Introduction

As the population continues to age, the incidence of knee osteoarthritis and, concomitantly, total joint replacement has increased [1]. Bilateral knee osteoarthritis is also increasing in prevalence with up to one-third of patients developing bilateral disease within 2 years of initial unilateral diagnosis [2]. Total knee arthroplasty (TKA) has been shown to be a successful treatment modality for end-stage knee osteoarthritis [2]. For patients with bilateral disease, TKA can be accomplished in a simultaneous (one anesthesia), staggered (single-admission, procedures separated by several days), or staged (separate admissions, procedures weeks or months apart) fashion [3]. Compared to staged bilateral TKA (BTKA), a simultaneous procedure has several advantages: 1) patient preference to undergo a single operation; 2) decreased total recovery time; and 3) reduced perioperative cost [4]. However, some studies have demonstrated higher complication rates associated with simultaneous BTKA, including increased intraoperative blood loss, greater need for perioperative blood transfusion, and increased rates of venous thromboembolism (VTE), cardiorespiratory complications, neurologic complications, wound breakdown, deep infection, and mortality [5,6,7,8]. Careful patient selection has been shown to reduce perioperative complications with simultaneous BTKA [9]. Patients with coronary artery disease with inducible ischemia, congestive heart failure, advanced chronic obstructive pulmonary disease, uncontrolled diabetes, peripheral vascular disease, renal failure, morbid obesity, history of VTE, or those who are older than 75 years are usually not considered eligible for simultaneous BTKA [10]. In such cases, treatment options include single-admission staggered BTKA (managed as two separate procedures performed on different days during a single hospitalization) or staged BTKA during two separate hospitalizations, usually performed within 1 year [11]. Staggered BTKA confers many of the same advantages as simultaneous BTKA, including 1) patient preference for single hospitalization; 2) decreased overall recovery time [10]. For medically complex patients who are contraindicated for simultaneous BTKA, staggered BTKA may offer a compromise to correct severe bilateral knee deformities in quick succession [10]. Meanwhile, staged BTKA may not be preferred by patients due to lengthier overall recovery time and multiple hospital admissions, but staged BTKA demonstrates the lowest complication rates of all BTKA options [12].

Recently, several clinical trials have been published in relation to staggered BTKA performed during a single hospitalization [10, 13,14,15,16,17]. However, no systematic or comprehensive review of the literature has been published to date. For this reason, the aims of this study were threefold: 1) to characterize the methodological quality of the relevant, available literature, 2) to summarize early postoperative complication rates and clinical outcomes associated with the use of staggered BTKA, and 3) to compare the early postoperative outcomes of staggered BTKA with those of simultaneous BTKA and staged BTKA.

Methods

Two reviewers (AG, NS) independently conducted the search in a systematic way according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [18] using the MEDLINE/PubMed database, Embase, and the Cochrane Database of Systematic Reviews without any publicly registered systematic review protocol (Fig. 1). These databases were searched using terms defined in detail in Table 1. To maximize the search, backward chaining of reference lists from retrieved papers was also undertaken. A preliminary assessment of only the titles and abstracts of the search results was performed. The second stage involved a careful review of the full-text publications.

Fig. 1
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Systematic review flow diagram

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Table 1 Search strategy
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Inclusion and exclusion criteria

The inclusion criteria were: 1) studies describing human subjects of any age and gender; 2) studies that include a population of at least ten patients who underwent staggered BTKA (managed as separate procedures performed in different days during a single hospitalization); 3) clinical trials investigating the clinical and/or functional and/or radiographic outcomes of staggered BTKA; 4) studies that compared staggered BTKA (managed as separate procedures performed in different days during a single hospitalization) to either simultaneous BTKA (both procedures performed in the same day during one anesthetic session) or staged BTKA (managed as separate procedures during two separate hospitalizations) or studies that compared staggered BTKA various time points; 5) full-text English articles published until October 30, 2018; and 6) perioperative or early postoperative follow-up (no restriction in minimum time, since we planned to examine perioperative and early postoperative complications).

The exclusion criteria were: 1) non clinical study; 2) general review and systematic review; 3) non-English articles; 4) studies stratifying patients based on perioperative management (anesthesia protocol, limitation of blood loss, surgical technique, prosthesis type, etc.); 5) number of cases being less than 10; 6) studies only dealing with staged BTKA (managed as separate procedures during two separate hospitalizations) and/or simultaneous BTKA (same-day, 1-anesthestic session) and/or unilateral TKA; 7) studies reporting on revision unilateral TKA and/or revision BTKA; 8) studies dealing with simultaneous or staged or staggered bilateral unicompartmental knee arthroplasty; 9) editorial comments, corrigenda; 10) non full-text articles; 11) studies without clinical and/or functional and/or radiographic results; and 12) articles published after October 30, 2018.

Data collection

Two authors independently conducted the search. Differences between reviewers were discussed until agreement was achieved. In cases of disagreement, the senior author (PS) had the final decision. The two reviewers independently extracted data from each study and assessed variable reporting of outcome data. Descriptive statistics were calculated for each study and parameters analyzed. The level of evidence in the included studies was determined using the Oxford Centre for Evidence-Based Medicine—Levels of Evidence [19]. The “quality assessment” of the studies for methodological deficiencies, as a common alternative to “risk of bias,” was examined by the modified Coleman Methodology Score [20]. The methodological quality of each study and the different types of detected bias were assessed independently by each reviewer and then combined. Selective reporting bias, such as publication bias, was not included in the assessment. Finally, a comprehensive analysis of the eligible studies was performed, focusing on specific questions which were relative to the topic.

During the initial review of the data, the following information was collected for each study: title, author, year of publication, study design, number of patients, number of knees, time between first and second surgery, gender, range of motion changes after the first and second surgeries, postoperative complications, and pre- and post-TKA clinical outcome scores. Early postoperative complications were categorized into mortality rate, systematic complications, orthopedic complications, blood transfusions, length of stay, intensive care unit (ICU) admissions, and hospital re-admissions. The primary outcome measure was the rate of early postoperative complications. Secondary outcome measures included clinical, functional, and radiographic outcomes.

Results

In total, 551 articles were identified utilizing the search criteria (Fig. 1). Following the removal of duplicate articles, 304 articles remained and were subjected to application of the predetermined inclusion and exclusion criteria. Following application of these criteria, 10 articles underwent a full-text screening process. Among those, 7 articles were eligible for analysis [10, 13,14,15,16,17, 21]. However, two articles assessed staggered BTKA utilizing the same dataset [16, 21]. We included one of the two articles that had more comprehensive analysis [16] and subsequently excluded the other [21]. Overall, six articles were included in this analysis [10, 13,14,15,16,17]. Among them, only one study was published after 2015 [14].

Study design, level of evidence

All papers included in this review were retrospective case–control studies (Table 2). In total, four out of six studies (66%) [13,14,15,16] made comparisons between the outcome of single-hospitalization staggered BTKA and simultaneous BTKA, whereas three studies [10, 13, 14] compared staggered BTKA (single hospitalization) with staged BTKA (different admissions). Furthermore, a comparison between staggered BTKA and unilateral TKA was conducted in one paper (16.7%) [15]. Two studies (33%) [16, 17] analyzed the impact of different time intervals in the same-admission staggered BTKA. In this analysis, all studies were level of evidence III [10, 13,14,15,16,17]. Four papers (66%) were 3-arm studies [13,14,15,16], while two papers (33.3%) were 2-arm trials [10, 17]. Finally, one paper was based on data extracted from a nationwide registry [16]. (Table 2).

Table 2 Type of study, level of evidence, follow-up, early clinical evaluation, modified Coleman methodology score (MCMS), and potential risk of bias
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Quality of the studies and possible high risk of bias

The “quality assessment” of the studies for methodological deficiencies, as a common alternative to “risk of bias” [22], was examined by the modified Coleman Methodology Score [23]. The total mean modified Coleman Score of the review was 55/100, ranging from 38 [17] to 62 [10, 13] (Table 2). All studies which were included in this review had a high risk of possible selection, performance, detection, and reporting bias [10, 13,14,15,16,17]. Furthermore, one study had high risk of potential other types of bias [16] (Table 2).

Demographics

In total, the review included 43,892 patients: 2,042 (4.7%) single-hospitalization staggered BTKA, 39,962 (91.6%) simultaneous BTKA, and 1,887 (4.3%) staged BTKA during different hospitalizations. Females (n = 25,931; 59.1% of all patients) outnumbered males (n = 17,961; 40.1% of all patients), and mean age of the staggered BTKA patients was 68.0 years. Additional patient demographics are listed in Table 3. Patient follow-up varied from 0 months (only perioperative follow-up [17]) to 12 months postoperatively [14, 15] (Table 2). For same-admission staggered BTKA, the time between the first and the second operation ranged from 1 [16] to 14 days [10], with the majority of the studies (83%) using a 1-week interval between surgeries [13,14,15,16,17] (Table 3).

Table 3 Number of patients per study, sex, mean age, and time between the first and the second surgery in the patients with staggered bilateral TKA
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All studies comparing simultaneous and staggered procedures reported significantly increased rates of preoperative comorbidities or higher ASA score in the patients who were treated with staggered BTKA [13,14,15,16]. In these studies, simultaneous BTKA patients were predominantly male, younger, and healthier, as compared to staggered BTKA patients [13,14,15,16]. Finally, one study noted that patients contraindicated for simultaneous BTKA (due to medical comorbidities), but presenting with major bilateral knee deformities requiring simultaneous correction (for accelerated postoperative rehabilitation) were recommended to undergo staggered instead of staged BTKA [10].

Mortality rate

All six trials reported postoperative mortality rate (Table 4). Mortality rate in staggered-treated patients ranged from 0 [17] to 1% [14], while mortality ranged from 0 [15] to 0.24% [14] for the simultaneous-treated patients, and from 0.06 [10] to 6% [13] for the staged-treated patients. Five of six studies (83%) reported no significant difference between staggered, simultaneous, or staged BTKA in regard to mortality rate [10, 14,15,16,17]. One study [12] reported that the staged group had an increased mortality rate in comparison with the staggered and the simultaneous groups (Table 4).

Table 4 Complications and outcomes measured as well as mortality rate and major complications’ rate per study
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Perioperative complications

Medical or systemic complications (not related to the wound or the implant) were reported in all 6 studies [10, 13,14,15,16,17], but the results were conflicting. Three out of the 6 studies depicted no difference between staggered, simultaneous, or staged BTKA in regard to the rate of medical complications [14, 15, 17]. Another study confirmed these results only when the staggered-treated patients had a 4–7-day interval between operations [16]. Staggered BTKA patients who had the second TKA within a 1–3-day interval showed increased complications rates [16]. In addition, one study reported increased rates of general complications after staggered BTKA compared to staged BTKA with the second operation performed within one year after the first one [10]. However, the two groups were not comparable since the staggered patients were more likely to be male and had a higher overall comorbidity burden than the staged patients [10]. In contrast, one study (16.7%) reported that the staged-treated group (different hospitalizations) experienced increased rates of complications when compared with the single-hospitalization staggered-treated group [13] (Table 4).

The rate of major complications of patients treated with staggered BTKA ranged widely from 0 [17] to 16% [10]. The exact ratios per study can be found in Table 4.

Three studies (50%) separately investigated the rate of acute renal failure [14,15,16]. Two of these studies (66.7%) depicted that staggered BTKA led to significantly decreased rate of acute renal failure in comparison with simultaneous BTKA [14, 16], while one study (33%) noted that there was not any significant difference among groups [15] (Table 4).

Surgery-related (or orthopedic) complications

Surgery-related (or orthopedic) complications were documented in three studies (50% of all) [10, 15, 16]. Two out of these three studies (66.7%) [10, 16] found that staggered BTKA led to an increased rate of surgery-related complications. One study (33.3% of these specific studies) [15] did not document any significant difference between staggered-treated and simultaneous-treated patients regarding the rate of orthopedic complications (Table 4).

Blood transfusions

Four studies (66.7% of all) assessed the rate of blood transfusion in the different groups of patients [10, 13, 15, 16]. Three studies (75% of these specific studies) compared staggered and simultaneous BTKA [13, 15, 16]. Two of them concluded that there was no difference among groups regarding the requirement for blood transfusion [13, 15], whereas one study noted that staggered BTKA resulted in increased rates of blood transfusion when compared with simultaneous BTKA [16]. Moreover, two studies (50% of these specific studies) compared single-hospitalization staggered and staged BTKA during different hospitalizations [10, 13]. Both studies showed that staggered BTKA led to an increased rate of blood transfusions in comparison with the staged BTKA [10, 13].

Length of stay, intensive care unit (ICU) admissions, and re-admissions

Four out of the six studies (66.7%) measured mean length of stay as an outcome variable [13,14,15, 17]. All studies which compared staggered and simultaneous BTKA concluded that the mean length of stay after the former was significantly longer [13,14,15]. The only study which compared single-hospitalization staggered and staged (during different hospitalizations) BTKA suggested that the former resulted in shorter mean length stay [15].

Two studies (33.3%) assessed the ratio of ICU admissions [15, 17]. One of these studies found that patients who were treated with staggered BTKA had lower rates of ICU admission in comparison with those who underwent a simultaneous BTKA [14]. The other study did not use any control group to compare the results of staggered BTKA, since the comparison was carried out between different intervals of single-hospitalization staggered BTKA [17].

Furthermore, two studies (33.3%) investigated readmission rates [13, 15]. Both these studies found that there was not any significant difference in the readmission rate between staggered BTKA and simultaneous BTKA [13, 15]

Staggered BTKA versus simultaneous BTKA: Overall

While four studies made comparisons between staggered BTKA and simultaneous BTKA [13,14,15,16], no consensus was found regarding the superiority of either procedure. Two studies [13, 14] noted that the staggered BTKA group had significantly better results in terms of primary outcomes (overall complication rate, acute kidney insufficiency) compared to the simultaneous BTKA group. One study [15] reported that there was not any difference among groups, whereas the final investigation [16] noted that the difference was insignificant in patients undergoing staggered BTKA with 4–7-day interval. Furthermore, the latter study [16] suggested that staggered-treated patients with a 1–3-day interval had inferior results compared to those treated with simultaneous BTKA (Table 5).

Table 5 Assessment of same-admission staggered BTKA in comparison with: a. simultaneous BTKA and b. staged BTKA (two separate hospitalizations). Take-home-message per study is also illustrated
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Staggered BTKA versus staged BTKA: Overall

Three studies compared single-hospitalization staggered and staged (different admissions) BTKA, but the results were conflicting [10, 13, 14]. Two studies (66.7% of these specific studies) showed better outcomes with the use of staggered BTKA [13, 14], whereas one study (33%) noted that staged BTKA during different hospitalizations led to significantly better results than staggered BTKA [10] (Table 5).

Timing of staggered BTKA

There was no consensus regarding the optimal interval between surgeries in single-hospitalization staggered BTKA. Two studies (33.3% of all) compared the outcome of two different intervals in patients treated with staggered BTKA [16, 17]. Wu et al. found that there was not any significant difference between the outcomes of 2-day interval and those of 7-day interval [17]. However, Liu et al. noted that the 4–7-day interval conferred better results (comparable to simultaneous BTKA) than the 1–3-day interval [16] (Table 6).

Table 6 Impact of Timing of Staggered BTKA on Postoperative Outcomes
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Discussion

Our systematic review of the literature illustrates that controversy continues about the optimal timing of the second surgery for patients with bilateral knee osteoarthritis and whether single-admission staggered bilateral TKA should be performed [13]. Eighty-one percent of participants in a consensus conference agreed that if a patient is not deemed a candidate for the same-day BTKA, a second TKA should be scheduled no sooner than 3 months after the first [9]. The most important finding of our review was that existing evidence regarding the safety and efficacy of staggered BTKA is lacking and further research is required to make more evidence-based conclusions. Particularly, there was no consensus among authors regarding the safety and efficacy of staggered BTKA when compared with staged or simultaneous BTKA. Although single-hospitalization staggered BTKA resulted in satisfactory clinical outcomes with relatively low complication rates in patients who were not considered eligible for the same-day BTKA, we could not conclude that staggered BTKA is superior to the staged procedure.

Regardless of the surgical strategy, bilateral TKA is considered a safe procedure [24, 25]. Staggered BTKA illustrated similar mortality rates as compared to both simultaneous or staged BTKA, in almost all studies [10, 14,15,16,17]. Furthermore, the rates of major complications were low, although they varied widely among studies in this review. Some trials showed special interest in the rate of postoperative acute renal failure [14,15,16,17]. All of them noted that staggered BTKA led to at least similar or better results regarding postoperative renal insufficiency when compared to simultaneous BTKA [14,15,16,17]. Koh et al. [14] reported that the incidence of acute kidney injury (AKI) was lower in the staggered group compared to the staged and simultaneous groups in primary bilateral TKA patients. Even though the preoperative demographic and laboratory data were comparable among groups, the authors suggested that this difference might have been related to the type of anesthesia, favoring spinal anesthesia instead of general anesthesia in order to reduce the occurrence of postoperative AKI [26]. On the other hand, it was not clear whether staggered BTKA resulted in different rates of surgery-related (orthopedic) complications when compared with staged or simultaneous BTKA [10, 15, 16].

As for the comparison between the overall complication rates of staggered and simultaneous BTKA, this systematic analysis showed that there was weak evidence in favor of the staggered procedure. Most studies which dealt with this kind of comparison found that staggered BTKA led to at least similar or better results than simultaneous BTKA [13,14,15], whereas only one study showed better results with the simultaneous procedure [16]. In addition, Poultsides et al. [10] reported that single-hospitalization staggered BTKA treated patients were more likely to develop minor or major complication compared to different-hospitalization staged BTKA treated patients. These complications included a higher incidence of cardiac and thromboembolic events, likely secondary to increased patient comorbidity in the single-hospitalization group. Finally, no recommendations can be made regarding the comparison of the overall complication rates between staggered and staged BTKA, since the results were conflicting [10, 13, 14]. In brief, it could be argued that staggered BTKA did not show an improved safety and complication profile compared to the well-established simultaneous or staged procedures.

Another point of interest was the requirement of blood transfusions. Increased need of blood transfusion in patients undergoing single-hospitalization staggered BTKA has been previously reported in a nationally representative data analysis including 43,350 patients [21]. In the present analysis, none of the studies depicted lower rates of blood transfusion with the use of staggered BTKA [10, 13, 15, 16]. On the contrary, all studies that compared staggered and staged BTKA patient cohorts showed that staggered BTKA led to increased rates of blood transfusions [13, 15, 16]. A higher rate of perioperative blood-product transfusion is considered a risk factor for the development of AKI [14]. Based on these findings, we suggest the standardized use of intraoperative tranexamic acid [21, 27] in all patients undergoing staggered BTKA, in order to reduce postoperative bleeding and blood transfusions.

In all studies, the mean length stay was longer for staggered compared to simultaneous BTKA [13,14,15]. As reported by Poultsides et al. [10], extended hospital stay found in patients treated with staggered BTKA may be associated with a higher in-hospital infection rate. Large institutional series have previously shown that longer hospitalization is a significant predictor of periprosthetic joint infection (PJI) [28, 29]. However, readmission rates were similar between staggered and simultaneous BTKA [13, 15]. In addition, recent economic studies have demonstrated a significative reduction of the economic burden with the use of simultaneous BTKA or single-hospitalization staggered BTKA compared to different-hospitalization staged BTKA [30].

The optimal time interval in the single-hospitalization staggered BTKA continues to be debated. The results of the two studies which dealt with this parameter were conflicting [16, 17]. We support the need for further studies to clarify whether “early” staggered BTKA (1–3 days after the first operation) results in different outcomes in comparison with “late” staggered procedures (4–7 days after the first operation).

This systematic review has several limitations. The studies involved in this review had several design limitations including a lack of prospective studies, randomization, and blinding. Specifically, there were no level I and II controlled trials, while all studies were level of evidence III. The quality of the studies ranged from low to moderate based on the modified Coleman Methodology Score, and potential biases related to the retrospective design might have influenced the results. Selection bias was an important issue in the studies. Some patients may have refused to undergo single-hospitalization staggered BTKA for medical reasons, because the perioperative complication risk may have been considered too high. Moreover, the studies varied widely in regard to follow-up, control groups, time interval between stages, and number of patients. In contrast, a strength of this review was the considerably high total number of patients included in analysis. Nonetheless, the number of patients who specifically underwent staggered BTKA was relatively low. Finally, the groups of patients involved in the studies that we review demonstrated heterogeneous baseline characteristics, leading to potential biases in the results when comparing outcomes among different groups.

Conclusions

While the quality of the current literature on the outcomes and complication rates of staggered bilateral TKA during the same-admission is low-to-moderate, same-admission staggered BTKA does not appear to be safer than the well-established simultaneous or staged BTKA. In addition, same-admission staggered BTKA is associated with increased rates of blood transfusions compared to staged BTKA and increased length of stay compared to simultaneous BTKA. Overall, the data suggest that staggered BTKA will probably continue to decline in utilization and does not appear to have much clinical applicability/advantage over simultaneous BTKA in a medically appropriate patient.