Table 2). Of
these 178 patients, 7 were excluded after randomization: 2 in study I, 1 in
study II, 2 in study III and 2 in study IV.

Table 2. Demographic data and type of surgery.

Paper n Age Female/male ASA I/II/III Surgery

I 40 65 (6) 20/20 16/24/0 UKA


II 48 71 (9) 26/22 12/35/1 TKA
III 50 71 (8) 31/19 6/40/4 TKA
IV 40 64 (7) 23/17 16/24/0 UKA

n = number of patients. Age is shown as mean (SD). ASA physical status I:


normal health; II: systemic disease with no limited activity; III: systemic
disease with limited activity. UKA = unicompartmental knee arthroplasty.
TKA = total knee arthroplasty.

Pain
In the first three studies, postoperative pain scores were lower at rest in the
LIA groups and this was even more pronounced on flexion. The lower pain
intensity at rest lasted until 27 h postoperatively when compared with
placebo (I, II) and up to 24 h when compared with intrathecal morphine
(III).
On flexion there was lower pain intensity up to 27 h postoperatively in
the LIA group following unicompartmental arthroplasty (I) (Fig. 5) and up
to 48 h during total knee arthroplasty in studies II (Fig. 6) and III (Fig. 7).
No differences in postoperative pain intensity were found when comparing
minimally invasive to conventional surgery where both groups received
LIA (IV) (Fig. 8).

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 29


Fig. 5. Pain on flexion (UKA) (Study I). Group A: LIA and Group P: Placebo. a) p< 0.05.

Fig. 6. Pain on flexion (TKA) (Study II). Group A: LIA and Group P: Placebo. a) p< 0.05.

30 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Fig. 7. Pain on flexion (TKA) (Study III). Group L: LIA and Group M: Intrathecal
morphine. a) p < 0.05.

Fig. 8. Pain on flexion (UKA) (Study IV). Group MIS and Group CON: Conven-
tional surgery.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 31


Morphine consumption
Morphine consumption was lower in the LIA groups than in the placebo
groups in unicompartmental (I), and in total knee arthroplasty (II), and
also compared to intrathecal morphine (III) (Table 3). No differences were
found when comparing minimally invasive and conventional surgery in
unicompartmental knee arthroplasty, where both groups received LIA (IV).

Tab. 3. Morphine consumption 048 h.

Paper Median (range) Median (range) p-value

I (UKA) 21 (0-68) 67 (17-126) <0.001


II (TKA) 18 (1-74) 87 (36-160) <0.001
III (TKA)* 23 (2-80) 42 (19-138) <0.001
IV (UKA) 14 (0-63) 8 (0-51) 0.19

IV PCA-morphine in mg. Studies III: LIA vs. Placebo; Study III: LIA vs.
intrathecal morphine; Study IV: MIS vs. Conventional surgery (LIA in both
groups). * Reported as mean (SD) in the published paper: 26 (15) vs. 54
(29) mg.

Home readiness, length of hospital stay


Time to fulfillment of discharge criteria (home readiness) was shorter in the
LIA groups compared to the placebo group (II) and compared to the in-
trathecal morphine group (III) during total knee arthroplasty. In study IV,
there were no differences between the minimally invasive and conventional
surgery, both groups were home ready after a median time of 24 hours.
A shorter length of hospital stay was found in the LIA groups compared
to the placebo group (I) (Fig. 9) and compared to the intrathecal group
(III). However, this shorter hospital stay in patients in the LIA group vs.
placebo in study II (4 vs. 6 day), did not reach statistical significance (p =
0.06) (Table 4). In study IV there was no difference between the groups in
terms of hospital stay and the proportions of patients who were discharged
during the first postoperative day were similar between the groups; 80 %
in group MIS compared to 83 % in group CON (p = 1.0). After 2 days,
only one patient in group MIS remained in the hospital and was discharged
on postoperative day 3. These results correspond well with the LIA group
in study I (Fig. 9).

32 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Fig. 9. Length of Hospital Stay (Study I). Group A: LIA and Group P: Placebo.

Tab. 4. Length of Hospital Stay.

Paper Median (range) Median (range) p-value

I (UKA) 1 (1-6) 3 (1-6) <0.001


II (TKA) 4 (2-8) 6 (3-10) 0.06
III (TKA) 3 (2-17) 4 (2-14) 0.03
IV (UKA) 1 (1-3) 1 (1-2) 0.19

Length of hospital stay (number of days). Study III: LIA vs. Placebo;
Study III: LIA vs. intrathecal morphine; Study IV: MIS vs. Conventional
surgery (LIA in both groups).

Surgical outcome
The only difference in knee function in the UKA study (I) was found after
27 h, with better knee extension and knee flexion in the LIA group com-
pared to the placebo group (medians of 5 degrees vs. 10; and 90 degrees vs.
80). In the TKA study (II) comparing LIA with placebo, we found that the
LIA group showed better knee flexion at 24 h (90 vs. 60 degrees); and at

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 33


48 h (75 vs. 60 degrees). No differences in knee function scores were found
in Studies III and IV.
In study I, 16 of 19 patients in the LIA group compared to 9 of 19 in the
placebo group were able to walk with a frame at 6 h postoperatively
(p=0.04). In study IV, comparing minimally invasive and conventional
surgery, no difference was found between the groups in the ability to walk
with a frame (14 of 17 patients vs. 13 of 15).
A greater proportion of patients given LIA compared to intrathecal mor-
phine (III) were able to climb stairs at 24 h (20 % vs. 4 %) and at 48 h (70
% vs. 22 %).
No differences were found between the groups in any of the studies in
the TUG-test, Oxford Knee Score or EQ-5D.

Patient satisfaction
Patient satisfaction was greater in the LIA groups in the TKA studies (II
and III), but no statistically significant differences between the groups were
found in the UKA studies (I and IV).

Side effects
There was a lower incidence of nausea, pruritus and sedation in the LIA
groups compared with placebo groups (I and II), but no differences were
found when LIA was compared with intrathecal morphine (III).
It was found that 14 of 171 cultures taken from the catheter tips were
positive for solitary coagulase-negative Staphylococcus, but no signs of
clinical infections were found in any of these patients. One patient in study
III was readmitted due to a swollen knee and mild fever, which resolved
following oral antibiotic administration. However, wound cultures were
negative and no deep infection developed in this patient.

Sub-study on ropivacaine blood concentration (II)


The individual maximum unbound venous plasma concentration of
ropivacaine varied between 0.032 and 0.121 g/mL in the subgroup of 8
patients studied, which was below the toxic level of 0.35 g/mL 48 (Fig.
10). The individual maximum total venous plasma concentration of
ropivacaine varied between 0.062 and 2.458 g/mL (Fig. 11). The highest
individual value of total venous plasma concentration (2.458 g/mL) corre-
sponded to an unbound venous plasma concentration of 0.093 g/mL.
None of the patients displayed any symptoms or signs of systemic LA tox-
icity.

34 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Fig. 10. Unbound venous plasma concentration of ropivacaine.

Fig. 11. Total venous plasma concentration of ropivacaine.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 35


Discussion
Knee arthroplasty is considered one of the most successful orthopedic pro-
cedures, usually resulting in a pain-free knee, restored function and with
excellent long-term outcomes for patients. Although successful, the proce-
dure is generally associated with moderate to severe postoperative pain.
This thesis addresses the important issue of postoperative pain manage-
ment using a new and promising technique, often called local infiltration
analgesia (LIA), which we have studied in patients undergoing knee ar-
throplasty.

The technique
The LIA technique has been used by several groups of researchers, particu-
larly in Scandinavia 26-34, 36, 49. However, there are many descriptions and
variations in the technique used, which may partly explain the variability
in reported results. In the studies performed by our group, we used the
original method outlined by Kerr and Kohan 23 with some minor modifica-
tions. In our initial study on patients undergoing UKA, we decided to use a
lower dose of ropivacaine (200 mg), since we were concerned about poten-
tial LA toxicity when infiltrating large doses into the soft tissue around the
knee joint. In that study, we found no signs or symptoms of LA toxicity.
Therefore, in our second study, in patients undergoing TKA, we decided to
increase the dose of intraoperative ropivacaine to 400 mg and the postop-
erative bolus dose to 200 mg. This was for two reasons: firstly, TKA in-
volves more extensive surgery and therefore the volume of injectate had to
be increased; secondly, we thought there may be a dose-response effect,
with increased dosage producing improved analgesia. To ensure the safety
of such high doses of ropivacaine, we first performed a sub-study investi-
gating the plasma concentration of ropivacaine prior to starting the main
study. We found that, although ropivacaine is absorbed to a significant
extent from the knee joint, the plasma concentration of ropivacaine con-
tinued to be low despite these high doses, and no patient showed any
symptoms of clinical LA toxicity. This could be because we used epineph-
rine in the mixture of drugs, which may have prevented rapid LA absorp-
tion from the tissues. Additionally, we used compression dressings and
hypothermic pads around the knee joint, which may also have reduced LA
absorption. However, no specific splint was applied to stabilize the knee,
except for the splinting effect of the compression and cooling bandages.
The effect-duration of LIA appears to vary between studies 26-29 and the
effect could be short-lasting. Therefore, several authors used catheters

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 37


placed intraarticularly in order to prolong the duration of action. We did
not use any additional top-up bolus injections, except for the one on the
first postoperative morning. It is possible that intermittent injections during
the evening and night may have improved pain-relief. However, this
method has two problems: firstly, there is a risk of LA toxicity when using
several doses after the large initial bolus. Secondly, administering intermit-
tent injections on hospital wards could be personnel-intensive and require
frequent patient monitoring to detect possible of LA toxicity, so therefore
we decided to give a single dose the following day in order to prolong the
effect.
In addition, it is important to perform the intraoperative injections care-
fully and in a standardized way in order to achieve the best effect. Not only
is sterility important in this situation, but also a careful injection protocol
is required to ensure proper spread of the drug into traumatized tissues and
therefore effective analgesia.

Catheter injections
The definition of LIA is not universally agreed upon at the present time 50
and therefore, in the studies published to date, either bolus injections 29, 36,
continuous infusions 27, 30, 51 or single dose at the end of the procedure 28
have been used to describe the same technique. In our studies, we used the
intraarticular catheter for one bolus injection, using a smaller volume of
the same mixture on the first postoperative morning, except in study III,
where we injected another dose of this mixture on the second postoperative
morning in order to further prolong the effect of LIA.
A number of studies reported that an intraarticular injection of local an-
esthetics, without infiltration into periarticular tissues, after TKA had no
effect on postoperative pain 52-55. At present, there is little information in
the literature regarding the specific effect of bolus injections following in-
traoperative infiltrations and the scientific evidence for these bolus injec-
tions has been questioned 56. Only one study has specifically addressed this
issue 57. In that study on hip arthroplasty, both groups received LIA during
the operation. Postoperatively at 10 and 22 hours, one group received the
LIA-mixture via the catheter while the other group received saline via the
catheter. The authors found no clinically important effect of bolus injection
following total hip arthroplasty. Although our studies were not designed to
examine the catheter-injections specifically, we believe that the decrease in
pain intensity following the catheter injections in the LIA groups indicates
a definitive but short-lasting effect of the bolus injection. The advantage of
catheter-use in relation to the potential risk of infection needs to be ad-
dressed in future studies.

38 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Pain intensity and morphine consumption
Effective pain relief is central to improving patient satisfaction and possibly
long-term outcomes. Therefore, it is important to confirm the efficacy of
LIA compared to placebo. We found lower VAS pain scores in the LIA
groups than the placebo groups (I, II) at rest and this difference was more
pronounced on flexion. This is an important finding, since adequate flex-
ion of the knee prevents stiffness and promotes mobilization.
Thus, we found a statistically significant difference between the LIA and
placebo groups that lasted up to 27 h postoperatively following UKA
(study I) and up to 48 h following TKA (study II). One explanation for the
difference in duration of analgesia between the two studies could be that
the pain intensity decreases faster following UKA, which is a less invasive
procedure than TKA. Another explanation could be that the dose of
ropivacaine in LIA was increased from 200 mg (study I) to 400 mg in the
TKA study (II). In addition to the lower pain intensity in patients receiving
LIA, we also found that morphine consumption was lower in the LIA
groups compared to the placebo groups in studies I and II. Our results are
in accordance with those of other authors comparing LIA with placebo 26,
28, 29
.
Having shown that LIA is beneficial compared to placebo in both UKA
and TKA, we were interested to assess its efficacy with intrathecal mor-
phine, another common technique for postoperative pain management.
The duration of action of intrathecal morphine varies between 8 and 24 h.
However, at least two recent studies reported reduced rescue analgesic
consumption up to 48 h after intrathecal morphine injection 58, 59. We
found that patients receiving LIA had lower pain intensity and reduced
morphine consumption for up to 48 h postoperatively (study III). How-
ever, the prolonged analgesia seen in this study could be because we gave a
bolus injection on the second postoperative morning (study III).
In study IV, comparing MIS with conventional surgery in UKA, we
found no differences between the groups regarding pain intensity or mor-
phine consumption. Traditionally, knee replacements have been performed
with a 2025 cm-long skin incision and a medial parapatellar capsule inci-
sion. The capsule incision is extended proximally into the quadriceps ten-
don and the patella is everted and dislocated laterally. This approach gen-
erally gives good access, but results in a fairly great trauma to soft tissue
around the knee.
MIS involves an 810 cm-long skin incision. The patella is not everted
or dislocated, and the extensor mechanism is left unharmed. The quadri-
ceps-sparing rather than the shorter skin incision is thought to be the key
factor in MIS knee surgery 60. We had expected greater postoperative pain

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 39


in the conventional exposure with a longer skin incision, but we were sur-
prised that the pain scores were rather low. Interestingly, we found that
median pain scores at rest were below 6 mm and on flexion below 20 mm
at all time points during the first 27 hours postoperatively in both groups.
Furthermore, the doses of morphine used were generally very low in study
IV. These findings relating to pain intensity are in agreement with another
randomized, controlled trial by Carlsson et al. 42. There could be several
possible explanations for the low pain intensity and low morphine con-
sumption in our study. For one, we used the local infiltration technique in
both groups, including a bolus injection on the first postoperative morning.
In addition, we had increased the dose of the local anesthetic (ropivacaine)
from 200 mg to 400 mg during the operation and from 150 mg to 200 mg
postoperatively in study IV compared to study I. Thus, the patients in the
conventional surgery group had the best possible pain management proto-
col that we had found over several years of research, with the result that
pain intensity was low in this group.

Knee function, patient satisfaction


In addition to satisfactory pain relief, good knee function and high patient
satisfaction are important patient-related end-points. Thus, our aim was to
achieve good pain relief in the expectation that this would lead to im-
proved knee function as well as patient satisfaction. It was previously
shown that severe pain may hinder mobilization 61.
We assumed that mobilization could be assessed, indirectly, by the maxi-
mum degree of knee flexion and extension. In other words, good knee
flexion and extension were taken to be prerequisites for early mobilization.
However, we saw only a small difference between LIA and placebos in
studies I and II during the first 48 postoperative hours; however, a signifi-
cantly greater proportion of LIA patients were able to walk using a frame
at 6 h postoperatively following UKA (study I). This is probably a more
direct measure of mobilization and a better predictor of early home dis-
charge than knee flexion/extension. This was also seen in study III, where
more patients were able to climb stairs at 24 and 48 h postoperatively,
indicating earlier mobilization in the LIA group compared to the intrathe-
cal morphine group. However, no differences were found in the TUG-test.
Although the TUG-test has been used as an objective measure of mobiliza-
tion in previous studies, we did not find that it was sensitive in detecting
differences between pain management techniques.
When comparing the two surgical techniques (study IV), we found no
differences in knee function scores. This is in contrast to another study on
MIS 41. Price found that patients undergoing UKA using MIS could be mo-

40 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


bilized twice as fast as conventional UKA. We could not confirm those
results. One explanation for these differences could be that all patients in
our study were mobilized early and more than 80 % were discharged home
on the first postoperative day.
Although greater patient satisfaction was found in the LIA groups in
studies II and III, only minor differences were seen in functional outcomes
as assessed by the Oxford Knee Score or in the health-related quality of life
as determined by EQ-5D, in all studies. This could partly be explained by
the fact that these assessments took place first after 2 weeks and after 3
and 6 months (I, IV), when the likely benefits of LIA were no longer pre-
sent. On the other hand, this supports the findings of other studies, that the
LIA technique with early home discharge is safe following unicompartmen-
tal knee arthroplasty 37-39.

Home readiness, length of hospital stay


Early home readiness and discharge are important parameters for quality
of care. Not only does this mean that patients are able to look after them-
selves but the costs of health-care are reduced. Indeed, we demonstrated
significantly earlier discharge from hospital in the LIA groups in studies I
and III. However, in study II, where we compared LIA with placebo during
TKA, the differences did not reach statistical significance. Thus, although
we demonstrated a definite reduction in pain intensity in the LIA group
during TKA, this did not result in earlier home discharge. Since length of
hospital stay can be influenced by several non-medical factors (administra-
tive reasons or the availability of a home-carer), it is not always possible to
demonstrate a difference in home discharge in small studies. Furthermore,
when we initially investigated the LIA technique, we did not adopt the
entire protocol outlined by Kerr and Kohan, which included pre-operative
patient education and post-discharge follow-up. Thus, it is possible that we
did not fully exploit the potential advantages of good postoperative pain
management in our protocol. Another explanation could be that this study
was not powered to detect a difference in home readiness.
We did, however, assess the time to fulfillment of all discharge criteria
(home readiness) in studies IIIV. In assessing home readiness it is impor-
tant to use objective parameters that can easily be assessed and have rele-
vance for both the patient and the care-giver. Since home readiness de-
pends on a composite of several factors, delay in one of these factors would
influence outcome. This outcome coincided well with hospital stay and
showed statistical significance in studies II and III, in favor of the LIA
groups.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 41


In contrast to our findings, other authors did not report a shorter hospi-
tal stay when comparing LIA with placebo 28, 29. One possible explanation
for this could be that Busch et al. used no bolus injections after 24 h as in
our study, while Vendittoli et al. used ropivacaine alone in the bolus injec-
tion. Of the other studies comparing LIA with other methods for postop-
erative pain relief, only one (LIA vs. EDA) demonstrated a reduction in
hospital stay 31. The other studies, where the authors compared LIA with
EDA 30, 32 or femoral nerve block 33, 34, 36, did not find any difference in
length of hospital stay. We do not have any clear explanation for the dif-
ference between these studies but, as mentioned earlier, it could be due to a
multitude of factors that influence home discharge, some of which can be
difficult to control in clinical studies. Additionally, if the whole protocol is
not adopted, the benefit of LIA in terms of early mobilization and dis-
charge might not be evident.
In the final study (IV), comparing minimally invasive surgery and con-
ventional surgery in unicompartmental knee arthroplasty (both groups
received LIA), we found no differences in home readiness or length of hos-
pital stay between the groups. This was somewhat surprising and contrary
to the study by Carlsson et al., who found a difference of 3 days (3 vs. 6
days) in hospital stay in favor of the MIS group 42. There could be several
explanations for this. It is possible that LIA provides excellent analgesia
even during more extensive surgery and therefore differences in postopera-
tive pain and mobilization were less obvious between the two operative
techniques. Another explanation could be that the bone preparations and
implant insertion during MIS are made through a limited exposure, which
may involve more extensive use of wound retractors and associated dam-
age to soft tissue, resulting in postoperative pain.

Adverse events
Lower morphine consumption reduces the risk of opioid-related side ef-
fects, such as nausea, pruritus and sedation. Indeed, we found lower inci-
dence of such side effects in the LIA groups when compared to placebo (I,
II), and, although a similar tendency was found in comparison with in-
trathecal morphine (III), this did not reach statistical significance. A greater
difference may have been anticipated between the groups in study III, since
the control group in this study received both intrathecal morphine and
PCA-morphine. However, the intrathecal morphine dose was relatively low
and the study was not powered to detect a difference in this parameter.

42 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Systemic and local toxicity
The possible hazards of the LIA technique need to be discussed. Injecting
such high doses of ropivacaine as we did presents a risk of systemic and
local toxicity. Ropivacaine is less cardiotoxic then bupivacaine 62, 63. When
increasing the dose from 200 mg (I) to 400 mg (II), we assessed the possi-
ble systemic toxicity of ropivacaine. The unbound venous blood concentra-
tion of ropivacaine was below known systemic toxic blood concentrations
48
and we found no clinical signs of systemic toxicity in any patient. These
results are in accordance with other studies, which also reported low blood
concentrations of ropivacaine 27, 28. Therefore, 400 mg ropivacaine appears
to be safe when injected using the method described.
Another important question is whether there is a risk of local toxicity of
ropivacaine injected intraarticularly. In recent years, there were reports of
chondrolysis associated with the use of another LA, bupivacaine, when
administered intraarticularly via a pump during shoulder surgery 64. How-
ever, this appears to have been specifically when using bupivacaine since
there are no published reports of similar effects for ropivacaine. Piper did
not find any evidence for chondrotoxicity of ropivacaine in vitro 65. Fur-
thermore, chondrotoxicity is mainly of concern in unicompartmental knee
arthroplasty, since all or nearly all of the cartilage is replaced by the im-
plant in TKA. However, in the 57 UKA patients receiving LIA in our stud-
ies, we saw no clinical evidence of any chondrolysis during the 6 months
follow-up. Two patients in study IV had residual pain in the medial part of
the knee after the 6 months follow-up. Clinical and radiological follow-up
of these patients did not show any signs of implant loosening or lateral
chondral damage. This may indicate that the proposed risk of toxic chon-
drolysis caused by the local infiltration analgesia is probably not evident in
unicompartmental knee arthroplasty. Additionally, we have used ropiva-
caine during knee as well as shoulder arthroscopies for over 10 years in our
institution without any evidence of chondrolysis.
The next question is whether ketorolac injected periarticularly has any
negative effect on implant fixation. There has long been a concern in the
orthopedic community regarding the effect of NSAIDs on bone-healing 66.
However, a recent study on NSAIDs administered during a 3-weeks period
did not show any negative effect on prosthesis fixation in total knee re-
placement 67. Therefore, it is our belief that NSAIDs are safe when used in
the LIA mixture as descibed.
Finally, there is a debate over whether it is safe to leave an intra-
articular catheter for 12 days following knee surgery. As an orthopedic
surgeon, one is always concerned when there is a possible risk of bacterial
invasion via the catheter and into the prosthesis. A number of studies in

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 43


addition to ours, using LIA and intraarticular catheters, have not reported
any infections related to the use of the wound catheter 27, 29, 36. However,
two studies did report deep infections. DeWeese et al. reported one deep
infection in 91 patients, while Rasmussen et al. found one case in 136
TKAs when a catheter was left in situ for 72 hours 51, 68. This low incidence
of deep infection following TKA can be expected even without intraarticu-
lar catheters 69. In the 171 patients included in this thesis, where catheters
were left in situ, we found no case of deep infection. It is important to
stress that all our patients were given antibiotics until the catheter was
removed, that the catheters were inserted during the operation under sterile
conditions and a bacterial filter was used during all postoperative intraar-
ticular injections. Furthermore, local anesthetics have been reported to
possess anti-inflammatory, bacteriostatic and antimicrobial effects 70, 71,
which may help explain the lack of any deep infection in our patients. In
conclusion, it seems safe to use an indwelling knee catheter in the method
described in these studies.

Limitations
There are some limitations with the three initial studies (I, II, III) that need
to be addressed. Should the control group have received systemic NSAIDs,
in order to exclude a possible systemic effect of ketorolac in patients receiv-
ing LIA? In our studies, the aim was to compare the concept of LIA to
placebo (I, II) or intrathecal morphine (III), rather than to investigate the
individual drugs. Furthermore, some studies have indicated a local (rather
than systemic) effect of NSAIDs 30, 31, 72-76. For example, Spreng et al. re-
ported a superior effect of ketorolac injected locally in the LIA-mixture
than when administered intravenously 31. To our knowledge, there are no
published studies where the systemic concentrations of ketorolac were
measured following peri- and intraarticular injections. Unpublished data
from Kerr in Australia show that peak blood-levels following local infiltra-
tion were significantly lower than when given intramuscularly, 0.28 g/mL
compared to 2.6 g/mL (Kerr 2011, personal communication). However, it
is possible that some of the analgesic effect of LIA could be contributed by
its systemic absorption of both LA and ketorolac, but we believe that this
is of minor importance. Although LA administered intraarticularly is ab-
sorbed into the systemic circulation, the concentrations are low. Neverthe-
less, this systemic absorption may contribute to the observed analgesic
effect.
We did not use any oral NSAID in the protocols for our studies. The use
of oral NSAIDs may have further reduced postoperative pain 77, 78. How-
ever, we decided not to include these for several reasons. We were con-

44 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


cerned about possible systemic toxicity, since we used another NSAID
(ketorolac) in the LIA-mixture. It is possible that we could have used oral
NSAIDs in the placebo group but this would have confounded the evalua-
tion of the LIA concept. Finally, there was an ongoing debate concerning
the cardiotoxic effects of NSAIDs at the time of writing the study proto-
cols, which possibly contributed to the decision to avoid oral NSAIDs.
Could a higher dose of morphine injected intrathecally resulted in better
pain relief and a minimal difference between the groups in study III? In one
study, the authors reported that morphine 0.1 or 0.2 mg resulted in similar
postoperative pain relief after hip arthroplasty 19. In addition, 0.1 mg mor-
phine was found to provide the best balance between efficacy and side
effects in elderly patients 19. We found few side effects at this dose and no
serious complications such as respiratory depression were seen in that
study, further supporting the use of this dose intrathecally.
The final study (IV) also has some limitations. Firstly, would a larger
sample-size have detected a difference between the groups in our primary
endpoint? Although this is possible, small differences between groups in
larger studies may be of statistical importance but are unlikely to have
practical clinical relevance. In addition, even the confidence interval calcu-
lated for the primary endpoint in this small study was very narrow and far
less than would be clinically relevant, suggesting that a larger study may
have likely resulted in even narrower confidence intervals, which would be
clinically meaningless. Furthermore, the lack of differences in our secon-
dary endpoints also supports that the differences between these groups, if
any, are rather small. Taken together, we believe that there is no clinically
important difference between the two surgical methods. One final limita-
tion is that this study was not blinded and therefore it is open to issues of
observer bias. However, despite this potential bias in favor of MIS, we
found no real differences between the groups.
To summarize, the results from our studies indicate that the LIA tech-
nique provides good postoperative analgesia and promotes early mobiliza-
tion, when compared with placebo following knee arthroplasty. The LIA
technique also seems to be superior to intrathecal morphine following total
knee arthroplasty. Moreover, when LIA is used, minimally invasive surgery
does not seem to improve the outcome compared with conventional sur-
gery in unicompartmental knee arthroplasty.

Clinical implications
In light of our results, LIA seems to be a simple, safe and potent technique
for postoperative pain management and early mobilization following knee
arthroplasty. The early mobilization has the potential to reduce the risk for

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 45


venous thrombo-embolism and nosocomial infection. Shorter hospital stay
reduces health-care costs and waiting time for surgery and patients also feel
more comfortable in the home environment.
Unicompartmental knee arthroplasty using LIA, might routinely be per-
formed as a day-surgery procedure in future. Furthermore, when using LIA
in unicompartmental knee arthroplasty, the type of surgery (MIS or con-
ventional surgery) can be guided by individual surgeon preference and local
hospital practices.

Future research
Further studies should be performed in order to investigate the role of the
different components of the LIA technique. What are the optimal doses of
the drugs used in the LIA-mixture? Should corticosteroids be added to this?
What is the role of the drugs administered after 24 h via the catheter and
do the advantages outweigh the risk of infection? Would larger long-term
follow-up studies reveal any side effects of the technique? More studies,
using a different implant system are warranted in order to evaluate the
concept of MIS in UKA when LIA is used.
Postoperative pain protocols aiming to minimize pain and promote early
mobilization often consist of several phases, such as patient information,
anesthesia protocols, MIS, LIA, pain management protocols, early physical
therapy protocols and home care. The exact role of each of these compo-
nents is yet to be explored. Visiting Drs Kerr and Kohan in Sydney re-
cently, I understand today that the LIA technique is merely one component
in the process of achieving good quality recovery after major orthopedic
surgery. However, LIA should be regarded as a key enabling technique,
promoting the rapid return of patients to normal activities of daily living.

46 I PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty


Conclusions
I Local infiltration analgesia (LIA) resulted in better postoperative
analgesia and earlier mobilization, compared to placebo, following
unicompartmental knee arthroplasty performed with minimally in-
vasive surgery (MIS).

II Local infiltration analgesia (LIA) resulted in better postoperative


analgesia and earlier mobilization, compared to placebo, following
total knee arthroplasty. Blood concentrations of the local anesthetic
were below known toxic levels.

III Local infiltration analgesia (LIA) provided better postoperative an-


algesia and earlier mobilization, compared to intrathecal morphine,
following total knee arthroplasty.

IV Minimally invasive surgery (MIS) did not result in reduced postop-


erative pain or earlier mobilization, compared to conventional expo-
sure in unicompartmental knee arthroplasty, when both groups re-
ceived local infiltration analgesia (LIA).

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 47


Summary in Swedish
Knartros r en vanlig komma och rligen utfrs ver 12000 knprotes-
operationer i Sverige.
Om endast en ledkammare r angripen kan man vervga en enkam-
marprotes. Om hela knet uppvisar artros anvnds oftast totalprotes.
Den postoperativa smrtan efter en knprotesoperation r ofta svr. Fle-
ra frsk att frbttra smrtlindring och mobilisering efter knprotesope-
rationer har gjorts de senaste ren. Lokal infiltrationsanalgesi (LIA) r en
teknik dr en blandning av lokalbedvningsmedel, inflammationshm-
mande medel och adrenalin infiltreras i operationsret i slutet av operatio-
nen och injiceras via en kvarliggande knkateter efter operationen. En an-
nan metod r utvecklingen av mini-invasiv kirurgi (MIS), som innebr en
minskad frilggning vid operationen.
I de inledande tv studierna jmfrdes LIA med placebo vid enkammar-
och totalprotesoperationer. Postoperativ smrta, morfintgng och biverk-
ningsfrekvensen var lgre i LIA-grupperna. I enkammarprotes-studien var
vrdtiden kortare och i totalprotes-studien var tid till hemgngsklar korta-
re i LIA-gruppen. Blodkoncentrationen av lokalbedvningsmedlet (ropiva-
kain) var under toxisk niv.
I den tredje studien jmfrdes LIA med en annan vanligt frekommande
metod fr postoperativ smrtlindring, morfin givet tillsammans med lokal-
bedvningsmedlet vid ryggbedvning (spinalt morfin). Postoperativ smrta
och morfintgng var lgre, vrdtiden kortare och patienttillfredstllelsen
hgre i LIA-gruppen jmfrt med spinalt morfin-gruppen.
I den sista studien undersktes effekten av mini-invasiv kirurgi (MIS)
jmfrt med konventionell kirurgi vid enkammarprotesoperationer, dr
bda grupperna erhll LIA. Vi fann ingen skillnad i tid till hemgngsklar,
vrdtid, postoperativ smrta eller morfintgng.
Sammanfattningsvis visade vra studier att LIA resulterade i bttre
smrtlindring och mobilisering n placebo, bde vid enkammar- och total-
protesoperationer. LIA gav ocks bttre smrtlindring och mobilisering n
spinalt morfin vid total knprotesoperationer. Mini-invasiv kirurgi (MIS)
resulterade inte i bttre smrtlindring och mobilisering, nr LIA anvndes i
bgge grupperna.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 49


Acknowledgements
I wish to express my sincere gratitude to everyone who has contributed to
this thesis. I would especially like to thank:

Kjell Axelsson, professor, my tutor, for your warm, competent and pas-
sionate guidance. Thank you, Kax, there could be no one better.

Anil Gupta, associate professor, my co-tutor, for excellent collaboration


and for transforming my early manuscripts into publishable papers.

Anders Lundin, MD, PhD, my co-tutor, for constructive discussions, for


help with data analysis and for always having a minute to spare.

Jill Kjellberg, Elisabeth berg, Lena Otterborg, research nurses, and


rjan Wallgren and Henrik Spnnar, research physiotherapists, for excel-
lent work with the data collections.

Kristina Nilsson for outstanding secretarial assistance and support at vari-


ous phases of the thesis.

Anders Magnuson for invaluable statistical support.

Sofie and David, my beloved daughter and son, for being who you are.

Margaretha, my wife and best friend, for everything.

PER ESSVING Local Infiltration Analgesia in Knee Arthroplasty I 51


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Publications in the series
rebro Studies in Medicine

1. Bergemalm, Per-Olof (2004). Audiologic and cognitive long-term


sequelae from closed head injury.
2. Jansson, Kjell (2004). Intraperitoneal Microdialysis.
Technique and Results.
3. Windahl, Torgny (2004). Clinical aspects of laser treatment of
lichen sclerosus and squamous cell carcinoma of the penis.
4. Carlsson, Per-Inge (2004). Hearing impairment and deafness.
Genetic and environmental factors interactions consequences.
A clinical audiological approach.
5. Wgster, Dick (2005). CXCL16 and CD137 in Atherosclerosis.
6. Jatta, Ken (2006). Inflammation in Atherosclerosis.
7. Dreifaldt, Ann Charlotte (2006). Epidemiological Aspects on
Malignant Diseases in Childhood.
8. Jurstrand, Margaretha (2006). Detection of Chlamydia trachomatis
and Mycoplasma genitalium by genetic and serological methods.
9. Norn, Torbjrn (2006). Clostridium difficile, epidemiology and
antibiotic resistance.
10. Anderzn Carlsson, Agneta (2007). Children with Cancer Focusing
on their Fear and on how their Fear is Handled.
11. Ocaya, Pauline (2007). Retinoid metabolism and signalling in
vascular smooth muscle cells.
12. Nilsson, Andreas (2008). Physical activity assessed by accelerometry
in children.
13. Eliasson, Henrik (2008). Tularemia epidemiological, clinical and
diagnostic aspects.
14. Walldn, Jakob (2008). The influence of opioids on gastric function:
experimental and clinical studies.
15. Andrn, Ove (2008). Natural history and prognostic factors in
localized prostate cancer.
16. Svantesson, Mia (2008). Postpone death? Nurse-physician
perspectives and ethics rounds.
17. Bjrk, Tabita (2008). Measuring Eating Disorder Outcome
Definitions, dropouts and patients perspectives.
18. Ahlsson, Anders (2008). Atrial Fibrillation in Cardiac Surgery.
19. Parihar, Vishal Singh (2008). Human Listeriosis Sources and Routes.
20. Berglund, Carolina (2008). Molecular Epidemiology of Methicillin-
Resistant Staphylococcus aureus. Epidemiological aspects of MRSA
and the dissemination in the community and in hospitals.
21. Nilsagrd, Ylva (2008). Walking ability, balance and accidental falls in
persons with Multiple Sclerosis.
22. Johansson, Ann-Christin (2008). Psychosocial factors in patients
with lumbar disc herniation: Enhancing postoperative outcome by
the identification of predictive factors and optimised physiotherapy.
23. Larsson, Matz (2008). Secondary exposure to inhaled tobacco
products.
24. Hahn-Strmberg, Victoria (2008). Cell adhesion proteins in different
invasive patterns of colon carcinoma: A morphometric and molecular
genetic study.
25. Bttiger, Anna (2008). Genetic Variation in the Folate Receptor-
and Methylenetetrahydrofolate Reductase Genes as Determinants
of Plasma Homocysteine Concentrations.
26. Andersson, Gunnel (2009). Urinary incontinence. Prevalence,
treatment seeking behaviour, experiences and perceptions among
persons with and without urinary leakage.
27. Elfstrm, Peter (2009). Associated disorders in celiac disease.
28. Skrberg, Kurt (2009). Anabolic-androgenic steroid users in treatment:
Social background, drug use patterns and criminality.
29. de Man Lapidoth, Joakim (2009). Binge Eating and Obesity Treatment
Prevalence, Measurement and Long-term Outcome.
30. Vumma, Ravi (2009). Functional Characterization of Tyrosine
and Tryptophan Transport in Fibroblasts from Healthy Controls,
Patients with Schizophrenia and Bipolar Disorder.
31. Jacobsson, Susanne (2009). Characterisation of Neisseria meningitidis
from a virulence and immunogenic perspective that includes variations
in novel vaccine antigens.
32. Allvin, Rene (2009). Postoperative Recovery. Development of a
Multi-Dimensional Questionnaire for Assessment of Recovery.
33. Hagnelius, Nils-Olof (2009). Vascular Mechanisms in Dementia
with Special Reference to Folate and Fibrinolysis.
34. Duberg, Ann-Sofi (2009). Hepatitis C virus infection. A nationwide
study of assiciated morbidity and mortality.
35. Sderqvist, Fredrik (2009). Health symptoms and potential effects on
the blood-brain and blood-cerebrospinal fluid barriers associated with
use of wireless telephones.
36. Neander, Kerstin (2009). Indispensable Interaction. Parents perspectives
on parentchild interaction interventions and beneficial meetings.
37. Ekwall, Eva (2009). Womens Experiences of Gynecological Cancer
and Interaction with the Health Care System through Different Phases
of the Disease.
38. Thulin Hedberg, Sara (2009). Antibiotic susceptibility and resistance
in Neisseria meningitidis phenotypic and genotypic characteristics.
39. Hammer, Ann (2010). Forced use on arm function after stroke.
Clinically rated and self-reported outcome and measurement during
the sub-acute phase.
40. Westman, Anders (2010). Musculoskeletal pain in primary health
care: A biopsychosocial perspective for assessment and treatment.
41. Gustafsson, Sanna Aila (2010). The importance of being thin
Perceived expectations from self and others and the effect on
self-evaluation in girls with disordered eating.
42. Johansson, Bengt (2010). Long-term outcome research on PDR
brachytherapy with focus on breast, base of tongue and lip cancer.
43. Tina, Elisabet (2010). Biological markers in breast cancer and acute
leukaemia with focus on drug resistance.
44. Overmeer, Thomas (2010). Implementing psychosocial factors in
physical therapy treatment for patients with musculoskeletal pain
in primary care.
45. Prenkert, Malin (2010). On mechanisms of drug resistance in
acute myloid leukemia.
46. de Leon, Alex (2010). Effects of Anesthesia on Esophageal Sphincters
in Obese Patients.
47. Josefson, Anna (2010). Nickel allergy and hand eczema epidemiological
aspects.
48. Almon, Ricardo (2010). Lactase Persistence and Lactase Non-Persistence.
Prevalence, influence on body fat, body height, and relation to the metabolic
syndrome.
49. Ohlin, Andreas (2010). Aspects on early diagnosis of neonatal sepsis.
50. Oliynyk, Igor (2010). Advances in Pharmacological Treatment of Cystic
Fibrosis.
51. Franzn, Karin (2011). Interventions for Urinary Incontinence in Women.
Survey and effects on population and patient level.
52. Loiske, Karin (2011). Echocardiographic measurements of the heart. With
focus on the right ventricle.
53. Hellmark, Bengt (2011). Genotypic and phenotypic characterisation of
Staphylococcus epidermidis isolated from prosthetic joint infections.
54. Eriksson Crommert, Martin (2011). On the role of transversus abdominis
in trunk motor control.
55. Ahlstrand, Rebecca (2011). Effects of Anesthesia on Esophageal Sphincters.
56. Hollndare, Fredrik (2011). Managing Depression via the Internet
self-report measures, treatment & relapse prevention.
57. Johansson, Jessica (2011). Amino Acid Transport and Receptor Binding
Properties in Neuropsychiatric Disorders using the Fibroblast Cell Model.
58. Vidlund, Mrten (2011). Glutamate for Metabolic Intervention in Coronary
Surgery with special reference to the GLUTAMICS-trial.
59. Zakrisson, Ann-Britt (2011). Management of patients with Chronic
Obstructive Pulmonary Disease in Primary Health Care. A study of a
nurse-led multidisciplinary programme of pulmonary rehabilitation.
60. Lindgren, Rickard (2011). Aspects of anastomotic leakage, anorectal
function and defunctioning stoma in Low Anterior Resection of the
rectum for cancer.
61. Karlsson, Christina (2011). Biomarkers in non-small cell lung carcinoma.
Methodological aspects and influence of gender, histology and smoking
habits on estrogen receptor and epidermal growth factor family receptor
signalling.
62. Varelogianni, Georgia (2011). Chloride Transport and Inflammation in
Cystic Fibrosis Airways.
63. Makdoumi, Karim (2011). Ultraviolet Light A (UVA) Photoactivation of
Riboflavin as a Potential Therapy for Infectious Keratitis.
64. Nordin Olsson, Inger (2012). Rational drug treatment in the elderly: To
treat or not to treat.
65. Fadl, Helena (2012). Gestational diabetes mellitus in Sweden: screening,
outcomes, and consequences.
66. Essving, Per (2012). Local Infiltration Analgesia in Knee Arthroplasty.