Knee Surg Sports Traumatol Arthrosc DOI 10.1007/s00167-014-2898-4
KNEE
Fibrin sealant before wound closure in total knee arthroplasty reduced blood loss: a meta-analysis Zhi-jun Li • Xin Fu • Peng Tian • Wen-xing Liu Yao-min Li • Yong-fa Zheng • Xin-long Ma • Wei-min Deng
•
Received: 5 January 2014 / Accepted: 26 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Fibrin sealant (FS) comprises a mixture of fibrinogen and thrombin that controls bleeding, reduces blood transfusions, improves tissue healing and shortens postoperative recovery time after various surgical procedures. However, no single study has been large enough to definitively determine whether fibrin sealant is safe and effective. We report a meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy and safety of fibrin sealant in total knee arthroplasty. Methods Articles published before August, 2012 were identified from PubMed, Embase, The Cochrane Library and other internet databases. Relevant journals and the recommendations of expert panels were also searched manually. We included only high-quality RCTs. Two independent reviewers searched and assessed the literature. Relevant data were analysed using RevMan 5.0.
Zhi-jun Li and Xin Fu have contributed equally to this study. Z. Li (&) Y. Zheng X. Ma Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300054, People’s Republic of China e-mail: [email protected] Z. Li W. Liu W. Deng Department of Immunology, Tianjin Medical University , Tianjin 300070, People’s Republic of China X. Fu P. Tian X. Ma Department of Orthopedics, Tianjin Hospital, Tianjin 300211, People’s Republic of China Y. Li Department of Rehabilitation, Tianjin Hospital, Tianjin 300211, People’s Republic of China
Results Seven RCTs met the inclusion criteria. Use of fibrin sealant significantly reduced haemoglobin decline mean difference (MD = -0.72), 95 % confidence interval [95 % CI (-0.83, -0.62), p \ 0.00001], postoperative drainage volume [MD = -354.53, 95 % CI (-482.43, 226.63), p \ 0.00001], the proportion of patients requiring blood transfusion risk differences [RD = -0.27, 95 % CI (-0.45, -0.08), p = 0.006] and the incidence of wound haematoma [RD = -0.11, 95 % CI (-0.22, -0.00), p = 0.04]. There were no significant differences in deep vein thrombosis, pulmonary embolism, infection rate or other complications between groups. Conclusions Use of fibrin sealant in total knee arthroplasty was effective and safe, reduced haemoglobin decline, postoperative drainage volume, incidence of haematoma and need for blood transfusion, and did not increase the risk of complications. Due to the limited quality of the evidence currently available, more highquality RCTs are required. Level of evidence II. Keywords Fibrin sealant Knee Arthoplasty Meta-analysis Blood loss
Introduction Total knee arthroplasty (TKA) is widely used to relieve pain, correct deformity, restore function and improve joint movement, and has become a reliable treatment for severe osteoarthritis and rheumatoid arthritis. TKA is particularly prone to large blood loss, ranging from 470 to 1,974 mL [5, 6, 25]. Although various methods of blood preservation have been used, including tourniquet, perioperative hemodilution, minimally invasive
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surgery, intraoperative and postoperative blood salvage and reinfusion, antifibrinolytic agents, hypotensive or epidural anaesthesia, and transfusion of predonated autologous blood [6, 23, 30], many patients need blood transfusion for significant intraoperative and postoperative blood loss. It is well known that allogeneic blood transfusion carries risks of transmission of infection (viral and bacterial), possible haemolytic transfusion reactions, transfusion-related lung injury and even death [1, 27]. Fibrin sealant (FS), or fibrin glue, is a mixture of fibrinogen and thrombin that is used to control bleeding, reduce blood transfusions, improve tissue healing and reduce postoperative recovery time following various surgical procedures [7, 13]. Numerous studies have investigated the efficacy and safety of FS in TKA [14, 15, 19–21, 24, 28]. However, some have been criticized for poor design, low power, inconclusive results and short followup. Therefore, we conducted a meta-analysis, pooling the data from randomized controlled trials (RCTs) to provide an evidence-based judgment regarding the use of FS in patients undergoing TKA.
Fig. 1 Search results and the selection procedure
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Materials and methods Search strategy In a meta-analysis conducted by us, in which the academic articles were identified from electronic databases, including MEDLINE (1966–August, 2012), EMBASE studies conducted on human subjects were included. The search strategy is presented in Fig. 1. In addition, the Google search engine was searched manually using the same search terms to seek further relevant studies that may have been missed in the database search. We used the key words ‘knee replacement OR arthroplasty’ and ‘fibrin sealant OR fibrin glue’ in combination with the Boolean operators AND or OR. Selection criteria and quality assessment All published RCTs and quasi-RCTs (those using methods of allocating participants to treatments that are not strictly random, e.g. date of birth, hospital record number and alternation) had been included that compared FS with a
Knee Surg Sports Traumatol Arthrosc
control (placebo or nothing) in patients undergoing TKA. The methodologic quality of the studies was assessed by the review authors (X. Fu and Z. Li) using a modification of the generic evaluation tool used by the Cochrane Bone, Joint and Muscle Trauma Group [17]. The methodologic quality of each trial was scored and ranged from 0 to 24. Data extraction For each eligible study, two of the authors (X. Fu and Z. Li) extracted all relevant data independently. Disagreement was resolved by discussion with a third investigator (P. Tian). When data were incomplete or unclear, attempts were made to contact the investigators for clarification. The following data were extracted: (1) demographical data of participants; (2) indication for TKA; (3) wound infection (superficial or deep), haematoma, wound dehiscence, limb swelling, ecchymosis, bleeding from the wound, reoperation because of a wound healing complication; (4) postoperative blood transfusion, decrease in haemoglobin or haematocrit, thromboembolic complications, patient discomfort, cost; (5) functional outcome such as time to regain mobility; and (6) any other outcomes as mentioned in individual studies were considered for inclusion. Statistical analysis The RevMan 5.0 for Windows (Cochrane Collaboration, Oxford, United Kingdom) was used to undertake this metaanalysis. We assessed the statistical heterogeneity of each study using the standard Chi-square test (statistical heterogeneity was considered at a significance level of p \ 0.1) and evaluated the I2 statistic [18]; an I2 value of 50 % was considered to indicate substantial heterogeneity. The origins of heterogeneity, if present, were analysed according to differences in methodologic quality, the characteristics of the participants and the intervention. When the data allowed, we performed subgroup analysis. When comparing trials showing heterogeneity, pooled data were meta-analysed using a random-effects model [19]. Otherwise, a fixed-effects model was used [20]. Relative risks (or risk differences) and 95 % confidence intervals (95 % CI) were calculated for dichotomous outcomes and mean differences (MDs) and 95 % CIs for continuous outcomes. When the data allowed, the authors of this paper performed subgroup analysis of the trials according to dose regimen and timing of FS delivery, transfusion trigger and administration of low molecular weight heparin.
Results Ninety-seven citations had been identified as potentially relevant studies. By screening the title and reading the
abstract and the entire article, seven RCTs including 408 knees at final follow-up were eligible for data extraction and meta-analysis (Fig. 1). The sample size ranged from 24 to 100. The studies were relatively well designed, and the quality assessment score was high, with a range of 16–22. However, the relevant RCTs had numerous methodologic weaknesses. Only one study stated that randomization was achieved by a computer assignment method [11]; the others did not provide randomization methods. One study provided a methodology for the blinding of subjects to group allocation [13], and three studies attempted to blind the assessors to group allocation. All studies reported final outcomes for a minimum of 85 % of their randomized patients. Inclusion and exclusion criteria were reported for all studies. All of the trials involved primary TKA; osteoarthritis was the most common diagnosis. The patients’ characteristics were comparable within each study group and are presented in Table 1. Two trials used regional anaesthesia alone [20, 21], only one used general anaesthesia [14]; the remaining four did not mention the type of anaesthesia used. All studies reported use of a tourniquet during TKA. The tourniquet was deflated after wound dressing in Molloy’s study and before haemostasis in three studies; the other studies did not mention the timing of deflation. Doses of FS ranged from 2 to 20 ml; five studies used 10 ml, Kluba et al. used 2 ml and Levy et al. used 10 or 20 ml. No placebo was used in the control group. Primary haemostasis was achieved in all patients in both treatment and control groups by electrocauterization of the bleeding vessels in the operative field. Four studies stated a transfusion trigger, which was related to either a fall in haemoglobin level or clinical symptoms of hypotension, tachycardia and dizziness. In one study, the transfusion trigger was reported to be based on the criteria and guidelines of the National Institutes of Health Consensus Conference [15]. One study did not mention the blood transfusion protocol. Five studies reported that postoperative drainage was measured between 24 and 48 h, when the drains were removed in most cases. Two studies stated that two drain tubes were used; the others did not mention this information. None of the included studies clamped the drain after TKA. The prostheses were cemented in five trials [14, 15, 19, 21, 24] and uncemented in two. The follow-up period ranged from discharge to 6 months. It was possible to perform a meta-analysis with 10 outcomes (Table 2). There were statistically significant differences between treatment and control group for transfusion requirements (RD = -0.27; Fig. 2), drainage volume (MD = -354.53; Fig. 3), reduction in Hb (MD = -0.72; Fig. 4) and the incidence of wound haematoma (RD = -0.11). Subgroup analysis was performed for transfusion requirements, which showed that
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Knee Surg Sports Traumatol Arthrosc Table 1 Cohort characteristics Studies
Cases (FS/C)
Mean age (FS/C)
Male patients (FS/C)
Dosage (ml)
DVT prophylaxis
Length of follow-up
QAS
Kluba et al. [14]
12/12
70.8/71
6/6
2
Enoxaparin, 40 mg
6 weeks
18
Levy et al. [15]
29/29
68.9/70.2
6/6
10 or 20
Enoxaparin, 30 mg
6 months
22
McConnell et al. [19]
21/22
NS
15/7
10
Aspirin, 150 mg
5 weeks
19
Molloy et al. [20]
50/50
NS
NS
10
Aspirin, 150 mg
3 months
21
Notarnicola et al. [21]
30/30
69.2
11/10
10
Enoxaparin, 40 mg
6 months
16
Sabatini et al. [24]
35/35
70.7/70.4
10/6
10
LMWH, NS
Discharge
20
Wang et al. [28]
25/28
NS
NS
10
Enoxaparin, 30 mg
6 months
17
FS fibrin sealant, DVT deep venous thrombosis, QAS quality assessment score, LMWH low molecular weight heparin, NS not state
Table 2 Meta-analysis results Outcome
Studies
Groups (FS/C)
Overall effect Effect estimate
Heterogeneity p value
I2 (%)
-0.45, -0.08
0.006
78
0.0005
-482.43, -226.63
\0.00001
85
\0.0001
95 % CI
p value
Transfusion requirements
6
181/184
-0.27
Drainage volume
5
131/134
-354.53
Reduction in Hb
5
169/172
-0.72
-0.83, -0.62
\0.00001
36
n.s.
Wound infections
4
144/144
-0.01
-0.04, 0.03
n.s.
0
n.s.
Deep venous thrombosis
4
144/144
0.01
-0.02, 0.05
n.s.
0
n.s.
Pulmonary embolism
3
114/114
0.00
-0.04, 0.04
n.s.
0
n.s.
Mean number of transfusions Mean calculated blood loss
2 2
80/80 79/79
-0.04 -451.70
-0.96, 0.17 -921.36, 17.97
n.s. n.s.
85 87
0.01 0.005
Hospital length of stay
2
42/42
-3.07
-6.32, 0.18
n.s.
74
n.s. \0.00001
Mean postoperative range of motion
2
42/42
16.79
13.73, 19.86
n.s.
97
Wound haematoma
2
60/63
-0.11
-0.22, -0.00
0.04
0
0.91
FS fibrin sealant, C control, 95 % CI 95 % confidence interval, n.s. non-significant
Experimental Study or Subgroup
Events
Control
Odds Ratio
Total Events Total Weight
Odds Ratio
M-H, Fixed, 95% CI
Kluba 2012
3
12
3
12
3.4%
1.00 [0.16, 6.35]
Levy 1999
6
29
24
29
28.6%
0.05 [0.01, 0.20]
Molloy 2007
7
50
11
50
14.2%
0.58 [0.20, 1.64]
Notarnicola 2012
7
30
19
30
21.9%
0.18 [0.06, 0.54]
Sabatini 2012
5
35
15
35
19.3%
0.22 [0.07, 0.71]
Wang 2001
9
25
14
28
12.7%
0.56 [0.19, 1.69]
184 100.0%
0.28 [0.18, 0.45]
181
Total (95% CI) Total events
37
M-H, Fixed, 95% CI
86
Heterogeneity: Chi² = 11.95, df = 5 (P = 0.04); I² = 58% Test for overall effect: Z = 5.24 (P < 0.00001)
0.01 0.1 1 10 100 Favours experimental Favours control
Fig. 2 Forest plot diagram showing effect of Fibrin sealant (FS) on the number of patients requiring transfusion
this positive effect persisted regardless of whether FS was delivered in dosage, whether the patient had low molecular weight heparin, a cemented TKA, and whether a transfusion protocol existed (Table 3). With respect to other outcome measurements, there were no statistically significant differences between FS and
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control groups in the risk of developing a wound infection or the length of hospital stay, deep venous thrombosis (DVT), pulmonary embolism (PE) or the mean number of transfusions required (n.s; Table 2). Several other outcome measurements were identified, but insufficient data were provided for meta-analysis. For
Knee Surg Sports Traumatol Arthrosc Experimental
Control
Mean
Kluba 2012
475.4 231.8
Mean Difference
12 813.3 433.4
12
0.6%
Mean Difference
-337.90 [-615.98, -59.82]
Levy 1999
360 287.7
29
878
403
29
1.5% -518.00 [-698.22, -337.78]
Notarnicola 2012
415
76.2
30
815 223.7
30
6.8% -400.00 [-484.57, -315.43]
Sabatini 2012
910
292
35 1,250
546
35
1.1% -340.00 [-545.13, -134.87]
184.5
28.9
25 408.3
54.6
28
90.0% -223.80 [-246.98, -200.62]
Wang 2001
134 100.0% -242.14 [-264.13, -220.15]
131
Total (95% CI)
IV, Fixed, 95% CI
IV, Fixed, 95% CI
SD Total Weight
SD Total Mean
Study or Subgroup
Heterogeneity: Chi² = 26.12, df = 4 (P < 0.0001); I² = 85%
-500 -250 0 250 500 Favours experimental Favours control
Test for overall effect: Z = 21.58 (P < 0.00001)
Fig. 3 Forest plot diagram showing effect of Fibrin sealant (FS) on drainage volume
Experimental Study or Subgroup Levy 1999 Molloy 2007
Mean
Control
SD Total Mean
Mean Difference
SD Total Weight
1
29
3.7
1.2
29
3.4% -1.20 [-1.77, -0.63]
2.68 1.02
50
3.2 1.12
50
6.2% -0.52 [-0.94, -0.10]
3.7
2
30
1.8% -1.20 [-1.98, -0.42]
2.5
Notarnicola 2012
2.5
0.9
30
Sabatini 2012
2.6 1.16
35
3 1.28
35
2.01 0.21
25
2.73 0.21
28
Wang 2001 Total (95% CI)
Mean Difference
169
3.3%
IV, Fixed, 95% CI
IV, Fixed, 95% CI
-0.40 [-0.97, 0.17]
85.3% -0.72 [-0.83, -0.61]
172 100.0% -0.72 [-0.83, -0.62]
Heterogeneity: Chi² = 6.25, df = 4 (P = 0.18); I² = 36%
-2 -1 0 1 Favours experimental Favours control
Test for overall effect: Z = 13.52 (P < 0.00001)
2
Fig. 4 Forest plot diagram showing effect of Fibrin sealant (FS) on haemoglobin decline
Table 3 Subgroup analysis of transfusion outcome
DVT deep venous thrombosis, LMWH low molecular weight heparin, CI confidence interval
Outcome or subgroup
Studies
Effect estimate v2
I2 (%)
RD
95 % CI
p value
Total dose C10 ml
5
19.96
80
-0.28
[-0.37, -0.19]
\0.00001
LMWH Transfusion protocol
5 4
14.01 10.99
71 73
-0.33 -0.38
[-0.44, -0.22] [-0.49, -0.26]
\0.00001 \0.00001
Cemented prosthesis
4
13.52
78
-0.31
[-0.58, -0.04]
instance, Sabatini et al. [24] reported a significant difference in requirement for more than one transfusion unit and no significant difference in operative time, Levy et al. [11] found no viral seroconversion at 3 or 6 months after TKA, and Molloy et al. [13] reported no statistical differences in C-reactive protein, pain scores or leg swelling between treatment and control groups.
Discussion The most important finding of the present study was that FS reduces blood transfusion rate and haemoglobin decline, decreases postoperative drainage volume, incidence of wound haematoma and does not appear to increase the risk of wound infection, DVT or PE. During the last 20 years, FS has been increasingly used to improve haemostasis and reduce blood loss after major surgery,
0.02
prompting a growing scientific interest in this technique [8]. Carless et al. [21] showed that FS might reduce blood loss and the amount of blood transfused during cardiac and pulmonary surgery, hepatic surgery, prostate surgery and TKA. In the present meta-analysis, use of FS tended to reduce the average number of red blood cell transfusions per patient, total blood loss and length of hospital stay and increased the mean postoperative range of motion, but not statistically significantly. One study found that perioperatively applied platelet gel and FS may reduce the incidence of allogeneic blood transfusions and complications associated with TKA [8]. Following a RCT, McConnell et al. concluded that 10 ml of topically applied fibrin spray reduced blood loss compared with a control group undergoing computer-navigated cemented total knee arthroplasty, whereas a 10 mg/kg bolus of tranexamic acid did not.
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Seven RCTs satisfied the defined eligibility criteria for this meta-analysis. Most of the included RCTs were of good methodologic quality, were relatively well designed and had high-quality assessment scores (16–22 score). All of the included studies reported randomization, though six did not describe the method of randomization used; with these latter studies, we were insufficiently confident with the available information to determine whether true randomization methods had been used. One study provided a methodology for the blinding of subjects to group allocation, and three studies attempted to blind the assessors to group allocation, which reduced expectation bias and the potential for type II statistical error in their clinical outcomes. All included studies had consistent baseline data, but no intention to treat analysis was performed for withdrawals and dropouts. These methodologic defects should be considered when interpreting the findings of the present meta-analysis. Substantial bleeding occurred via drains during the first few postoperative days [2, 12, 16], and 24–58 % of patients required blood transfusions [11, 22]. Many researches have demonstrated that FS can improve perioperative haemostasis and diminish the need for allogeneic RBC transfusion in patients undergoing TKA [3]. In the present metaanalysis, more homologous blood transfusions were required in the control patients (20.4 vs. 46.7 %). This may be due to greater postoperative blood loss or drainage volume in controls after TKA (MD = -354.53). However, Massin et al. [18] found that 5 ml of FS did not significantly diminish transfusion requirements in a non-randomized comparative study. Acute anaemia (low haemoglobin) sometimes leads to tachycardia and hypotension, and can increase the risk of myocardial infarction. Blood transfusion is thus necessary for more severe degrees of anaemia. In this meta-analysis, the mean haemoglobin decrease in patients treated with FS was lower than that in controls (MD = -0.72 g/dl). Usually, postoperative haemoglobin decline is used to calculate total blood loss from a formula adjusted for the weight and height of the patient [9]. It is interesting that two studies reported that use of FS reduced the mean calculated total blood loss [15, 20]. The reason could be that different methods were used for the calculation. Two of the included studies found no significant difference in intraoperative blood loss between FS and control groups [15, 24]. It is well known that substantial inapparent postoperative blood loss is caused by extravasation of the blood into the tissues. Apparent postoperative blood loss is largely seen as the volume observed in suction drain bottles [16, 17]. In this systematic review, use of FS significantly reduced the average drainage volume compared with that in control patients (MD = -354.53 ml).
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Infection is relatively rare after TKA, but can be devastating in terms of morbidity and cost [31]. This metaanalysis found no significant difference in the incidence of infection, which was 1.4 % with FS and 2.1 % in controls; the overall infection rate was 1.7 %. The reported incidence of infection after TKA ranges from 0.6 to 3 % [4, 10, 26, 29]. Because infection may also occur later, assessment after a longer follow-up period may be required. DVT is a common complication of TKA and when it develops into PE may result in morbidity or death. Prophylactic measures against DVT and PE were adapted in all of the included RCTs. Pooled results suggest that there was no difference in the incidence of DVT or PE between FS and control groups. The amount of wound haematoma in the affected knees was reported objectively [24, 28]. Pooled data demonstrated no significant difference in the incidence of wound haematoma, which was 5 % in patients receiving FS and 15.9 % in controls. Thus, FS seemed to reduce wound haematoma. Two studies [14, 21] mentioned the mean and standard deviation of the length of hospital stay and range of motion at 1 week postoperatively, but the pooled data in this metaanalysis found no significant differences. Levy et al. [15] also reported FS did not improve postoperative range of motion. There are several potential limitations in the results of meta-analysis delivered by us. (1) Only seven reports were included, and their sample sizes were small, which may have affected our conclusions. We were unable to conduct a valid statistical analysis of the safety of FS in TKA. (2) The follow-up of patients in some of the trials was limited. Many patients were followed for only until 6 weeks after surgery or hospital discharge. This may have resulted in underreporting of, for example, infection and DVT. (3) There were insufficient data to support analyses of functional outcome scores, cost, rehabilitation, postoperative swelling, pain relief and time to active straight leg raise as were originally planned. However, all of the included studies were high-quality RCTs with good homogeneity. The aim of the current literature was evaluating the efficacy and safety of FS in total knee arthroplasty in the daily clinic working. The results indicated that FS reduces blood transfusion rate and haemoglobin decline, decreases postoperative drainage volume, incidence of wound haematoma and does not increase the risk of wound infection, DVT or PE. Therefore, FS is safe and effective in the procedure of the TKA, which is useful for helping with showing the better prognosis of the TKA. Due to the limited quality of the evidence currently available, more highquality RCTs are required. These should be designed to examine the best therapeutic dose of using FS in the procedure of the TKA.
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Conclusion The meta-analysis of the current literature indicates that FS can safely and effectively reduce haemoglobin decline and postoperative drainage volume after TKA and decrease the need for blood transfusion, and does not increase the incidence of wound infection, haematoma, DVT or PE. Acknowledgments The authors are grateful for the support by the National Natural Science Foundation of China (Grant 21205087, Grant 81201945 and Grant 81101362) and the Tianjin Health Bureau Science and Technology Foundation (No. 2011kz117). Conflict of interest of interest.
The authors declare that they have no conflict
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14. Kluba T, Fiedler K, Kunze B, Ipach I, Suckel A (2012) Fibrin sealants in orthopaedic surgery: practical experiences derived from use of QUIXIL((R)) in total knee arthroplasty. Arch Orthop Trauma Surg 132(8):1147–1152 15. Levy O, Martinowitz U, Oran A, Tauber C, Horoszowski H (1999) The use of fibrin tissue adhesive to reduce blood loss and the need for blood transfusion after total knee arthroplasty. A prospective, randomized, multicenter study. J Bone Joint Surg Am 81(11):1580–1588 16. Lotke PA, Faralli VJ, Orenstein EM, Ecker ML (1991) Blood loss after total knee replacement. Effects of tourniquet release and continuous passive motion. J Bone Joint Surg Am 73(7):1037–1040 17. Marmor L, Avoy DR, McCabe A (1991) Effect of fibrinogen concentrates on blood loss in total knee arthroplasty. Clin Orthop Relat Res 273:136–138 18. Massin P, Scemama C, Jeanrot C, Boyer P (2012) Does fibrin sealant use in total knee replacement reduce transfusion rates? A non-randomised comparative study. Orthop Traumatol Surg Res 98(2):180–185 19. McConnell JS, Shewale S, Munro NA, Shah K, Deakin AH, Kinninmonth AW (2012) Reducing blood loss in primary knee arthroplasty: a prospective randomised controlled trial of tranexamic acid and fibrin spray. Knee 19(4):295–298 20. Molloy DO, Archbold HA, Ogonda L, McConway J, Wilson RK, Beverland DE (2007) Comparison of topical fibrin spray and tranexamic acid on blood loss after total knee replacement: a prospective, randomised controlled trial. J Bone Joint Surg Br 89(3):306–309 21. Notarnicola A, Moretti L, Martucci A, Spinarelli A, Tafuri S, Pesce V, Moretti B (2012) Comparative efficacy of different doses of fibrin sealant to reduce bleeding after total knee arthroplasty. Blood Coagul Fibrinolysis 23(4):278–284 22. Padala PR, Rouholamin E, Mehta RL (2004) The role of drains and tourniquets in primary total knee replacement: a comparative study of TKR performed with drains and tourniquet versus no drains and adrenaline and saline infiltration. J Knee Surg 17(1):24–27 23. Rajesparan K, Biant LC, Ahmad M, Field RE (2009) The effect of an intravenous bolus of tranexamic acid on blood loss in total hip replacement. J Bone Joint Surg Br 91(6):776–783 24. Sabatini L, Trecci A, Imarisio D, Uslenghi MD, Bianco G, Scagnelli R (2012) Fibrin tissue adhesive reduces postoperative blood loss in total knee arthroplasty. J Orthop Traumatol. 13(3):145–151 25. Sehat KR, Evans R, Newman JH (2000) How much blood is really lost in total knee arthroplasty? Correct blood loss management should take hidden loss into account. Knee 7(3):151–155 26. Silva M, Tharani R, Schmalzried TP (2002) Results of direct exchange or debridement of the infected total knee arthroplasty. Clin Orthop Relat Res 404:125–131 27. Varney SJ, Guest JF (2003) The annual cost of blood transfusions in the UK. Transfus Med 13(4):205–218 28. Wang GJ, Hungerford DS, Savory CG, Rosenberg AG, Mont MA, Burks SG, Mayers SL, Spotnitz WD (2001) Use of fibrin sealant to reduce bloody drainage and hemoglobin loss after total knee arthroplasty: a brief note on a randomized prospective trial. J Bone Joint Surg Am 83-A(10):1503–1505 29. Winiarsky R, Barth P, Lotke P (1998) Total knee arthroplasty in morbidly obese patients. J Bone Joint Surg Am 80(12):1770–1774 30. Zanasi S (2011) Innovations in total knee replacement: new trends in operative treatment and changes in peri-operative management. Eur Orthop Traumatol 2(1–2):21–31 31. Zhang QD, Guo WS, Zhang Q, Liu ZH, Cheng LM, Li ZR (2011) Comparison between closed suction drainage and nondrainage in total knee arthroplasty: a meta-analysis. J Arthroplasty 26(8):1265–1272
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Fibrin sealant before wound closure in total knee arthroplasty reduced blood loss: a meta-analysis Zhi-jun Li • Xin Fu • Peng Tian • Wen-xing Liu Yao-min Li • Yong-fa Zheng • Xin-long Ma • Wei-min Deng
•
Received: 5 January 2014 / Accepted: 26 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Fibrin sealant (FS) comprises a mixture of fibrinogen and thrombin that controls bleeding, reduces blood transfusions, improves tissue healing and shortens postoperative recovery time after various surgical procedures. However, no single study has been large enough to definitively determine whether fibrin sealant is safe and effective. We report a meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy and safety of fibrin sealant in total knee arthroplasty. Methods Articles published before August, 2012 were identified from PubMed, Embase, The Cochrane Library and other internet databases. Relevant journals and the recommendations of expert panels were also searched manually. We included only high-quality RCTs. Two independent reviewers searched and assessed the literature. Relevant data were analysed using RevMan 5.0.
Zhi-jun Li and Xin Fu have contributed equally to this study. Z. Li (&) Y. Zheng X. Ma Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300054, People’s Republic of China e-mail: [email protected] Z. Li W. Liu W. Deng Department of Immunology, Tianjin Medical University , Tianjin 300070, People’s Republic of China X. Fu P. Tian X. Ma Department of Orthopedics, Tianjin Hospital, Tianjin 300211, People’s Republic of China Y. Li Department of Rehabilitation, Tianjin Hospital, Tianjin 300211, People’s Republic of China
Results Seven RCTs met the inclusion criteria. Use of fibrin sealant significantly reduced haemoglobin decline mean difference (MD = -0.72), 95 % confidence interval [95 % CI (-0.83, -0.62), p \ 0.00001], postoperative drainage volume [MD = -354.53, 95 % CI (-482.43, 226.63), p \ 0.00001], the proportion of patients requiring blood transfusion risk differences [RD = -0.27, 95 % CI (-0.45, -0.08), p = 0.006] and the incidence of wound haematoma [RD = -0.11, 95 % CI (-0.22, -0.00), p = 0.04]. There were no significant differences in deep vein thrombosis, pulmonary embolism, infection rate or other complications between groups. Conclusions Use of fibrin sealant in total knee arthroplasty was effective and safe, reduced haemoglobin decline, postoperative drainage volume, incidence of haematoma and need for blood transfusion, and did not increase the risk of complications. Due to the limited quality of the evidence currently available, more highquality RCTs are required. Level of evidence II. Keywords Fibrin sealant Knee Arthoplasty Meta-analysis Blood loss
Introduction Total knee arthroplasty (TKA) is widely used to relieve pain, correct deformity, restore function and improve joint movement, and has become a reliable treatment for severe osteoarthritis and rheumatoid arthritis. TKA is particularly prone to large blood loss, ranging from 470 to 1,974 mL [5, 6, 25]. Although various methods of blood preservation have been used, including tourniquet, perioperative hemodilution, minimally invasive
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surgery, intraoperative and postoperative blood salvage and reinfusion, antifibrinolytic agents, hypotensive or epidural anaesthesia, and transfusion of predonated autologous blood [6, 23, 30], many patients need blood transfusion for significant intraoperative and postoperative blood loss. It is well known that allogeneic blood transfusion carries risks of transmission of infection (viral and bacterial), possible haemolytic transfusion reactions, transfusion-related lung injury and even death [1, 27]. Fibrin sealant (FS), or fibrin glue, is a mixture of fibrinogen and thrombin that is used to control bleeding, reduce blood transfusions, improve tissue healing and reduce postoperative recovery time following various surgical procedures [7, 13]. Numerous studies have investigated the efficacy and safety of FS in TKA [14, 15, 19–21, 24, 28]. However, some have been criticized for poor design, low power, inconclusive results and short followup. Therefore, we conducted a meta-analysis, pooling the data from randomized controlled trials (RCTs) to provide an evidence-based judgment regarding the use of FS in patients undergoing TKA.
Fig. 1 Search results and the selection procedure
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Materials and methods Search strategy In a meta-analysis conducted by us, in which the academic articles were identified from electronic databases, including MEDLINE (1966–August, 2012), EMBASE studies conducted on human subjects were included. The search strategy is presented in Fig. 1. In addition, the Google search engine was searched manually using the same search terms to seek further relevant studies that may have been missed in the database search. We used the key words ‘knee replacement OR arthroplasty’ and ‘fibrin sealant OR fibrin glue’ in combination with the Boolean operators AND or OR. Selection criteria and quality assessment All published RCTs and quasi-RCTs (those using methods of allocating participants to treatments that are not strictly random, e.g. date of birth, hospital record number and alternation) had been included that compared FS with a
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control (placebo or nothing) in patients undergoing TKA. The methodologic quality of the studies was assessed by the review authors (X. Fu and Z. Li) using a modification of the generic evaluation tool used by the Cochrane Bone, Joint and Muscle Trauma Group [17]. The methodologic quality of each trial was scored and ranged from 0 to 24. Data extraction For each eligible study, two of the authors (X. Fu and Z. Li) extracted all relevant data independently. Disagreement was resolved by discussion with a third investigator (P. Tian). When data were incomplete or unclear, attempts were made to contact the investigators for clarification. The following data were extracted: (1) demographical data of participants; (2) indication for TKA; (3) wound infection (superficial or deep), haematoma, wound dehiscence, limb swelling, ecchymosis, bleeding from the wound, reoperation because of a wound healing complication; (4) postoperative blood transfusion, decrease in haemoglobin or haematocrit, thromboembolic complications, patient discomfort, cost; (5) functional outcome such as time to regain mobility; and (6) any other outcomes as mentioned in individual studies were considered for inclusion. Statistical analysis The RevMan 5.0 for Windows (Cochrane Collaboration, Oxford, United Kingdom) was used to undertake this metaanalysis. We assessed the statistical heterogeneity of each study using the standard Chi-square test (statistical heterogeneity was considered at a significance level of p \ 0.1) and evaluated the I2 statistic [18]; an I2 value of 50 % was considered to indicate substantial heterogeneity. The origins of heterogeneity, if present, were analysed according to differences in methodologic quality, the characteristics of the participants and the intervention. When the data allowed, we performed subgroup analysis. When comparing trials showing heterogeneity, pooled data were meta-analysed using a random-effects model [19]. Otherwise, a fixed-effects model was used [20]. Relative risks (or risk differences) and 95 % confidence intervals (95 % CI) were calculated for dichotomous outcomes and mean differences (MDs) and 95 % CIs for continuous outcomes. When the data allowed, the authors of this paper performed subgroup analysis of the trials according to dose regimen and timing of FS delivery, transfusion trigger and administration of low molecular weight heparin.
Results Ninety-seven citations had been identified as potentially relevant studies. By screening the title and reading the
abstract and the entire article, seven RCTs including 408 knees at final follow-up were eligible for data extraction and meta-analysis (Fig. 1). The sample size ranged from 24 to 100. The studies were relatively well designed, and the quality assessment score was high, with a range of 16–22. However, the relevant RCTs had numerous methodologic weaknesses. Only one study stated that randomization was achieved by a computer assignment method [11]; the others did not provide randomization methods. One study provided a methodology for the blinding of subjects to group allocation [13], and three studies attempted to blind the assessors to group allocation. All studies reported final outcomes for a minimum of 85 % of their randomized patients. Inclusion and exclusion criteria were reported for all studies. All of the trials involved primary TKA; osteoarthritis was the most common diagnosis. The patients’ characteristics were comparable within each study group and are presented in Table 1. Two trials used regional anaesthesia alone [20, 21], only one used general anaesthesia [14]; the remaining four did not mention the type of anaesthesia used. All studies reported use of a tourniquet during TKA. The tourniquet was deflated after wound dressing in Molloy’s study and before haemostasis in three studies; the other studies did not mention the timing of deflation. Doses of FS ranged from 2 to 20 ml; five studies used 10 ml, Kluba et al. used 2 ml and Levy et al. used 10 or 20 ml. No placebo was used in the control group. Primary haemostasis was achieved in all patients in both treatment and control groups by electrocauterization of the bleeding vessels in the operative field. Four studies stated a transfusion trigger, which was related to either a fall in haemoglobin level or clinical symptoms of hypotension, tachycardia and dizziness. In one study, the transfusion trigger was reported to be based on the criteria and guidelines of the National Institutes of Health Consensus Conference [15]. One study did not mention the blood transfusion protocol. Five studies reported that postoperative drainage was measured between 24 and 48 h, when the drains were removed in most cases. Two studies stated that two drain tubes were used; the others did not mention this information. None of the included studies clamped the drain after TKA. The prostheses were cemented in five trials [14, 15, 19, 21, 24] and uncemented in two. The follow-up period ranged from discharge to 6 months. It was possible to perform a meta-analysis with 10 outcomes (Table 2). There were statistically significant differences between treatment and control group for transfusion requirements (RD = -0.27; Fig. 2), drainage volume (MD = -354.53; Fig. 3), reduction in Hb (MD = -0.72; Fig. 4) and the incidence of wound haematoma (RD = -0.11). Subgroup analysis was performed for transfusion requirements, which showed that
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Knee Surg Sports Traumatol Arthrosc Table 1 Cohort characteristics Studies
Cases (FS/C)
Mean age (FS/C)
Male patients (FS/C)
Dosage (ml)
DVT prophylaxis
Length of follow-up
QAS
Kluba et al. [14]
12/12
70.8/71
6/6
2
Enoxaparin, 40 mg
6 weeks
18
Levy et al. [15]
29/29
68.9/70.2
6/6
10 or 20
Enoxaparin, 30 mg
6 months
22
McConnell et al. [19]
21/22
NS
15/7
10
Aspirin, 150 mg
5 weeks
19
Molloy et al. [20]
50/50
NS
NS
10
Aspirin, 150 mg
3 months
21
Notarnicola et al. [21]
30/30
69.2
11/10
10
Enoxaparin, 40 mg
6 months
16
Sabatini et al. [24]
35/35
70.7/70.4
10/6
10
LMWH, NS
Discharge
20
Wang et al. [28]
25/28
NS
NS
10
Enoxaparin, 30 mg
6 months
17
FS fibrin sealant, DVT deep venous thrombosis, QAS quality assessment score, LMWH low molecular weight heparin, NS not state
Table 2 Meta-analysis results Outcome
Studies
Groups (FS/C)
Overall effect Effect estimate
Heterogeneity p value
I2 (%)
-0.45, -0.08
0.006
78
0.0005
-482.43, -226.63
\0.00001
85
\0.0001
95 % CI
p value
Transfusion requirements
6
181/184
-0.27
Drainage volume
5
131/134
-354.53
Reduction in Hb
5
169/172
-0.72
-0.83, -0.62
\0.00001
36
n.s.
Wound infections
4
144/144
-0.01
-0.04, 0.03
n.s.
0
n.s.
Deep venous thrombosis
4
144/144
0.01
-0.02, 0.05
n.s.
0
n.s.
Pulmonary embolism
3
114/114
0.00
-0.04, 0.04
n.s.
0
n.s.
Mean number of transfusions Mean calculated blood loss
2 2
80/80 79/79
-0.04 -451.70
-0.96, 0.17 -921.36, 17.97
n.s. n.s.
85 87
0.01 0.005
Hospital length of stay
2
42/42
-3.07
-6.32, 0.18
n.s.
74
n.s. \0.00001
Mean postoperative range of motion
2
42/42
16.79
13.73, 19.86
n.s.
97
Wound haematoma
2
60/63
-0.11
-0.22, -0.00
0.04
0
0.91
FS fibrin sealant, C control, 95 % CI 95 % confidence interval, n.s. non-significant
Experimental Study or Subgroup
Events
Control
Odds Ratio
Total Events Total Weight
Odds Ratio
M-H, Fixed, 95% CI
Kluba 2012
3
12
3
12
3.4%
1.00 [0.16, 6.35]
Levy 1999
6
29
24
29
28.6%
0.05 [0.01, 0.20]
Molloy 2007
7
50
11
50
14.2%
0.58 [0.20, 1.64]
Notarnicola 2012
7
30
19
30
21.9%
0.18 [0.06, 0.54]
Sabatini 2012
5
35
15
35
19.3%
0.22 [0.07, 0.71]
Wang 2001
9
25
14
28
12.7%
0.56 [0.19, 1.69]
184 100.0%
0.28 [0.18, 0.45]
181
Total (95% CI) Total events
37
M-H, Fixed, 95% CI
86
Heterogeneity: Chi² = 11.95, df = 5 (P = 0.04); I² = 58% Test for overall effect: Z = 5.24 (P < 0.00001)
0.01 0.1 1 10 100 Favours experimental Favours control
Fig. 2 Forest plot diagram showing effect of Fibrin sealant (FS) on the number of patients requiring transfusion
this positive effect persisted regardless of whether FS was delivered in dosage, whether the patient had low molecular weight heparin, a cemented TKA, and whether a transfusion protocol existed (Table 3). With respect to other outcome measurements, there were no statistically significant differences between FS and
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control groups in the risk of developing a wound infection or the length of hospital stay, deep venous thrombosis (DVT), pulmonary embolism (PE) or the mean number of transfusions required (n.s; Table 2). Several other outcome measurements were identified, but insufficient data were provided for meta-analysis. For
Knee Surg Sports Traumatol Arthrosc Experimental
Control
Mean
Kluba 2012
475.4 231.8
Mean Difference
12 813.3 433.4
12
0.6%
Mean Difference
-337.90 [-615.98, -59.82]
Levy 1999
360 287.7
29
878
403
29
1.5% -518.00 [-698.22, -337.78]
Notarnicola 2012
415
76.2
30
815 223.7
30
6.8% -400.00 [-484.57, -315.43]
Sabatini 2012
910
292
35 1,250
546
35
1.1% -340.00 [-545.13, -134.87]
184.5
28.9
25 408.3
54.6
28
90.0% -223.80 [-246.98, -200.62]
Wang 2001
134 100.0% -242.14 [-264.13, -220.15]
131
Total (95% CI)
IV, Fixed, 95% CI
IV, Fixed, 95% CI
SD Total Weight
SD Total Mean
Study or Subgroup
Heterogeneity: Chi² = 26.12, df = 4 (P < 0.0001); I² = 85%
-500 -250 0 250 500 Favours experimental Favours control
Test for overall effect: Z = 21.58 (P < 0.00001)
Fig. 3 Forest plot diagram showing effect of Fibrin sealant (FS) on drainage volume
Experimental Study or Subgroup Levy 1999 Molloy 2007
Mean
Control
SD Total Mean
Mean Difference
SD Total Weight
1
29
3.7
1.2
29
3.4% -1.20 [-1.77, -0.63]
2.68 1.02
50
3.2 1.12
50
6.2% -0.52 [-0.94, -0.10]
3.7
2
30
1.8% -1.20 [-1.98, -0.42]
2.5
Notarnicola 2012
2.5
0.9
30
Sabatini 2012
2.6 1.16
35
3 1.28
35
2.01 0.21
25
2.73 0.21
28
Wang 2001 Total (95% CI)
Mean Difference
169
3.3%
IV, Fixed, 95% CI
IV, Fixed, 95% CI
-0.40 [-0.97, 0.17]
85.3% -0.72 [-0.83, -0.61]
172 100.0% -0.72 [-0.83, -0.62]
Heterogeneity: Chi² = 6.25, df = 4 (P = 0.18); I² = 36%
-2 -1 0 1 Favours experimental Favours control
Test for overall effect: Z = 13.52 (P < 0.00001)
2
Fig. 4 Forest plot diagram showing effect of Fibrin sealant (FS) on haemoglobin decline
Table 3 Subgroup analysis of transfusion outcome
DVT deep venous thrombosis, LMWH low molecular weight heparin, CI confidence interval
Outcome or subgroup
Studies
Effect estimate v2
I2 (%)
RD
95 % CI
p value
Total dose C10 ml
5
19.96
80
-0.28
[-0.37, -0.19]
\0.00001
LMWH Transfusion protocol
5 4
14.01 10.99
71 73
-0.33 -0.38
[-0.44, -0.22] [-0.49, -0.26]
\0.00001 \0.00001
Cemented prosthesis
4
13.52
78
-0.31
[-0.58, -0.04]
instance, Sabatini et al. [24] reported a significant difference in requirement for more than one transfusion unit and no significant difference in operative time, Levy et al. [11] found no viral seroconversion at 3 or 6 months after TKA, and Molloy et al. [13] reported no statistical differences in C-reactive protein, pain scores or leg swelling between treatment and control groups.
Discussion The most important finding of the present study was that FS reduces blood transfusion rate and haemoglobin decline, decreases postoperative drainage volume, incidence of wound haematoma and does not appear to increase the risk of wound infection, DVT or PE. During the last 20 years, FS has been increasingly used to improve haemostasis and reduce blood loss after major surgery,
0.02
prompting a growing scientific interest in this technique [8]. Carless et al. [21] showed that FS might reduce blood loss and the amount of blood transfused during cardiac and pulmonary surgery, hepatic surgery, prostate surgery and TKA. In the present meta-analysis, use of FS tended to reduce the average number of red blood cell transfusions per patient, total blood loss and length of hospital stay and increased the mean postoperative range of motion, but not statistically significantly. One study found that perioperatively applied platelet gel and FS may reduce the incidence of allogeneic blood transfusions and complications associated with TKA [8]. Following a RCT, McConnell et al. concluded that 10 ml of topically applied fibrin spray reduced blood loss compared with a control group undergoing computer-navigated cemented total knee arthroplasty, whereas a 10 mg/kg bolus of tranexamic acid did not.
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Seven RCTs satisfied the defined eligibility criteria for this meta-analysis. Most of the included RCTs were of good methodologic quality, were relatively well designed and had high-quality assessment scores (16–22 score). All of the included studies reported randomization, though six did not describe the method of randomization used; with these latter studies, we were insufficiently confident with the available information to determine whether true randomization methods had been used. One study provided a methodology for the blinding of subjects to group allocation, and three studies attempted to blind the assessors to group allocation, which reduced expectation bias and the potential for type II statistical error in their clinical outcomes. All included studies had consistent baseline data, but no intention to treat analysis was performed for withdrawals and dropouts. These methodologic defects should be considered when interpreting the findings of the present meta-analysis. Substantial bleeding occurred via drains during the first few postoperative days [2, 12, 16], and 24–58 % of patients required blood transfusions [11, 22]. Many researches have demonstrated that FS can improve perioperative haemostasis and diminish the need for allogeneic RBC transfusion in patients undergoing TKA [3]. In the present metaanalysis, more homologous blood transfusions were required in the control patients (20.4 vs. 46.7 %). This may be due to greater postoperative blood loss or drainage volume in controls after TKA (MD = -354.53). However, Massin et al. [18] found that 5 ml of FS did not significantly diminish transfusion requirements in a non-randomized comparative study. Acute anaemia (low haemoglobin) sometimes leads to tachycardia and hypotension, and can increase the risk of myocardial infarction. Blood transfusion is thus necessary for more severe degrees of anaemia. In this meta-analysis, the mean haemoglobin decrease in patients treated with FS was lower than that in controls (MD = -0.72 g/dl). Usually, postoperative haemoglobin decline is used to calculate total blood loss from a formula adjusted for the weight and height of the patient [9]. It is interesting that two studies reported that use of FS reduced the mean calculated total blood loss [15, 20]. The reason could be that different methods were used for the calculation. Two of the included studies found no significant difference in intraoperative blood loss between FS and control groups [15, 24]. It is well known that substantial inapparent postoperative blood loss is caused by extravasation of the blood into the tissues. Apparent postoperative blood loss is largely seen as the volume observed in suction drain bottles [16, 17]. In this systematic review, use of FS significantly reduced the average drainage volume compared with that in control patients (MD = -354.53 ml).
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Infection is relatively rare after TKA, but can be devastating in terms of morbidity and cost [31]. This metaanalysis found no significant difference in the incidence of infection, which was 1.4 % with FS and 2.1 % in controls; the overall infection rate was 1.7 %. The reported incidence of infection after TKA ranges from 0.6 to 3 % [4, 10, 26, 29]. Because infection may also occur later, assessment after a longer follow-up period may be required. DVT is a common complication of TKA and when it develops into PE may result in morbidity or death. Prophylactic measures against DVT and PE were adapted in all of the included RCTs. Pooled results suggest that there was no difference in the incidence of DVT or PE between FS and control groups. The amount of wound haematoma in the affected knees was reported objectively [24, 28]. Pooled data demonstrated no significant difference in the incidence of wound haematoma, which was 5 % in patients receiving FS and 15.9 % in controls. Thus, FS seemed to reduce wound haematoma. Two studies [14, 21] mentioned the mean and standard deviation of the length of hospital stay and range of motion at 1 week postoperatively, but the pooled data in this metaanalysis found no significant differences. Levy et al. [15] also reported FS did not improve postoperative range of motion. There are several potential limitations in the results of meta-analysis delivered by us. (1) Only seven reports were included, and their sample sizes were small, which may have affected our conclusions. We were unable to conduct a valid statistical analysis of the safety of FS in TKA. (2) The follow-up of patients in some of the trials was limited. Many patients were followed for only until 6 weeks after surgery or hospital discharge. This may have resulted in underreporting of, for example, infection and DVT. (3) There were insufficient data to support analyses of functional outcome scores, cost, rehabilitation, postoperative swelling, pain relief and time to active straight leg raise as were originally planned. However, all of the included studies were high-quality RCTs with good homogeneity. The aim of the current literature was evaluating the efficacy and safety of FS in total knee arthroplasty in the daily clinic working. The results indicated that FS reduces blood transfusion rate and haemoglobin decline, decreases postoperative drainage volume, incidence of wound haematoma and does not increase the risk of wound infection, DVT or PE. Therefore, FS is safe and effective in the procedure of the TKA, which is useful for helping with showing the better prognosis of the TKA. Due to the limited quality of the evidence currently available, more highquality RCTs are required. These should be designed to examine the best therapeutic dose of using FS in the procedure of the TKA.
Knee Surg Sports Traumatol Arthrosc
Conclusion The meta-analysis of the current literature indicates that FS can safely and effectively reduce haemoglobin decline and postoperative drainage volume after TKA and decrease the need for blood transfusion, and does not increase the incidence of wound infection, haematoma, DVT or PE. Acknowledgments The authors are grateful for the support by the National Natural Science Foundation of China (Grant 21205087, Grant 81201945 and Grant 81101362) and the Tianjin Health Bureau Science and Technology Foundation (No. 2011kz117). Conflict of interest of interest.
The authors declare that they have no conflict
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