Effects of Computer Navigation versus Conventional Total Knee Arthroplasty on Endothelial Damage Marker Levels: A Prospective Comparative Study
Effects of Computer Navigation versus Conventional Total Knee Arthroplasty on Endothelial Damage Marker Levels: A Prospective Comparative Study
Shu-Jui Kuo 0 1 2 3 4
Feng-Sheng Wang 0 1 2 3 4
Ching-Jen Wang 0 1 2 3 4
Jih-Yang Ko 0 1 2 3 4
Sung-Hsiung Chen 0 1 2 3 4
Ka-Kit Siu 0 1 2 3 4
0 Accepted: April 5 , 2015
1 Received: August 3 , 2014
2 Academic Editor: Robert K Hills, Cardiff University , UNITED KINGDOM
3 1 Department of Orthopedic Surgery, China Medical University Hospital , Taichung, Taiwan , 2 Department of Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan, 3 Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center , Kaohsiung , Taiwan
4 Published: May 8 , 2015
Total knee arthroplasty (TKA) inevitably perturbs the femoral medullary canal, which increases blood loss or morbidities associated with marrow embolization postoperatively. Computer navigation TKA reportedly minimizes medullary disturbance to alleviate perioperative blood loss. We performed a prospective comparative study, enrolling 87 patients with osteoarthritic knees from March 2011 to December 2011 in our hospital. The patients were separated into two groups, according to the surgeon they visited. Fifty-four patients underwent computer navigation TKAs and 33 had conventional TKAs. Levels of cell adhesion molecules (CAMs), including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet endothelial cellular adhesion molecule-1 (PECAM-1) in sera and hemovac drainage were measured by ELISA before and 24 hours after the surgery. We showed that patients receiving computer navigation TKAs had less blood loss and lower CAMs in serum and hemovac drainage after the operation. Less postoperative elevation of serum ICAM-1 (p=0.022) and PECAM-1 (p=0.003) from the preoperative baseline after the surgery was also noted. This study provides molecular evidence for the differential extent in vascular injury between conventional and navigation TKAs and sheds light on the possible benefits of computer navigation TKAs.
Competing Interests: The authors have declared
that no competing interests exist.
Total knee arthroplasty (TKA) is a well-established modality with a high satisfaction rate for
various knee disorders. However, this surgical procedure inevitably perturbs the femoral
medullary canal, leading to marrow embolization that reportedly increases the risk of
myocardial infarction or cardiac stress postoperatively[2, 3]. Minimizing femoral medullary canal
destruction, thus reducing marrow embolism-related morbidities, is an important issue for
In addition to improving prosthetic alignment, computer-assisted navigation TKAs also
contribute to reduced operative blood loss and systemic emboli. These observations
imply that navigation TKAs may cause less microvascular damage than conventional TKAs.
However, the molecular evidence for the differential extent in vascular injury between
conventional and navigation TKAs remains elusive.
Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1),
and platelet endothelial cellular adhesion molecule-1 (PECAM-1) are cell adhesion molecules
(CAMs) that contribute to endothelial activation and leukocyte recruitment. They have
been employed as markers for endothelial or vascular damage or hemorrhage, including
coronary artery disease. After total joint surgeries, patients reportedly had higher serum
levels of leucocytes and endothelial markers . Therefore, we postulated that serum levels of
CAMs in patients receiving navigation TKAs may be different from those receiving
The purpose of this prospective comparative study was to compare ICAM-1, VCAM-1 and
PECAM-1 levels in serum and hemovac drainage of patients receiving navigation and
conventional TKAs. We hypothesized that navigation TKAs would lead to less postoperative elevation
of serum CAMs compared to preoperative baselines than conventional TKAs.
The protocol for this trial and supporting TREND checklist are available as supporting
information (see S1 TREND Checklist and S1 Protocol).
This prospective comparative study was approved by the Institutional Review Board of
Kaohsiung Chang Gung Memorial Hospital (IRB 100-0038A3) before recruiting the patients,
and was conducted from March 2011 to December 2011 (see S1 IRB). Local officials did not
mandate registration before recruiting the patients, but this study was later registered in the
ClinicalTrials.gov system (ID: NCT02206321). Our study adhered to the TREND reporting
Patients in need of TKA surgery due to degenerative osteoarthritis of the knee visited the
outpatient department first and then were scheduled for admission for TKA surgery. They
were self-separated into two groups when they visited the outpatient department. Those
patients who visited Dr. CJ Wang would undergo conventional TKA, and those who visited Dr.
JY Ko would undergo computer navigation TKA. Both senior surgeons had performed more
than 1,000 TKAs using the conventional and the computer navigation method, respectively,
before the beginning of our study. The patients did not know which surgeon performed
conventional or computer navigation TKA before admission. After admission and before the
surgery, all of the patients were asked whether they consented to participate in this study. All but
three patients consented to participate. The patients knew their allocation as they completed
written informed consent, because there were four additional small skin incisions (0.5 cm
each) for the insertion of reference arrays for the navigation procedures. No patients shifted to
the other group during the study. Those with autoimmune diseases, rheumatoid arthritis,
malignancies, previous knee surgery or post-traumatic arthritis were excluded.
All surgical procedures, including aseptic dragging and skin preparation were performed
with standard protocols in a standard surgical facility. Each patient was given intravenously a
single dose of 1 mg prophylactic cefazolin and a pneumatic tourniquet (300 mm Hg), followed
by a mid-vastus approach after midline skin incision.
Because of the pilot nature of the study, we planned to enroll at least 30 patients for each
group after consultation with the statistician.
The bone cuts were extramedullary-guided and mapped using navigation and infrared-based
systems (Vector Vision; Brain LAB, Heimstetten, Germany), according to the manufacturers
instructions. Briefly, two fixed reference arrays with marker spheres were tracked using an
infra-red camera, and the marker spheres were fixed to the distal femur (4 mm pins) and
proximal tibia (3 mm pins) via two bi-cortical half pins. The hip joint center, distal femur and
proximal tibia articulating surfaces, and the medial/lateral malleolus of the ankle were mapped and
registered. The femoral component was referenced to the anterior cortex of the distal femur. A
multiple-referencing method using epicondylar line, Whiteside line, and posterior condylar
line was adopted to determine the appropriate rotation of the femoral component, and the size
and position of the femoral prosthesis was optimized by the navigation system. The distal
femur cut and chamber cut were guided by the real-time navigation system without reaming
and destroying the bone marrow cavity.
An extramedullary guide connected to a reference array was employed to determine the
tibia cutting level, varus-valgus angle and tibia slope. The rotation of the tibia component was
adjusted to fit the femoral component. An extramedullary guiding rod was used to reference
the center of the anterior ankle joint, assisting the determination of the tibial component
rotation. Bone cut was achieved under real-time navigation.
After completing the femur and tibia bone cut, femoral and tibia components (LPS-Flex
system, Nexgen; Zimmer, Warsaw, IN, USA) were implanted with antibiotic-loaded cement
fixation. A neutral mechanical axis with a deviation of less than 1 degree was obtained after soft
tissue balancing, with the assistance of a real-time computer screen. A 1/8-inch hemovac
(Zimmer Haemovac; Zimmer, Warsaw, IN, USA) was inserted as a closed drainage system, and
then removed 24 hours after surgery.
Femoral bone cuts (distal and chamber cuts) were guided by an intramedullary system and
guiding instruments. The proper size and positioning of the prosthesis (LPS-Flex system,
Nexgen; Zimmer, Warsaw, IN, USA) was based on the surgeons experience, and was followed by
the implantation of the prosthesis with antibiotic-loaded cement fixation. A 1/8-inch hemovac
(Zimmer Haemovac; Zimmer, Warsaw, IN, USA) was inserted as a closed drainage system and
removed 24 hours postoperatively.
Administration of anti-coagulants was halted 1 week before surgery and resumed on the day
after surgery. Patients without previous use of anti-coagulants received aspirin for chemical
prophylaxis if no contraindications. Intravenous cefazolin 1 g every 8 hours was administered
for 3 doses after surgery. The hemovac drainage was kept in place for 24 hours, and then
removed. Hemoglobin and hematocrit levels were measured before surgery and 24 hours after
the operation. If patients had hemoglobin < 8 mg/dL or hemoglobin 89 mg/dL with unstable
vital signs, blood transfusion with packed red blood cells was provided. After removing the
hemovac drainage, patients proceeded with continuous passive motion, including active
flexion-extension, quadriceps training and walker-aided ambulation with the assistance of
physical therapists. Patients with a clean operative wound and stable general condition were
discharged if range of motion of the knee exceeded 95 degrees. All complications before
manuscript preparation (July 2014) were scrutinized and reported.
Five milliliters of drainage from the hemovac was harvested and processed to collect
supernatants. Ten milliliters of peripheral blood was drawn from each patient before and 24 hours
after TKA and processed to collect sera. All processed supernatants and sera were stored at
-80C till ELISA analysis. Concentrations of all CAMs in sera and drainage supernatants were
measured by respective ELISA kits (R & D Systems), according to the manufacturers
instructions. The technician performing the ELISA analysis was blinded to the patient profile and
grouping via the de-labeling process.
Blood loss assessment
Blood loss during the first 24 hours was calculated by the method proposed by Sehat et al. and
other authors [14, 15], which can be summarized by the following formula: blood loss = total
blood volume (Hctpre-op-Hctpost-op)/ Hctmean + volume transfused
where total blood volume was calculated based on sex, height and weight, using the method
described by Nadler et al (https://www.easycalculation.com/medical/blood-volume.php).
Data are expressed as median (lower quartiles, upper quartiles). Categorical variables were
compared by Chi-square test. As for continuous variables, the Mann-Whitney U test and
Wilcoxon signed-rank test were utilized for between-group and within-group comparisons,
respectively. The Spearmans correlation coefficient was used to measure the strength of
correlation between the two variables. All statistics were performed by SPSS software, and a p
value < 0.05 was regarded as statistically significant.
Ninety patients met the inclusion criteria from March 2011 to December 2011. Three of the 90
patients that underwent TKA surgery declined to participate and were excluded from the
study. Finally, 87 eligible patients provided written informed consent and were enrolled.
Fiftyfour patients underwent computer-assisted TKAs and 33 received conventional TKAs. All 87
patients completed the preoperative and postoperative blood sampling and the collection of
drainage from the hemovac (Fig 1).
There were no significant differences in gender, affected side, age or BMI between the
computer navigation and conventional TKA group. The numbers of patients afflicted with
coronary artery disease and coronary artery equivalent disease (including symptomatic carotid
artery disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes, and chronic
kidney disease) in both groups were not significantly different (Table 1).
The calculated volume of blood loss in the computer navigation group was 955 (772, 1164)
mL, significantly lower (p = 0.001) than the 1265 (963, 1475) mL in the conventional group.
Fig 1. Flowchart of the participants through each stage of the study.
Table 2. Serum concentrations of ICAM-1(unit: ng/mL) in patients before and after navigation and conventional TKAs, and the changes from
preoperative baseline after surgery (post-OPpre-OP).
Table 3. Serum concentrations of VCAM-1 (unit:ng/mL) in patients before and after navigation and conventional TKAs, and the changes from
preoperative baseline after surgery (post-OPpre-OP).
Table 4. Serum concentrations of PECAM-1 (unit: pg/mL) in patients before and after navigation and conventional TKAs, and the changes from
preoperative baseline after surgery (post-OPpre-OP).
The skin to skin closure time was 116 (103, 124) minutes in the navigation group and 110
(101. 115) minutes in the conventional group. (p = 0.141)
The baseline serum CAMs did not differ between the two groups before surgery. Of interest,
postoperative serum ICAM-1 (Table 2), VCAM-1 (Table 3) and PECAM-1 (Table 4) levels in
the computer navigation group were 35.5% (p <0.001), 2.0% (p = 0.037) and 49.3% (p <0.001)
lower, respectively, than those in the conventional group. The extent of postoperative elevation
of serum ICAM-1 (p = 0.022) and PECAM-1 (p = 0.003) in the navigation group was
significantly milder than that in the conventional group. However, there was no significant difference
(p = 0.435) in the postoperative elevation of VCAM-1 between groups (Tables 24).
The patients in the computer navigation group had lower ICAM-1 levels in hemovac
drainage supernatants than patients in the conventional group. The ICAM-1 (Table 5) and
VCAM1 (Table 6) levels in hemovac drainage supernatants were significantly correlated with those in
sera. However, PECAM-1 levels in hemovac were not significantly correlated with those in sera
Up to the time of manuscript preparation (July 2014), two patients, an 85-year-old female
in the conventional group and a 64-year old male in the computer navigation group, were
admitted for angina symptoms, with an interval between surgery and admission of 12 and 14
months, respectively. Coronary angiography revealed no apparent stenosis for the 85-year-old
female patient and single-vessel disease for the 64-year-old male patient. Percutaneous
angioplasty was performed smoothly for the 64-year-old male. However, no major complications
were noted in any of the patients of both groups postoperatively.
Complications secondary to bone marrow violation are significant concerns after TKA
surgeries. Computer navigation TKAs do not involve the reaming of the medullary canal, thus
minimizing the destruction of the femoral medullary cavity. While this modality reportedly
improves blood loss and prosthesis accuracy, biochemical verification of vascular injury has
not been defined[7, 8]. In this study, we provided novel evidence that patients had decreased
blood loss concomitant with mitigated postoperative elevation of levels of CAMs after
computer navigation TKA, which is indicative of its less-invasive nature with regard to the integrity of
the femoral medullary cavity. The results of the current study shed new light on the known
advantages of computer-aided TKA procedures for patients.
Compared to patients with conventional TKAs, patients that underwent computer
navigation TKAs had milder postoperative elevation of serum ICAM-1 and PECAM-1 from the
preoperative baseline. These molecules are associated with vessel damage, thrombosis and
hemorrhage, and reportedly promote atherogenesis of various tissues in pathologic contexts[9,
12, 1821]. In the current study, the milder elevation of postoperative serum CAMs from the
preoperative baseline reflects the milder vessel-deleterious reactions after computer navigation
Marrow embolism after conventional TKA might be associated with increased risks of acute
cardiac disorders. A retrospective study argued that the increased risk of acute myocardial
infarction was attributable to the destruction of the femoral medullary canal in the TKA procedure
. Serum ICAM-1 levels are linked to macrovascular disease, and serum VCAM-1
concentrations have been correlated with the occurrence of acute coronary syndrome [11, 22, 23].
Although the current study does not correlate the milder elevation of postoperative serum CAMs
from baseline to the lower risk of cardiovascular complications in patients after computer-aided
TKA, the timing of our observation overlapped exactly with the hazardous first two weeks for
myocardial infarction . The significance of differential serum CAMs and the correlation with
the incidence of heart disorders after different TKA modalities merits long-term follow-up.
We acknowledge the limitation of this study, which is that all participants came from the
outpatient department and chose surgeons to perform elective TKA surgery of their own free
will. However, the patients did not know which surgeon performed navigation or conventional
TKA until the day before the operation, and no patient shifted to the other group during the
study. The two physicians were arthroplasty specialists who had performed more than 1,000
TKAs using the method they were familiar with before the study, and neither of them shifted
to performing the other technique throughout the course. The shift to a less familiar technique
might introduce performance bias, and the choice of a less familiar method would probably
prolong the operation time and confound the results. While the current study may not be a
double-blinded or truly randomized study design, patient attributes, including gender, age, side
in need of TKA, BMI, and heart comorbidities were not significantly different between the
groups. The skin to skin closure time for the two groups was similar. All procedures for ELISA
analysis were performed using stringent de-coding procedures, and technicians were all
blinded to the identity and source of the specimens. Despite all endeavors to minimize possible
bias, more rigorously-designed studies, such as randomized double-blind studies, are still
necessary to substantiate the preliminary finding. The results of this study cannot be extrapolated
to conclude that navigation TKAs lead to fewer postoperative cardiac events and fewer
postoperative thromboembolic complications. The correlations between the postoperative CAMs and
the incidence of cardiac events or thromboembolic complications warrant a larger study
population for further validation.
Taken together, our results reveal that conventional TKAs inevitably perturb the femoral
medullary canal, leading to the destruction of vascular integrity, and thereby contribute to more
apparent elevations of concentrations of CAMs after the surgery. Computer navigation TKA
impedes the medullary canal to a lesser extent, which minimizes vessel deterioration and leads
to milder elevation of CAMs after the surgery. This study highlights low serum CAMs as
emerging biochemical indicators that strengthen the advantage of navigation TKA. The correlation
between differential CAM levels and the incidence of heart events deserves further investigation.
We are thankful for the technical support of colleagues in the Fifth Central Lab of the
Department of Medical Research. We are also thankful for the invaluable suggestion for the amendment
of this manuscript during the revision process by professor Hsien-Yuan Lane, the chairman of
the Graduate Institute of Clinical Medical science, China Medical Univeristy, Taichung.
Conceived and designed the experiments: JYK FSW. Performed the experiments: FSW.
Analyzed the data: SJK. Contributed reagents/materials/analysis tools: CJW JYK SHC KKS. Wrote
the paper: SJK.
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