Background

Total knee arthroplasty (TKA) is an effective intervention for end-stage knee diseases and could relieve pain, restore function, and improve patients’ quality of life [1]. However, patients usually experience moderate-to-severe postoperative knee pain [2]. Due to osteophytes removal and soft tissue release on the backside of the knee, posterior knee pain is also a significant issue [3]. Insufficient pain control may hinder early ambulation, hamper the quality of recovery, and increase the utilization of opioids [4].

The interspace between the popliteal artery and capsule of the knee (IPACK) is a novel regional anesthetic approach that could supply analgesic effects on the posterior capsule without compromising muscle strength [5]. Cadaveric data demonstrated that IPACK mainly anesthetizes the articular branches from the tibial and obturator nerves [6]. Several randomized controlled trials (RCTs) reported the benefits of IPACK complemented many regional anesthesia modalities [3, 7,8,9,10,11,12]. However, these studies yielded conflicting results regarding the use of IPACK for analgesia after TKA. Three studies [7, 10, 13] reported lower pain visual analogue scale (VAS) scores, while the other two studies [3, 14] found similar pain scores with the addition of IPACK. Two studies [12, 15] found longer postoperative ambulation distances in the IPACK group, while the other three studies had contract results [3, 11, 16]. IPACK has been adopted into clinical practice, but the efficacy of IPACK has not been confirmed by synthesized evidence. Two reviews discussed the efficacy of IPACK in the practice of multimodal pain management. However, their conclusions lacked the support of quantity information, and the certainty of evidence cannot be measured. Moreover, previous studies found that the analgesic effect of IPACK usually disappeared within 24 h, while the long-term effects were unclear.

Therefore, we conducted a systematic review and meta-analysis to ascertain the benefit of IPACK in combination with other analgesic methods concerning (1) pain scores (at rest, at ambulation); (2) morphine consumption (amount and frequency); (3) functional recovery (range of motion, muscle strength, ambulation distances, time-up-and-go test time); (4) complications (needle puncture, postoperative nausea, vomiting, sleep disturbance); and (5) clinical outcomes (length of stay, operation duration, patients satisfaction).

Methods

This review was reported according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Additional file 1) [17]. The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO—CRD42021252156).

Search strategy

We searched for databases including PubMed, Medline, Embase, the Cochrane Library, Ovid, Web of Science, and websites including Clinicaltrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), and Google Scholar till February 1, 2021. The following terms were used: (IPACK OR “interspace between the popliteal artery and posterior capsule of the knee”) AND (total knee arthroplasty OR knee arthroplasty OR total knee replacement OR knee replacement OR TKA OR TKR) AND ((randomize* control* trial*) OR RCT)). No language or date limits were placed on the search. We also used a manual search strategy, checked references, and contacted authors to identify additional studies. Two authors screened studies with a third author adjudicating in case of disagreement.

Trial selection

The studies had to be RCTs comparing TKA patients with IPACK. Any non-RCTs, quasi-RCTs, retrospective studies, cadaver studies, comments, letters, editorials, protocols, guidelines, surgical registries, and review papers were excluded. Follow-up reports at different time points or different comparisons in one trial will be extracted separately. Studies with multiple arms were eligible, as were studies in which multiple regional anesthetic techniques were performed, so long as an IPACK was one of the arms or one of the used techniques. There was no restriction on language or publishing year. Two investigators independently screened titles and abstracts to exclude non-relevant trials. Discrepancies were resolved by a third author. Relevant full-text articles were retrieved and analyzed for eligibility using the pre-defined inclusion criteria.

Data extraction

Data were extracted via a standardized spreadsheet according to a pre-agreed protocol. The following information was collected: first author, publication year, country, number of participants in each group, patient demographics, inclusion and exclusion criteria, and conclusions. We collected: interventions, dosages, and types of anesthesia drug administered, the method of anesthesia, pain rescue methods, multimodal analgesia protocol, surgeons, prothesis, approach, follow-up duration, and numbers of patients lost to follow. If data cannot be extracted directly or missing, we will contact the authors by email or calculate data with the Cochrane Review Manager calculator [18]. Two authors independently extracted the information, and any discrepancies were resolved by a third author. Pain scores reported on visual, verbal, or numerical rating scales were converted to a standardized 0–10 scale. All opioids were converted to oral milligram morphine equivalents via an online website (http://opioidcalculator.practicalpainmanagement.com/).

Outcomes

The primary outcome was the ambulation pain score. The secondary outcomes were rest pain score, morphine consumption, functional recovery outcomes, clinical outcomes, and complications. The morphine consumption was collected as a continuous variable (amount) and category variable (used or not). The functional recovery outcomes included the range of motion (ROM), quadriceps muscle strength (QMS), ambulation distances, and time-up-and-go test (TUG) time. The clinical outcomes included the length of hospital stay, operation time, and patient satisfaction. The complications were postoperative nausea and vomiting (PONV) and sleep disturbance.

Subgroup analyses

Our pre-defined subgroup analysis was based on multiple time points. The subgroups were as closest to 6, to 12, to 24, to 48 h and beyond one week or as the postoperative day (POD) 0, 1, and 2 described in original studies.

Trial sequential analysis

We performed Trial Sequential Analysis (TSA) using the TSA program (www.ctu.dk/tsa.) on the three critical outcomes (pain at rest, pain at ambulation, morphine consumption). TSA tests the credibility of the results by combining the estimation of information size (a cumulative sample size of included RCTs) with an adjusted threshold of statistical significance for the cumulative meta-analysis. The required information size (RIS) and meta-analysis monitoring boundaries (Trial Sequential Monitoring Boundaries) were quantified, alongside adjusted 95% confidence intervals. Diversity adjustment was performed according to an overall type I error of 5% and power of 80%.

Meta-regression

High heterogeneity not fully explained by subgroup analysis was further investigated with a post hoc mixed-model meta-regression on the primary outcome (pain at ambulation). To avoid overfitting, meta-regression was performed only in the following clinically meaningful and explanatory variables: patient number, the multimodal analgesia protocol, types of other nerve blocks, anesthesia drug.

Risk of bias assessment and publication bias

The methodology quality was independently evaluated by two reviewers using the Cochrane Collaboration’s Risk of Bias Tool [19]. The following domains were assessed and evaluated: randomization process, deviation from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Each domain can be judged as low risk of bias, high risk of bias, or unclear, and overall risk of bias is expressed on a three-grade scale (low risk of bias, high risk of bias or unclear).

The funnel plots were used to assess publication bias when the included studies were more than 10 in the outcome, and the Egger test was further performed (when visual asymmetry was observed).

Quality of evidence

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess the certainty of the evidence in key outcomes. Study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect were considered. The level of evidence could be divided into four degrees: high, moderate, low, and very low. The rules for downgrade evidence were referenced in Guyatt’s studies [20,21,22,23,24,25]. We defined the following as critical outcomes: pain at ambulation, pain at rest, morphine consumption amount, the rate of rescue morphine use.

Statistical analysis

Weight mean difference (WMD) for continuous variables (Mantel–Haenszel method) and risk ratios (RR) for dichotomous variables (inverse variance method) with 95% confidence intervals (95% CIs) were used. P values of < 0.05 were considered statistically significant. A random-effect model was used in the study. The heterogeneity was reported by I2 statistics. (I2 > 70% was considered as high heterogeneity.) Sensitivity analysis will be applied to examine the effect of deleting one single study on the overall estimate when observed high heterogeneity, and Publication bias was evaluated both by a visual inspection of funnel plots and by Egger test (p < 0.05 indicating a possible publication bias) using Egger’s regression intercept to quantify publication bias. The Review Manager 5.3 was used for drafting figures of risk of bias, and STATA 13.0 was used for data analysis.

Results

Study selection, data retrieval, and characteristics

Our search initially yielded 310 potentially relevant papers and 181 articles remaining after duplicates. After title and abstract screening, 33 relevant papers were identified and remained full-text selection (Fig. 1). After reading the full text, we included 13 RCTs with 1347 patients (675 with IPACK; 672 without IPACK) [3, 7,8,9,10,11,12,13,14,15,16, 26, 27]. The overall analysis is summarized in Table 1. The sample size ranged from 56 to 120 patients. All studies were published between 2018 and 2020, and the mean follow-up period ranged from 2 days to 3 months. A detailed description of all included studies can be found in Tables 2 and 3. More confounding information can be found in Table 3.

Fig. 1
figure 1

PRISMA flow diagram describing the selection process of studies

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Table 1 The results of meta-analysis
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Table 2 The baseline characteristics
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Table 3 The confounding factors of included studies
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Methodological quality

According to the risk of bias evaluation, twelve studies clearly described randomization methods except one [27]. In eleven studies, appropriate methods were used to describe allocation concealment [3, 7,8,9,10,11,12,13, 15, 16, 26]. Blinding of the participants and personnel in eight studies was well described [3, 7, 10,11,12,13, 15, 16, 26]. The blinding of outcome assessors in nine studies was well performed [3, 7, 9,10,11,12, 15, 16, 26]. The proportion of patients lost to follow-up was less than 10% in all studies, indicating low attrition bias. All studies reported satisfactory outcomes, and the risk of reporting bias was low. No other bias was detected. The risk of bias overall and in each domain can be seen in Fig. 2.

Fig. 2
figure 2

Risk of bias a risk of bias graph. b Risk of bias summary

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Pain scores at ambulation

IPACK reduced ambulation pain scores (WMD = − 0.49 VAS, 95% CI − 0.72 to − 0.26, p < 0.0001). Subgroup analysis suggested that IPACK had lower scores within 12 h (2–4 h, WMD = − 0.48, 95% CI − 0.96 to − 0.008, p = 0.046; 6–12 h, WMD = − 0.69, 95% CI − 1.06 to − 0.32, p < 0.0001), and beyond 1 week (WMD = − 0.59 95% CI − 0.95 to − 0.22, p < 0.0001). T.S.A. confirmed the effect of IPACK when performed at a power of 80%. The cumulative z-score crossed the monitoring boundary for the benefit and reached the required sample size (Fig. 3). Due to the inconsistency, the certainty of the evidence was evaluated as moderate (Table 4).

Fig. 3
figure 3figure 3figure 3

Forest plots a forest plot of pain, at ambulation; b trial sequential analysis of pain, at ambulation (adjusted boundaries). c Trial sequential analysis of pain at ambulation (penalized test)

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Table 4 GRADE, summary of findings, IPACK versus non-IPACK for patients with primary TKA
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Pain scores at rest

IPACK was associated with lower pain scores at rest (WMD = − 0.49 VAS, 95% CI − 0.74 to − 0.24, p < 0.0001). Subgroup analysis suggested lower rest pain scores with IPACK between 6 and 12 h (WMD = − 0.96, 95% CI − 1.47 to − 0.45, p < 0.0001), and beyond 1 week (WMD = − 0.31, 95% CI − 0.62 to − 0.02, p = 0.039). T.S.A. confirmed the effect of IPACK, and the cumulative z-score crossed the monitoring boundary for the benefit and reached the required sample size (Fig. 4). Due to the inconsistency, the certainty of the evidence was evaluated as moderate (Table 4).

Fig. 4
figure 4

Forest plots a forest plot of pain at rest; b trial sequential analysis of pain at rest (adjusted boundaries). c Trial sequential analysis of pain at rest (Penalized Test)

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Morphine consumption

IPACK was associated with a reduction in overall oral morphine consumption (WMD = − 2.56 mg, 95% CI − 4.63 to − 0.49, p = 0.015). Subgroup analysis suggested that IPACK reduced the oral morphine consumption from 24 to 48 h postoperatively (WMD = − 2.97 mg, 95% CI − 5.71 to − 0.24, p = 0.033). The rate of morphine requirement was reduced with a statistically significant difference in the subgroup of 12 to 24 h (RR = 0.51, 95% CI 0.31 to 0.83, p = 0.007). The cumulative z-score failed to cross the benefit’s monitoring boundary or reach the required sample size (Fig. 5). The certainty of the evidence was evaluated as moderate (Table 4).

Fig. 5
figure 5

Forest plot of morphine consumption. a Forest plot of pain, at rest; b trial sequential analysis of morphine consumption (Adjusted Boundaries). c Trial sequential analysis of morphine consumption (Penalized Test)

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Functional recovery

We found that patients who received an additional IPACK could achieve longer ambulation distances during the hospital stay (WMD = 1.12 feet, 95% CI 0.37 to 1.88, p = 0.004). A better result was also observed on POD2 (p = 0.015). No difference was found on POD0, POD1, or POD3. The synthesized results found that the level of quadriceps muscle strength favored patients in the IPACK group when measured at 0 degrees (WMD = 0.41, 95% CI 0.04 to 0.77, p = 0.029). No statistically significant difference was found when patients flexed at 45 or 90 degrees. Moreover, we found no difference regarding the outcomes of ROM (p = 0.66) or TUG (p = 0.58).

Complications

Four studies reported the rate of postoperative nausea and vomiting (PONV), and we found no difference in the synthesized rate of PONV between patients who received IPACK and not (p = 0.60). The incidence of sleep disturbance was reduced following the use of IPACK (RR = 0.50, 95% CI 0.31 to 0.80, p = 0.04). Subgroup analysis found a similar benefit on POD 1 for IPACK using (p = 0.012).

Clinical outcomes

In our study, IPACK was associated with a shorter length of hospital stay while the difference lost significance (p = 0.07). No significant difference was found in either operation time (p = 0.71) or patient satisfaction (p = 0.058).

Sensitivity analysis

We conducted a sensitivity analysis on all outcomes with moderate-to-high heterogeneity (I2 > 50%) to validate our results. The conclusions remain unchanged in all outcomes, which suggests the stability of our outcomes.

Publication bias

The symmetrical distribution of funnel plots and the p value of the egger test both showed no publication bias (Fig. 6). Egger’s test revealed no potential publication bias (p > 0.01). No publication bias was found in the trials included.

Fig. 6
figure 6

Funnel plots a funnel plot of publication bias for the surgery length; b funnel plot of publication bias for the morphine consumption; c funnel plot of publication bias for the TUG; and d funnel plot of publication bias for the pain (at ambulation);

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Post hoc meta-regression

Meta-regression results found that other nerve blocks can explain 70.08% of heterogeneity, while the others cannot (Additional file 2: Table S1).

Discussion

Our meta-analysis suggests that the administration of IPACK significantly reduced pain scores when measured at ambulation and rest, and the differences vanished over 24 h. Similarly, IPACK was associated with lower morphine consumption and reduced rate of morphine requirement without increasing the rate of complications. Moreover, functional metrics such as ambulation distances and quadriceps muscle strengthen also favored IPACK, but these differences were marginal and lacked clinical importance.

Due to the rich supply of sensory innervation around the knee joint, patients after TKA always complained about their knee pain. Postoperative pain will increase opioid consumption, prolonged functional immobility, and diminished patient satisfaction. Therefore, adequate analgesia is of paramount importance. Peripheral nerve blocks are effective for TKA pain management. Femoral nerve block targets the anteromedial aspects of the knee, while the weakness of the quadriceps muscle will delay ambulation and increase the risk of fall [4]. The sciatic nerve block provided posterior knee analgesia, while foot drop often occurred [6]. The adductor canal block is gaining popularity by providing better motor preservation and non-inferior analgesia to a femoral nerve block. However, the posterior knee cannot be covered in an isolated adductor canal block [28]. IPACK is a novel but simple procedure that provides adequate analgesia of the posterior capsule of the knee by anesthetizing the articular branches from the sciatic and obturator nerves [29]. Recent evidence confirmed the effect of IPACK in controlling pain, improving physical performance, and decreasing hospital stay [6].

In our analysis, the addition of IPACK improved pain scores at rest and pain scores at ambulation within 24 h, and our results were consistent with previous studies [1, 6, 28]. There was no difference concerning pain VAS scores after 24 h, and possible reasons are that the duration of anesthetic had worn off by one day due to the simple formulation. A new finding was that subgroup analysis suggested the benefits existed beyond one week, suggesting a long-term analgesic effect of IPACK. The associations between immediate postoperative pain and chronic pain after TKA may explain this difference [30]. Of note, the minimal clinically important difference (MCID) for pain scores in TKA was 1.0. The differences brought by the administration of IPACK did not surpass the pre-designated threshold for the clinical importance of 1.0. Possible reasons are that the efficacy of an isolated IPACK was relatively small since the volume was usually 20 to 30 ml and could not infiltrate the membrane. Moreover, there were differences between the architecture of tissue and the properties of injectate and unavoidable variations (i.e., the position of the patient, muscle contraction, needle orientation, etc.) that affect the efficacy of IPACK. Two studies used questionnaires in postoperative pain measurement. Ochroch et al. found reduced average pain scores with IPACK (p < 0.01) by the Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R). Kim et al. [16] found improved analgesia results in the IPACK group (i.e., worst pain scale, least pain scale, severe pain experience on POD1 and POD2) by the patient self-reported questionnaire (Pain OUT). Most studies classified pain as rest and ambulation pain but did not locate the origin of knee pain (i.e., anterior, posterior, medial, lateral). Only two studies reported posterior knee pain [12, 26]. Adequate analgesia following TKA can reduce pain scores and opioid use to prevent complications and facilitate functional recovery. Our study also found positive results regarding reduced morphine consumption. Our results were consistent with previous studies [31,32,33]. However, the differences failed to reach MCID since a reduction of 40% in opioid usage were considered clinically relevant differences after TKA.

As for functional recovery, patients receiving an additional IPACK block performed better than those who did not receive regarding ambulation distances and muscle strength, indicating that the IPACK might provide potential additional functional improvement when combined with other regional anesthesia methods but was not associated with any meaningful clinical benefits. Possible reasons are that the improved pain experience can promote early ambulation, and decreased opioid consumption reduces adverse events, thereby improving patients’ functional outcomes. Moreover, several studies used questionnaires in measuring knee recovery. Li et al. [3] reported the Knee Society Score (KSS) at discharge, and in three months, they found similar results with IPACK and without. El-Emam et al. [13] found superior Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the IPACK group (2–12 weeks), while Li [3] found no difference (at discharge, three months). In general, a marginally better benefit on functional ability was found in our study, which required more data for clarification.

Complications were rare when applying IPACK into the multimodal analgesia pain management, which also proved the safety of IPACK in our study. Possible reasons are that effective pain control reduced opioid consumption and minimized associated side effects further. Some complications cannot be quantitatively synthesized. Li et al. reported two patients with slight numbness on the operative lower extremity with IPACK [3]. Tak et al. found two cases of cardiac events with IPACK, which they believed was not ascribed to IPACK [10]. Kertkiatkachorn et al. used the VAS to assess the severity of PONV and dizziness and found no difference [7]. Moreover, improved sleep quality was found in the IPACK group on POD1 in our study, which improved knee pain and mitigated anxiety [34]. Studies demonstrated that patient satisfaction is not a sole reliable proxy for pain relief and functional recovery outcomes since the factors affecting satisfaction are complex [35, 36]. However, overall patient satisfaction was similar in our study.

New techniques of IPACK have been discussed in several studies. Kampitak et al. [26] compared the effect of proximal IPACK with distal IPACK and found a lower rate of posterior knee pain in the proximal IPACK group. Possible explanations were that the injection point of the proximal IPACK block was closer to the popliteal plexus and promoted the spread of local anesthetic [38,39,40].

This study has some limitations. First, there was relatively high heterogeneity in several outcomes. However, sensitivity analysis was carried out, and all outcomes’ conclusions remained unchanged. Second, the control groups were not a placebo, and these interventions were various. A network meta-analysis would be of extreme interest. In addition, considering the small sample size and low incidence of the complications, we also designed similar RCTs with a larger sample size to evaluate complications of IPACK (ChiCTR2000032963, ChiCTR2000032964, ChiCTR2000032965, ChiCTR2000032966).

Conclusions

Our trial demonstrated significantly better pain scores, opioid consumption, and functional outcomes after using IPACK. However, the differences were small and lacked clinical importance, suggesting that IPACK was a relatively effective perioperative analgesia method. Taken as a whole, the current results support the performance of IPACK as a supplement analgesic method. Further investigation with larger samples would lend further insight and implications on the use of IPACK.