Abstract
Background
Motor-sparing local infiltration analgesia (LIA) enhances recovery after total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, LIA can induce local anesthetic systemic toxicity (LAST), sometimes necessitating rescue lipid emulsion therapy. Our institute initiated a pilot study to pretreat patients with lipid emulsion (SMOFlipid®) to test its efficacy in mitigating LIA-induced LAST events.
Methods
This retrospective study enrolled 1,621 adult patients who received LIA with bupivacaine (2–3 mg/kg, maximum 300 mg) for unilateral primary THA or TKA under general anesthesia between January 2020 and April 2022. A total of 439 patients received lipid pretreatment, while 1,182 did not. Demographics, surgical and anesthesia profiles, along with LAST events affecting the neurological, cardiovascular, and respiratory systems, were compared after propensity score matching for age, sex, body mass index (BMI), and surgery type.
Results
The incidence of severe LAST events requiring rescue lipid emulsion slightly decreased after lipid pretreatment (from 2.54 to 2.28 per 1000). Lipid pretreatment significantly reduced the incidence of bradycardia and new-onset arrhythmia (odds ratio: 0.13, adjusted p-value: 0.024) but increased postoperative opioid requirement (odds ratio: 1.71, adjusted p-value: 0.032) after Benjamini-Hochberg correction for multiplicity.
Conclusions
The efficacy of lipid pretreatment (SMOFlipid® 1.5 ml/kg, maximum 100 ml) in mitigating LIA-induced LAST remains controversial. While lipid pretreatment reduced the incidence of new-onset arrhythmia, it showed no clear benefits for neurologic and respiratory outcomes. Additionally, lipid pretreatment might hinder postoperative recovery by increasing the need for rescue opioid analgesia. Further prospective pharmacokinetic studies are required to assess plasma bupivacaine concentrations following LIA and lipid pretreatment, examine their relationship to LAST events, and establish the efficacy and safety of lipid pretreatment.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13018-024-05189-7.
Keywords: Lipid emulsion, Local anesthetic systemic toxicity, Local infiltration analgesia, Total hip arthroplasty, Total knee arthroplasty
Introduction
In the United States, total knee arthroplasty (TKA) and total hip arthroplasty (THA) are the two most commonly performed joint replacement procedures [1]. Currently, the preferred strategy for managing postoperative pain after total joint arthroplasty involves multimodal analgesia, combining local infiltration analgesia (LIA), peripheral nerve blocks, and two or more analgesics with different mechanisms of action [2]. Among them, a surgeon-performed LIA is a motor-sparing technique that offers tremendous advantages over traditional opioids. The benefits of LIA include reduced total analgesic consumption, decreased postoperative nausea and vomiting, enhanced early mobilization, improved joint range of motion, and expedited rehabilitation [3, 4].
Our institute has incorporated LIA using bupivacaine (2–3 mg/kg, maximum 300 mg) into our standardized clinical protocol for fast-track THA and TKA for nearly a decade [5]. Under this fast-track protocol, the majority of patients experience rapid recovery after surgery and can be discharged on the first postoperative day with satisfactory mobility. However, LIA with bupivacaine at doses approaching the toxicity threshold carries a potential risk of local anesthetic systemic toxicity (LAST) [6]. In a recent single-center retrospective observational cohort, the incidence of severe LAST requiring rescue lipid emulsion after LIA was reported as 0.7 per 1000 and 2.0 per 1000 following unilateral TKA and THA, respectively, which is similar to the rate observed in peripheral nerve blocks [7]. In our clinical practice, the critical manifestations of LAST include seizure, unconsciousness, new-onset ventricular arrhythmia, severe bradycardia, and respiratory suppression. Fortunately, most of these LAST events were self-limited and resolved within 2 h after LIA procedures, without impeding early ambulation and rehabilitation. These LAST events were typically managed in the post-anesthesia care unit (PACU) with interventions such as nasal or oral airway insertion for airway support, along with medications like midazolam, atropine, and antiarrhythmics. In cases of severe LAST events with refractory arrhythmia or seizure episodes, a rescue infusion of lipid emulsion was administered [6].
Lipid emulsion was first found to attenuate LAST in experimental animals in 1998, and its application has been integrated into clinical practice since 2006 [8]. Lipid emulsions bind to lipophilic free-form local anesthetics (LA), and this combination is shuttled to toxic neutral organs, such as liver and muscle, for storage and detoxification, thus reducing the plasma half-time of LA [8]. Lipid emulsion has been predicted to reduce bupivacaine concentration in cardiac tissue by 11% within 3 min and in brain tissue by 18% within 15 min after initiating lipid therapy [9]. SMOFlipid®, a third-generation lipid emulsion, is composed of medium-chain triglycerides (MCTs) and soybean oil (long-chain triglycerides) (LCTs) in a MCT/LCT ratio of 7:3 [10]. In an isolated guinea pig myocardium model in vitro, a mixed lipid emulsion with MCTs and LCTs demonstrated superior performance compared to an LCT emulsion (Intralipid® 20%) in promoting the recovery of contractile function and was more effective in terms of LA binding and metabolic enhancement [11].
Since October 2021, our institute initiated a pilot pretreatment (prior to the onset of LAST events) using lipid emulsion (SMOFlipid®, 1.5 ml/kg for patients weighing < 70 kg; maximum 100 ml for patients weighing ≧ 70 kg) for patients receiving LIA for THA and TKA in order to reduce the incidence of LAST [12]. This observational, retrospective, single-center study aimed to evaluate the efficacy of lipid infusion 10–15 min after LIA procedures in reducing the incidence of LAST and improving recovery profiles.
Materials and methods
Study population
This retrospective observational study aimed to evaluate the preventive efficacy of lipid emulsion (SMOFlipid® 20%, Fresenius Kabi, Uppsala, Sweden) in preventing LAST occurrences after LIA for THA and TKA. This cohort study enrolled participants who underwent unilateral THA and TKA at Linkou Chang Gung Memorial Hospital, the largest medical center in Northern Taiwan, from January 2020 to April 2022. The study was approved by the Institutional Ethics Committee of the Chang Gung Medical Foundation (approval number: 202200080B0). The need for informed consent was waived owing to the retrospective nature of the study and the use of anonymized personal information.
The study design and group allocations are shown in Fig. 1. A total of 1,621 adult patients who underwent LIA for unilateral primary THA or TKA using an enhanced recovery protocol were enrolled. Patients with known contraindications to SMOFlipid® administration, such as severe hyperlipidemia, liver cirrhosis, coagulopathy, and end-stage renal disease, were excluded [12]. Patients with impaired liver function (AST or ALT ≧ 200 IU/L) were also excluded, as poor liver function may interfere with LA metabolism and the production of albumin and α1-acid glycoprotein, which reduces the plasma concentration of unbound LA [13]. Among patients without lipid pretreatment, 796 underwent THA and 386 underwent TKA. A total of 439 patients received pretreatment with lipid emulsions, of which 347 underwent THA and 92 underwent TKA. All enrolled participants were admitted for unilateral primary THA or TKA following the same standardized clinical protocol. All surgeries were performed by the same orthopedic team, led by Dr. Hsieh. These orthopedic surgeons specialize in THA and TKA procedures, with most surgeries completed within 1 h, resulting in minimal blood loss and complications. The enhanced recovery after surgery (ERAS) protocol for fast-track THA and TKA was designed to provide optimal patient care, enabling rapid recovery after surgery with satisfactory mobility. All patients underwent preoperative optimization, intraoperative stress minimization, and postoperative early mobilization (details in Fig. 2). These surgical interventions were complemented by preemptive and postoperative multimodal analgesia, including parenteral nonsteroidal anti-inflammatory drugs, acetaminophen, parecoxib, LIA, ice packing, and intramuscular opioid rescue, to promote early ambulation and ensure a smooth next-day discharge for most patients. Baseline patient demographics, surgical and anesthesia data (including anesthetic usage, blood loss, LA dose, and anesthesia duration), and postoperative recovery data (including numeric rating scale (NRS), observed LAST events, and hospitalization duration) were collected and compared.
Fig. 1.
Flow chart of the study design and group allocation
Fig. 2.
Preset clinical protocol for fast-track total hip arthroplasty (THA) and total knee arthroplasty (TKA) performed in this cohort
To estimate the required sample size, we performed a power calculation based on a recent study that reported a 0.12% incidence (3 cases out of 2,417 patients) of severe LAST events among TKA or THA patients [7]. Assuming lipid emulsion could reduce the incidence by one-third (to 0.0079%), a sample size of 303 patients per group was required to achieve an alpha level of 5% and a power of 80%. Therefore, 302 patients were enrolled in each matched group for comparison.
General anesthesia, joint replacement surgery, LIA procedure, and administration of lipid emulsion
All patients recruited in this cohort underwent joint replacement surgeries under general anesthesia. General anesthesia was induced with fentanyl (0.5–1.5 mcg/kg), 2% xylocaine (20 mg), propofol (1.5–2.0 mg/kg), cisatracurium (0.1–0.2 mg/kg) or rocuronium (0.5–1.0 mg/kg), and then maintained with either sevoflurane (Ultane, Abbott, UK) or propofol (Fresofol, Fresenius Kabi, Austria) after tracheal intubation. In all TKA surgeries, a tourniquet was used to reduce intraoperative blood loss.
For THA or TKA, the prescription principle for LIA involved administering 2–3 mg/kg of bupivacaine (maximum: 300 mg) (0.5%, AstraZeneca, France) mixed with normal saline to create a 60 ml LIA mixture. Half of the dose was infiltrated beneath the tensor fascia lata before arthrotomy (or posterior capsule in TKA), while the other half was infiltrated into the gluteus medius muscle (or anterior capsule in TKA) and subcutaneous tissue after implantation and reduction [14]. Previous pharmacokinetic studies have indicated that the median time to peak plasma concentration of bupivacaine is 20–40 min after nerve block or epidural anesthesia [15]. The plasma half-life of SMOFlipid® is 21.9 ± 8.2 min [16]. Therefore, in the present study, lipid emulsion pretreatment was scheduled for 10–15 min after LIA procedures to account for the assumed peak plasma concentration of bupivacaine following LIA, administered as a bolus injection over 2–3 min. The dosage of the lipid emulsion was set at 1.5 ml/kg for patients with actual body weights of less than 70 kg and 100 ml for heavier patients.
Postoperative management of LAST events
Upon wound closure, all patients were expected to undergo extubation within 10 min and then be transferred to the PACU to make the operating room available for the next surgery. However, if the extubation criteria were not met or the patient experienced delayed emergence, delayed extubation at the PACU or oral/nasal airway insertion for airway support was performed at the judgement of the duty anesthesiologists. Patients receiving high-dose LA for LIA had an increased probability of developing LAST. The major systemic toxicities of LAST involve the CNS, cardiovascular, and respiratory systems. The CNS-related manifestations included seizure (generalized convulsion), agitation (irritability or restlessness), tremor (focal muscle twitching), and unconsciousness (defined as delayed emergence with a Glasgow Coma Scale (GCS) score of < 8 at PACU arrival). The cardiovascular-related toxicities included severe bradycardia (heart rate ≤ 45 bpm), ventricular arrhythmia (ventricular tachycardia, or ventricular fibrillation), and new-onset arrhythmia (ventricular premature contraction, heart block, widening QRS complex). Respiratory suppression was indicated by dyspnea or apnea, delayed extubation, oral/nasal airway insertion to support airway, and oxygen desaturation (SpO2 < 95% in room air) during postoperative care. Midazolam was immediately administrated to patients experiencing seizures. A rescue dose of lipid emulsion is infused to patients with severe LAST events such as refractory seizures or ventricular arrhythmias. After observation in the PACU for 1–2 h and achieving a stable condition (Modified Aldrete Score of ≥ 8 and an NRS for pain of ≤ 3), these patients were transferred to the medical ward for further care. However, residual systemic effects of LA, such as dizziness or postoperative nausea and vomiting, might persist, even though ondansetron (8 mg, Supren, Taiwan Biotech Co.) was routinely administrated to every patient before the end of surgery. With regard to pretreatment with lipid emulsion, no adverse events (such as phlebitis, allergic reactions) were observed or reported by the medical staff or patients in this cohort.
Each LAST event in our study was collaboratively diagnosed by a duty anesthesiologist and a caring doctor in the PACU, and was documented through a quality assurance system. We used electronic anesthesia records, surgical notes, and nursing records in the PACU and ward to retrospective re-check the association of these documented events with LAST prior to enrollment. The definitions of the LAST events are summarized in Supplementary Table 1.
Comparison of LAST incidence rates in patients with or without lipid pretreatment
The incidence of LAST in patients with and without lipid emulsion pretreatment was compared to evaluate the efficacy of lipid pretreatment in reducing LAST incidence. These patients were propensity matched according to age, sex, BMI, and surgery type. The preventive efficacy of lipid pretreatment on the incidences of LAST in patients undergoing THA and TKA was subsequently compared.
Statistical analysis
The primary outcome of this observational study was the efficacy of lipid pretreatment in reducing LAST incidence. Given the substantial differences in the baseline characteristics of the patients with or without lipid pretreatment, propensity score-matched comparisons were performed between the study groups. The propensity scores were obtained using multivariate logistic regression and utilized for matching according to age, sex, BMI, and surgery type. The outcomes for binary values (such as LAST events) were compared using a univariate logistic regression model, while outcomes for continuous variables (such as pain scores) were analyzed with linear regression. The regression coefficients (B) represent the change in the outcome variable per unit change in the predictor variable. The Benjamini-Hochberg correction was used for multiple testing adjustment [17]. To account for within-pair outcome dependency, a robust standard error, known as the generalized estimating equation, was employed. All statistical analyses were performed using SAS software (version 9.4; SAS Institute Inc. NC, USA), and a two-sided p value of < 0.05 was considered statistically significant.
Results
Incidence of severe LAST events in patients with or without lipid pretreatment
The comparison of patients with or without lipid pretreatment who developed severe LAST events requiring rescue lipid infusion after LIA for THA and TKA is listed in Table 1. Four patients developed severe LAST events with refractory seizures despite midazolam, three of which occurred in patients without lipid pretreatment and one in the lipid pretreatment group. The incidence of severe LAST events was slightly reduced after lipid pretreatment (2.54 to 2.28 per 1000 LIA procedures). All these severe LAST events occurred after LIA for THA, but were alleviated soon after rescue lipid infusion and did not delay postoperative recovery.
Table 1.
Demographics of patients developing severe LAST events
| Characteristics | No lipid pretreatment (n = 1182) | Lipid pretreatment (n = 439) | |
|---|---|---|---|
| Rescue lipid infusion | 3 | 1 | |
| Incidence (per 1000) | 2.54 | 2.28 | |
| Seizure | 3 (100) | 1 (100) | |
| Ventricular arrhythmia | 0 (0) | 0 (0) | |
| Bradycardia or new-onset arrhythmia | 2 (66.7) | 0 (0) | |
| Surgery | |||
| Unilateral THA | 3 (100) | 1 (100) | |
| Unilateral TKA | 0 (0) | 0 (0) | |
| Age (years old) | 46.0 ± 7.0 | 53 | |
| Male, n (%) | 2 (66.7) | 1 (100) | |
| BMI (kg/M2) | 23.1 ± 1.8 | 22.5 | |
| Bupivacaine dose (mg) | 289.0 ± 19.05 | 300 | |
| Diseases | |||
| Arrhythmia | 0 | 0 | |
| CNS disease | 0 | 0 | |
| Intraoperative blood loss (ml) | 250 ± 132.3 | 400 | |
| Duration of anesthesia (min) | 83 ± 10.5 | 82 | |
| PACU stay (min) | 112.0 ± 13.8 | 120 | |
| Hospitalization (days) | 3 ± 0 | 3 | |
| Pain score at 24 h (NRS) | 2 ± 0 | 2 | |
Data were presented as number (%) or mean ± standard deviation. *p < 0.05 represented a significant difference. Abbreviations BMI, body mass index; CNS, central nervous system; LAST, local anesthetic systemic toxicity; NRS, numeric rating scale; PACU, post-anesthesia care unit; THA, total hip arthroplasty; TKA, total knee arthroplasty
Lipid pretreatment reduced CV-related LAST events, but increased CNS- and respiratory-related events
To compare the incidence of LAST in patients with or without lipid pretreatment for different surgery types, we recruited a total of 604 patients with or without lipid pretreatment (221 in the THA group and 81 in the TKA group, respectively) and performed propensity score matching by age, sex, BMI, and surgery type (Fig. 1). No significant demographic differences were observed between the two groups after matching (Table 2). A matched comparison of patients with or without lipid pretreatment found that patients pretreated with lipid emulsion had a lower incidence of CV-related events such as bradycardia or new-onset arrhythmia (OR: 0.13, adjusted p = 0.024) after adjusting for multiple testing (Table 3). In addition, pretreated patients tended to require more opioid rescue compared to patients without pretreatment, even though there was no significant difference in their bupivacaine dose for LIA.
Table 2.
Clinical characteristics of matched patients with or without lipid pretreatment
| Variables | No lipid pretreatment (n = 302) | Lipid pretreatment (n = 302) | P value |
|---|---|---|---|
| Age (years old) | 62.58 ± 14.16 | 63.08 ± 13.64 | 0.657 |
| Male, n (%) | 108 (35.76) | 105 (35.10) | 0.798 |
| BMI (kg/M2) | 25.90 ± 4.53 | 26.03 ± 4.26 | 0.722 |
| Diseases | |||
| Hypertension | 128 (42.38) | 140 (46.36) | 0.326 |
| Diabetes | 35 (11.59) | 42 (13.91) | 0.393 |
| Coronary artery disease | 3 (0.99) | 6 (1.99) | 0.314 |
| Arrhythmia | 12 (3.97) | 10 (3.31) | 0.664 |
| CNS disease | 10 (3.31) | 11 (3.64) | 0.824 |
| Asthma/COPD | 2 (0.66) | 4 (1.32) | 0.412 |
| Malignancy | 6 (1.98) | 4 (1.32) | 0.524 |
| Surgery | 1.00 | ||
| Unilateral THA | 221 (73.17) | 221 (73.17) | |
| Unilateral TKA | 81 (26.82) | 81 (26.82) | |
| Maintained anesthetics | 0.832 | ||
| Propofol | 55 (18.21) | 53 (17.55) | |
| Sevoflurane | 247 (81.79) | 249 (82.45) | |
| Intraoperative blood loss (ml) | 146.32 ± 82.61 | 138.43 ± 77.26 | 0.062 |
| Duration of anesthesia (min) | 74.99 ± 13.01 | 77.46 ± 11.34 | 0.061 |
| Bupivacaine dose (mg) | 269.74 ± 39.50 | 269.31 ± 37.08 | 0.893 |
Data are shown as mean ± standard deviation or number (%). *p < 0.05 represented a significant difference between two groups. Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; CNS, central nervous system; SD, standard deviation; THA, total hip arthroplasty; TKA, total knee arthroplasty
Table 3.
Comparison of LAST events and recovery profiles between patients with or without lipid pretreatment after propensity score matching
| Outcomes | No lipid pretreatment (n = 302) |
Lipid pretreatment (n = 302) | OR/B (95% CI) |
P
value |
Adjusted p value# |
|---|---|---|---|---|---|
| All LAST events | 49 (16.23) | 63 (20.86) | 1.36 (0.90–2.05) | 0.210 | 0.480 |
| Seizure | 3 (0.99) | 8 (2.65) | 2.71 (0.71–10.42) | 0.139 | 0.247 |
| Tremor | 7 (2.31) | 16 (5.29) | 2.89 (1.01–8.23) | 0.047* | 0.150 |
| Agitation | 3 (0.99) | 11 (3.64) | 3.79 (1.03–13.78) | 0.030* | 0.160 |
| Delayed emergence | 31 (10.26) | 39 (12.91) | 1.30 (0.77–2.17) | 0.325 | 0.472 |
| Bradycardia or new-onset arrhythmia | 15 (4.96) | 2 (0.66) | 0.13 (0.04–0.81) | 0.003* | 0.024* |
| Delayed extubation | 14 (4.63) | 20 (6.62) | 1.45 (0.72–2.94) | 0.210 | 0.420 |
| Airway insertion | 31 (10.26) | 49 (16.23) | 1.69 (1.05–2.74) | 0.020* | 0.080 |
| Oxygen requirement | 29 (9.60) | 33 (10.93) | 1.16 (0.67–1.98) | 0.540 | 0.576 |
| Recovery profiles | |||||
| Post-operative vomiting | 20 (6.62) | 11 (3.64) | 0.51 (0.25–1.15) | 0.090 | 0.144 |
| PACU stay (min) | 72.61 ± 14.42 | 71.42 ± 18.32 | -0.02 (-0.07, 0.03) | 0.539 | 0.616 |
| Hospitalization (days) | 3.01 ± 0.13 | 3.01 ± 0.08 | -0.003 (-0.02, 0.01) | 0.705 | 0.705 |
| Rescue opioid requirement | 79 (26.16) | 114 (37.74) | 1.71 (1.21–2.43) | 0.002* | 0.032* |
| Pain score at 1 h (NRS) | 1.87 ± 1.83 | 2.28 ± 2.91 | 0.25 (0.07, 0.26) | 0.036* | 0.096 |
| Pain score at 6 h (NRS) | 2.51 ± 1.30 | 2.59 ± 1.25 | 0.09 (-0.33, 0.15) | 0.461 | 0.567 |
| Pain score at 24 h (NRS) | 2.12 ± 0.54 | 2.22 ± 0.76 | 0.09 (-0.02, 0.21) | 0.120 | 0.160 |
Data were presented as number (%) or mean ± standard deviation. The outcomes of the binary values (such as LAST events) were compared using a univariate logistic regression model (expressed as OR). The outcomes of continuous variables (such as pain scores) were compared using a linear regression analysis (expressed as B). *p < 0.05 represented a significant difference. #p value was adjusted using Benjamini-Hochberg correction to account for multiple testing. T. Abbreviations: CI, confidence interval; CNS, central nervous system; LAST, local anesthetic systemic toxicity; OR, odds ratio; B, regression coefficient; PACU, post-anesthesia care unit
Lipid pretreatment decreased the incidence of bradycardia and vomiting in the THA group
Our study further evaluated the efficacy of lipid pretreatment in preventing LIA-induced LAST events in matched THA and TKA patients (Tables 4 and 5). THA patients who received lipid pretreatment had a lower incidence of bradycardia or new-onset arrhythmia compared to those without lipid pretreatment. However, THA patients receiving lipid pretreatment exhibited higher pain scores in the first postoperative hour than those without pretreatment. The effects of lipid pretreatment on overall LAST incidence (composites of CNS-, CV- and respiratory-related events) are compared in Fig. 3. Lipid pretreatment significantly reduced CV events in patients undergoing unilateral THA.
Table 4.
Comparison of LAST events and recovery profiles between patients with or without lipid pretreatment in the matched THA groups
| Outcomes | No lipid pretreatment (n = 221) | Lipid pretreatment (n = 221) | OR/B (95% CI) | P value | Adjusted p value# |
|---|---|---|---|---|---|
| Composite of all LAST events, n (%) | 42 (19.00) | 59 (26.69) | 1.50 (0.95–2.35) | 0.082 | 0.357 |
| Composite CNS outcome | 30 (13.57) | 46 (20.81) | 1.60 (0.95–2.71) | 0.078 | 0.313 |
| Seizure | 3 (1.35) | 8 (3.62) | 2.63 (0.69–9.99) | 0.138 | 0.414 |
| Tremor | 5 (2.26) | 14 (6.33) | 2.78 (0.98–7.92) | 0.079 | 0.338 |
| Agitation | 3 (1.36) | 11 (4.97) | 3.69 (1.01–13.45) | 0.031* | 0.279 |
| Delayed emergence | 29 (13.12) | 37 (16.74) | 1.28 (0.75–2.21) | 0.252 | 0.504 |
| Bradycardia or new-onset arrhythmia | 13 (5.88) | 1 (0.45) | 0.05 (0.01–0.83) | 0.002* | 0.036* |
| Composite respiratory outcome | 27 (12.22) | 48 (21.72) | 1.92 (1.13–3.26) | 0.010* | 0.090 |
| Delayed extubation | 10 (4.52) | 19 (8.59) | 1.93 (0.88–4.23) | 0.102 | 0.392 |
| Airway insertion | 27 (12.22) | 47 (21.26) | 1.87 (1.10–3.18) | 0.018* | 0.252 |
| Oxygen requirement | 20 (9.05) | 24 (10.86) | 1.19 (0.64–2.22) | 0.531 | 0.803 |
| Recovery profiles | |||||
| Post-operative vomiting | 15 (6.78) | 5 (2.26) | 0.31 (0.11–0.88) | 0.030* | 0.270 |
| PACU stay (min) | 73.24 ± 15.02 | 73.26 ± 19.80 | 0.001 (-0.06, 0.06) | 0.978 | 0.978 |
| Hospitalization (day) | 3.00 ± 0.12 | 3.01 ± 0.09 | 0.004 (-0.02, 0.02) | 0.669 | 0.803 |
| Rescue opioid requirement | 59 (26.69) | 76 (34.39) | 1.38 (0.92–2.09) | 0.119 | 0.357 |
| Pain score at 1 h (NRS) | 1.83 ± 1.11 | 2.19 ± 1.00 | 0.37 (0.15, 0.58) | 0.001* | 0.018* |
| Pain score at 6 h (NRS) | 2.49 ± 1.24 | 2.55 ± 1.17 | 0.06 (-0.31, 0.18) | 0.612 | 0.803 |
| Pain score at 24 h (NRS) | 2.13 ± 0.55 | 2.24 ± 0.80 | 0.10 (-0.04, 0.24) | 0.168 | 0.420 |
Data were presented as number (%) or mean ± standard deviation. The outcomes of the binary values (such as LAST events) were compared using a univariate logistic regression model (expressed as OR). The outcomes of continuous variables (such as pain scores) were compared using a linear regression analysis (expressed as B). *p < 0.05 represented a significant difference. #p value was adjusted using Benjamini-Hochberg correction to account for multiple testing. Abbreviations: CI, confidence interval; LAST, local anesthetic systemic toxicity; NA, not applicable; NRS, numerical rating scale; OR, odds ratio; B, regression coefficient; PACU, post-anesthesia care unit; THA, total hip arthroplasty; TKA, total knee arthroplasty
Table 5.
Comparison of LAST events and recovery profiles between patients with or without lipid pretreatment in the matched TKA groups
| Outcomes | No lipid pretreatment (n = 81) | Lipid pretreatment (n = 81) | OR/B (95% CI) | P value | Adjusted p value# |
|---|---|---|---|---|---|
| Composite of all LAST events, n (%) | 7 (8.64) | 4 (4.93) | 0.59 (0.17–2.07) | 0.411 | 0.747 |
| Composite CNS outcome | 2 (2.47) | 2 (2.47) | 1.08 (0.16–7.42) | 0.938 | 1.000 |
| Seizure | 0 (0.00) | 0 (0.00) | NA | NA | NA |
| Tremor | 2 (2.47) | 2 (2.47) | 1.08 (0.16–7.42) | 0.938 | 1.000 |
| Agitation | 0 (0.00) | 0 (0.0) | NA | NA | NA |
| Delayed emergence | 2 (2.47) | 2 (2.47) | 1.08 (0.16–7.42) | 0.938 | 1.000 |
| Bradycardia or new-onset arrhythmia | 2 (2.47) | 1 (1.23) | 0.55 (0.05–6.04) | 0.624 | 0.936 |
| Composite respiratory outcome | 4 (4.94) | 2 (2.47) | 0.53 (0.10–2.78) | 0.443 | 0.747 |
| Delayed extubation | 4 (4.94) | 1 (1.3) | 0.26 (0.03–2.25) | 0.224 | 0.672 |
| Airway insertion | 4 (4.94) | 2 (2.47) | 0.53 (0.10–2.78) | 0.443 | 0.747 |
| Oxygen requirement | 4 (4.94) | 4 (4.94) | 1.11 (0.41–3.00) | 0.938 | 1.000 |
| Recovery profiles | |||||
| Post-operative vomiting | 5 (6.17) | 6 (7.41) | 1.36 (0.39–4.75) | 0.632 | 0.936 |
| PACU stay (min) | 68.44 ± 12.60 | 65.46 ± 13.82 | -0.06 (-0.14, 0.03) | 0.193 | 0.672 |
| Hospitalization (day) | 3.02 ± 0.15 | 3.00 ± 0.00 | -0.02 (-0.06, 0.01) | 0.152 | 0.672 |
| Rescue opioid requirement | 20 (24.69) | 38 (46.91) | 3.04 (1.55–5.95) | 0.001* | 0.018* |
| Pain score at 1 h (NRS) | 1.90 ± 0.95 | 2.31 ± 0.93 | 0.42 (0.08, 0.75) | 0.015* | 0.270 |
| Pain score at 6 h (NRS) | 2.59 ± 1.45 | 2.71 ± 1.49 | 0.11 (-0.15, 0.42) | 0.682 | 0.936 |
| Pain score at 24 h (NRS) | 2.08 ± 0.50 | 2.15 ± 0.60 | 0.06 (-0.13, 0.24) | 0.542 | 0.936 |
Data were presented as number (%) or mean ± standard deviation. The outcomes of the binary values (such as LAST events) were compared using a univariate logistic regression model (expressed as OR). The outcomes of continuous variables (such as pain scores) were compared using a linear regression analysis (expressed as B). *p < 0.05 represented a significant difference. #p value was adjusted using Benjamini-Hochberg correction to account for multiple testing. Abbreviations: CI, confidence interval; LAST, local anesthetic systemic toxicity; NA, not applicable; NRS, numerical rating scale; OR, odds ratio; B, regression coefficient; PACU, post-anesthesia care unit; THA, total hip arthroplasty; TKA, total knee arthroplasty
Fig. 3.
Comparison of the effects of lipid pretreatment on local anesthetic systemic toxicity (LAST) incidence shown as composites of CNS-, CV- and respiratory-related events. Patients underwent (A)unilateral total hip arthroplasty, or (B) unilateral total knee arthroplasty. The analyses are performed using a chi-square test. *p < 0.05 represented a significant difference between the two groups
Lipid pretreatment was associated with higher rescue opioid requirement in the TKA group
In patients who underwent TKA with lipid pretreatment, no difference in LAST incidence was observed compared to patients without lipid pretreatment. However, pretreated patients had a higher rescue opioid requirement than those without lipid pretreatment (Table 5). Since we had a limited number of TKA patients, these results should be interpreted cautiously.
Discussion
This retrospective observational study aimed to investigate the efficacy of lipid emulsion pretreatment in reducing the incidence of LAST after LIA for fast-track THA and TKA. Our study introduces a novel concept and tests its efficacy in an Asian population with a calculated sample size, providing valuable evidence for clinical practice. Our data revealed that lipid emulsion pretreatment reduced the incidence of arrhythmia in patients who underwent THA but increased the requirement for rescue opioid analgesia compared to those without pretreatment. Lipid pretreatment reduced the incidence of LAST, particularly cardiovascular events, possibly due to the lipid shuttle effect from heart tissue or the direct cardiotonic effect of the LCT/MCT emulsion [11]. Conversely, lipid pretreatment did not significantly reduce the occurrence of LAST in TKA patients and was associated with an increased postoperative rescue opioid requirement. As a result, lipid pretreatment might reduce the analgesic efficacy of LIA and hinder enhanced recovery by increasing opioid-related adverse effects. The efficacy of lipid pretreatment in alleviating LAST remains controversial, and its routine clinical use for LIA is not recommended unless its benefits are confirmed by further prospective studies.
Fast-track or ERAS pathways are multi-modal and multi-professional approaches designed to mitigate surgical and anesthesia risks and improve the quality of medical care, rather than focusing solely on expediting discharge [18, 19]. LIA provides effective opioid-free analgesia when combined with multi-modal analgesia after joint arthroplasty and is recommended by the ERAS Society, particularly for TKA [4, 20]. However, the clinical evidence supporting the use of LIA for THA is limited. A recent meta-analysis found that LIA improved pain relief and decreased opioid consumption in patients undergoing THA compared to controls [21]. Judging from our analysis of LIA in fast-track TKA and THA, motor-sparing LIA has significantly reduced postoperative pain and facilitated the swift return of patients to their daily lives after joint replacement surgery. Although most LAST events in our patients resolved within two hours with conservative treatment in the PACU, some patients experienced self-limited symptoms such as dizziness, nausea, or vomiting the day after surgery [5]. Therefore, it is important to acknowledge the clinical scenario and explore strategies to reduce the incidence and severity of LIA-induced LAST, such as adding dexmedetomidine, dexamethasone, or vasoconstrictor to the LIA mixture, reducing LA dose for LIA, prolonged lipid infusion following the initial bolus rescue of lipid infusion, or considering novel measure like lipid pretreatment [22].
Our result found that the incidence of severe LAST events requiring rescue lipid infusion after lipid pretreatment slightly decreased from 2.54 to 2.28 per 1000, which is close to the rate reported in a previous cohort (2.0 per 1000 after LIA for THA) [7]. However, previous small-scale population pharmacokinetic analyses of LIA for THA and TKA did not report LAST events, even with LIA doses up to 400 mg ropivacaine, and their reported free plasma ropivacaine concentrations were all below the pre-defined toxic threshold (0.600 mcg/ml) [23]. Affas et al. evaluated 15 patients undergoing LIA with 200 mg ropivacaine for primary THA. The 95% upper prediction value of maximal unbound plasma concentration of ropivacaine was 0.032 mcg/ml within 30 h after LIA [24]. Gromov et al. investigated 28 patients who received 400 mg ropivacaine for LIA in unilateral TKA, and reported peak free-form ropivacaine concentrations of 0.030 mcg/ml in unilateral TKA and 0.095 mcg/ml in bilateral TKA [25]. Other small-population pharmacokinetic studies of LIA using ropivacaine for TKA yielded similar results, with free-form ropivacaine levels all below the threshold for CNS toxicity [26–28]. However, the sample sizes in these studies were relatively small, and they did not report the incidence of clinical LAST events. Our analysis involved 1,621 Asian individuals with naturally lower α1-acid glycoprotein levels, yet there is limited literature focusing on this population [29]. This retrospective cohort reported various presentations of clinical LAST events and found that lipid pretreatment reduced the incidence of LAST events, particularly in cases of bradycardia and new-onset arrhythmia. Pharmacokinetic analysis of plasma bupivacaine concentrations after LIA and lipid pretreatment to correlate with our observed LAST events is required to explain our observation [30].
Our study presents a novel concept of lipid pretreatment after LIA to reduce LAST occurrence, which has not been previously reported in the literature. The proposed multi-modal mechanisms of lipid emulsion as a resuscitation therapy for LAST include scavenging (lipid shuttle and organ redistribution) and non-scavenging effects (such as cardiotonic, postconditioning, and vasoconstrictive effects) [8, 9, 31, 32]. Existing evidence suggests that lipid emulsions do not significantly decrease LA concentrations in target organs [8]. A clinical pharmacokinetic study in 16 volunteers found that administering intralipids 2 min after intravenous infusion of ropivacaine or levobupivacaine reduced peak plasma concentration by only 26–30% and did not prevent the development of CNS toxicity [33]. However, the mechanism of preemptive administration of lipid emulsions before the onset of LAST is rarely discussed. In rat models, lipid pretreatment not only reduced the incidence of bupivacaine-induced cardiotoxicity [34], but also ameliorated convulsions by inhibiting the increase in blood-brain barrier permeability and enhancing GABA-mediated currents [35]. In a clinical pharmacokinetic study by Chen et al., intralipid pretreatment (1.5 ml/kg) before femoral and sciatic nerve blocks increased the volume of distribution and significantly reduced both free and total levobupivacaine concentrations [36]. Since the half-life of the lipid emulsion (21.9 ± 8.2 min) is substantially shorter than that of bupivacaine (4.6 ± 2.6 h) and ropivacaine (2.3 ± 0.8 h) [10, 16], our lipid pretreatment may exert only temporary cardiotonic effects, thus contributing to fewer CV events. In the lipid sink model, simulated lipid emulsion infusion requires much longer time to reduce bupivacaine concentration in brain tissues (15 min) than in cardiac tissues (3 min) [9]. This phenomenon might partially explain why we observed fewer CV events but no obvious change in CNS and respiratory events following lipid pretreatment in our results. Regarding the higher incidence of tremor, agitation, and respiratory events in the THA group receiving lipid pretreatment, a reduced effect of LA compared to those without lipid pretreatment might explain this shift from catastrophic LAST presentations like seizures and cardiac arrhythmias to relatively milder events. The actual mechanisms behind the different CV and CNS presentations of LAST after lipid pretreatment in our study required further investigation through pharmacokinetic studies.
In our results, we found no difference in LAST incidence between TKA patients with or without lipid pretreatment, but those receiving lipid pretreatment required more rescue opioid analgesia. Since lipid pretreatment may reduce peak plasma bupivacaine concentration by 30% [33], it could further decrease LIA’s analgesic efficacy in TKA. The observed differences in rescue opioid requirements in THA or TKA patients after lipid pretreatment might be partially explained by the variable analgesic efficacy of LIA for THA or TKA. However, due to the limited number of TKA patients, these findings should be interpreted with caution.
To summarize the pros and cons of lipid pretreatment, our results demonstrated a minimal reduction in severe LAST events, a lower incidence of cardiovascular events, but no clear benefit for neurologic or respiratory outcomes. Additionally, patients receiving lipid pretreatment required more rescue opioid analgesia and had higher pain scores in the first postoperative hour, after correction for multiplicity. Although no adverse events were reported in our study, the safety of lipid pretreatment in routine practice still requires further investigation [37]. Given the small sample size and retrospective nature of this study, the efficacy of lipid pretreatment for managing LIA-induced LAST cannot be justified. Overall, the efficacy of lipid pretreatment remains controversial, as it slightly reduced cardiovascular LAST events but might hinder postoperative recovery by increasing rescue opioid requirements. This decreased analgesic efficacy of LIA for THA and TKA by lipid pretreatment could exacerbate patient recovery, particularly in the context of modern multimodal opioid-minimizing analgesia. The slight reduction in cardiovascular LAST events does not offset the increased risk of opioid-related side effects, especially in patients where opioid-sparing techniques are essential for enhanced recovery. The increased postoperative pain after lipid pretreatment might ultimately undermine the initial benefits of fast-track protocols for THA and TKA. Therefore, lipid emulsion pretreatment should not be advocated until more robust prospective studies can demonstrate clear benefits without increasing other risks.
To the best of our knowledge, this study is the first to evaluate the efficacy of lipid pretreatment in reducing the incidences of LAST after LIA for THA and TKA. We utilized Benjamini–Hochberg correction to account for multiple testing and reduce the false discovery rate. Our retrospective analysis serves as a reminder that LAST is an ongoing concern that cannot be overlooked when using LA for LIA or nerve blocks, especially in Asian populations, who have lower levels of α1-acid glycoprotein compared with Western populations [28]. Adequate preparations for managing LAST should always be in place.
The present study has several limitations. First, as an observational cohort study, inherent demographic differences existed between the THA and TKA groups, as well as other comparisons. Despite using propensity score matching and correcting for multiple testing, these differences could not be completely eliminated. Second, the study participants underwent THA or TKA between 2020 and 2022, and were grouped based on lipid pretreatment status. When comparing the groups with or without lipid pretreatment, the distribution of patients was not randomly selected, which might have introduced temporal bias. However, all patients were treated by the same surgeons, anesthesiologists, and medical teams, following standardized protocols, which likely minimized this bias. Third, non-recorded LAST events, such as subclinical tremors or agitation, QT prolongation, or short-term arrhythmia, were not captured in this cohort, potentially leading to underestimation. Nevertheless, since our results were based on group comparisons, similar underestimations would likely have occurred in both groups. Fourth, plasma levels of albumin, α1-acid glycoprotein, bupivacaine, and lipid emulsion were not measured in this study. Patients with low plasma levels of albumin or α1-acid glycoprotein are more susceptible to LAST [13]. Without measuring plasma bupivacaine levels, it is difficult to conclusively attribute these events to LAST, leaving room for alternative explanations. Given these limitations, along with the retrospective design and small sample size of this study, the true efficacy and safety of lipid pretreatment for LIA-induced LAST remain unjustified. Further carefully designed prospective studies with larger patient populations and pharmacokinetic monitoring are required to verify the causal relationship between plasma bupivacaine concentrations following LIA and LAST events, and to establish the true efficacy and safety of lipid pretreatment.
Conclusion
The present study revealed that lipid pretreatment administered 10–15 min after LIA reduced the incidences of arrhythmia in patients undergoing THA, but it also increased the requirement for rescue opioid analgesia compared to patients without pretreatment. The efficacy of lipid pretreatment for LIA-induced LAST remains controversial, and its routine use in LIA for THA and TKA cannot be justified. Further prospective pharmacokinetic studies are required to clarify the association between plasma bupivacaine concentration after LIA and LAST events, and to verify the efficacy and safety of lipid pretreatment. Rebalancing the LIA strategy with the risks of LAST is essential to further improve perioperative patient safety and recovery.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank Raising Statistics Consultant Inc. for statistic assistance. We would like to thank Editage for English editing.
Abbreviations
- BMI
Body mass index
- COPD
Chronic obstructive pulmonary disease
- CNS
Central nervous system
- CV
Cardiovascular
- ERAS
Enhanced recovery after surgery
- LA
Local anesthetics
- LAST
Local anesthetic systemic toxicity
- LIA
Local infiltration analgesia
- LCT
Long-chain triglycerides; MCT, medium-chain triglycerides; SD, standard deviation; THA, Total hip arthroplasty
- TKA
Total knee arthroplasty
Author contributions
Material preparation and data collection were performed by H-T Lin, P-H Hsieh, J-T Liou, Y-T Chung, and Y-F Tsai. Analysis was performed by H-T Lin and Y-F Tsai. All authors contributed to the study conception and design of this study. The first draft of the manuscript was written by H-T Lin and Y-F Tsai, and all the authors commented on the previous versions of the manuscript. All authors have reviewed and approved the final manuscript.
Funding
This work was supported by the Ministry of Science and Technology, Taiwan (MOST 111-2320-B-182 A-008-MY3), and the Chang Gung Memorial Hospital, Taiwan (CMRPG3K1051-3 and CMRPG3N0591). The funders played no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.
Data availability
The data is available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the Institutional Ethics Committee of the Chang Gung Medical Foundation (approval number: 202200080B0). The need for informed consent was waived owing to the retrospective nature of the study and the use of anonymized personal information.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
The data is available from the corresponding author on reasonable request.