What literature is available for Exparel use in pediatric patients? Are there any safety concerns in this population?

Comment by InpharmD Researcher

Several studies have investigated the use of Exparel (liposomal bupivacaine) in pediatric patients (see tables). Available pediatric evidence includes randomized trials, retrospective cohorts, and case reports across numerous surgical specialties. Exparel may reduce postoperative opioid use in selected higher-pain procedures, but improvements in pain scores, length of stay, recovery, and costs are inconsistent, and a clear advantage over conventional bupivacaine has not been established. Short-term safety findings are generally acceptable: adverse-event rates have been similar to comparators, systemic bupivacaine concentrations have remained below recognized adult toxicity thresholds, and no cases of local anesthetic systemic toxicity have been reported in the reviewed pediatric studies. However, rare or delayed toxicity cannot be excluded because most studies were observational, adverse-event monitoring was inconsistent, sample sizes were inadequate to detect uncommon events, and long-term safety data are limited.
Background

A 2025 scoping review evaluated liposomal bupivacaine (Exparel) for postoperative pain management in pediatric patients. The authors identified 26 studies involving 1,496 patients, including two randomized controlled trials, one multi-cohort interventional study, 14 retrospective cohort studies, and nine case reports or case series. Liposomal bupivacaine was studied across spinal, cardiothoracic, orthopedic, gastrointestinal, plastic, urologic, and bone-graft procedures. Administration methods included local infiltration and several regional nerve blocks, with substantial variation in dosing and whether conventional bupivacaine was administered concurrently. Many applications were off-label because pediatric approval is limited to single-dose local infiltration in patients aged 6 years and older. [1]

Postoperative opioid use was reported in 24 studies. Most retrospective studies found reduced opioid consumption or administration with liposomal bupivacaine, although the randomized trial in ambulatory urologic surgery found no significant opioid-sparing benefit from adding liposomal bupivacaine to conventional bupivacaine. Some evidence suggested that any opioid reduction may be limited primarily to the first 24 hours. Pain outcomes were similarly inconsistent: some observational studies reported lower scores, while others, including the randomized trial, found no difference. Seven retrospective studies reported statistically shorter hospital stays, but the reductions were generally 1 day or less and never exceeded 2 days. Three retrospective studies also reported lower hospital costs, largely related to reduced room-and-board expenses, but these analyses were considered low quality and potentially affected by confounding factors. [1]

Adverse events were reported in 14 studies and were generally similar between liposomal bupivacaine and control groups. No cases of local anesthetic systemic toxicity were reported, but adverse-event monitoring methods and durations were often inadequately described, limiting conclusions about uncommon or delayed toxicity. Overall, liposomal bupivacaine may reduce opioid use, pain, length of stay, and costs in some pediatric settings, but the evidence is limited by few randomized trials, heterogeneous procedures and dosing regimens, inconsistent outcome measurements, retrospective designs, and potential manufacturer-related conflicts of interest. The authors concluded that additional independent, well-designed randomized trials with standardized protocols are needed before routine inclusion of liposomal bupivacaine in pediatric multimodal postoperative pain regimens can be supported. [1]

Background References: [1] Patel, T.D., Dusza, M. & Lee, CT. Efficacy and safety of liposomal bupivacaine administration in the pediatric population: a scoping review of the literature. Anesthesiol. Perioper. Sci. 3, 13 (2025). https://doi.org/10.1007/s44254-025-00095-5
Literature Review

A search of the published medical literature revealed 9 studies investigating the researchable question:

What literature is available for Exparel use in pediatric patients? Are there any safety concerns in this population?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-9 for your response.

 

Effectiveness of Liposomal Bupivacaine With Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Local Anesthetic for Children Undergoing Ambulatory Urologic Surgery: The Baby ORIOLES Randomized Clinical Trial
Design

Prospective, phase 3, single-blinded, single-center randomized trial with superiority design

N= 104
Objective To determine if the addition of liposomal bupivacaine to bupivacaine hydrochloride improves opioid-free rate and postoperative pain scores among children undergoing ambulatory urologic surgery
Study Groups

Intervention (liposomal bupivacaine plus bupivacaine hydrochloride) (n= 52)

Control (bupivacaine hydrochloride alone) (n= 52)
Inclusion Criteria Children aged 6 to 18 years undergoing ambulatory urologic procedures between October 2021 and April 2023
Exclusion Criteria Not specified
Methods Patients were randomized 1:1 to receive either liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The intervention group received 0.5 mg/kg of 0.25% bupivacaine hydrochloride followed by 2.5 mg/kg of 1.33% liposomal bupivacaine. The control group received 0.5 mg/kg of 0.25% bupivacaine hydrochloride alone. All patients underwent general anesthesia and were instructed to alternate acetaminophen and ibuprofen for pain management postoperatively.
Duration October 2021 to April 2023
Outcome Measures

Primary: Opioid-free rate at 48 hours

Secondary: Parents’ postoperative pain measure (PPPM) scores, numerical pain scale scores, weight-based opioid utilization at 48 hours and 10 to 14 days
Baseline Characteristics   Intervention (N = 52) Control (N = 52)
Age, median (IQR), y 9.5 (8-13) 11.0 (8-12)
BMI, median (IQR), kg/m2 18.5 (16-21) 18.6 (16-20)
Caucasian 29 (55%) 32 (61%)
African American 13 (25%) 7 (14%)
Asian 5 (10%) 9 (17%)
Hispanic 5 (10%) 4 (8%)
Results   Intervention (N = 52) Control (N = 52) Estimated difference (95% CI) P-value
No opioids administered through 48 h (%) 60 62 -1.9 (-20-16) 0.8
PPPM score at 48 h, median (IQR) 2 (1-3) 2.5 (2-4) -0.7 (-1.4 to -0.01) 0.05
Parent numerical pain score at 48 h, median (IQR) 3 (0.75-4) 3 (1-4) -0.02 (-0.9-0.8) 0.9
OMEQ/kg administered through 48 h, median (IQR) 0 (0-0.10) mg/kg 0 (0-0.22) mg/kg -0.1 (-0.2 to -0.02) mg/kg 0.4
Adverse Events No difference in adverse events was observed between the intervention and control groups.
Study Author Conclusions The addition of liposomal bupivacaine to bupivacaine hydrochloride did not significantly improve opioid-sparing effect or postoperative pain compared with bupivacaine hydrochloride alone among children undergoing ambulatory urologic surgery.
Critique The study was well-designed with a randomized, single-blinded approach and high follow-up rate. However, it was limited by being single-center, lacking cost-effectiveness analysis, and including mostly low-morbidity procedures, which might have reduced differences in outcomes between groups. Additionally, the study did not find a significant benefit of liposomal bupivacaine, questioning its cost-effectiveness given its higher price compared to standard bupivacaine hydrochloride.
Table 1 References:
[2] Gabrielson AT, Galansky L, Sholklapper T, et al. Effectiveness of Liposomal Bupivacaine With Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Local Anesthetic for Children Undergoing Ambulatory Urologic Surgery: The Baby ORIOLES Randomized Clinical Trial. J Urol. 2024;211(1):37-47. doi:10.1097/JU.0000000000003764

 

A multicenter study to evaluate the pharmacokinetics and safety of liposomal bupivacaine for postsurgical analgesia in pediatric patients aged 6 to less than 17 years (PLAY)
Design

Multicenter, open-label, phase 3, randomized trial

N= 95
Objective To evaluate the pharmacokinetics and safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery
Study Groups

12 to < 17 years: Liposomal bupivacaine (n= 31), Bupivacaine HCl (n= 30)

6 to < 12 years: Spine surgery (n= 5), Cardiac surgery (n= 29)
Inclusion Criteria Pediatric patients aged 6 to <17 years undergoing spine or cardiac surgery, BMI within 5th to 95th percentile for age and sex, ASA physical status I, II, or III
Exclusion Criteria Pregnant, hypersensitivity to amide-type local anesthetics or opioids, contraindication to bupivacaine HCl, received liposomal bupivacaine or bupivacaine HCl within the past 30 days, coagulopathies or immunodeficiency disorders, history of drug or alcohol abuse in the past 2 years, clinically significant medical or psychiatric disease, received an investigational drug within 30 days.
Methods

Patients were divided into two age groups. Those aged 12 to younger than 17 years undergoing spine surgery were randomized 1:1 to receive a single dose of either liposomal bupivacaine 4 mg/kg, up to 266 mg, or bupivacaine hydrochloride 2 mg/kg, up to 175 mg. Both products were expanded with normal saline and administered by local infiltration at the end of surgery. All patients aged 6 to younger than 12 years undergoing spine or cardiac surgery received liposomal bupivacaine 4 mg/kg, up to 266 mg, without a comparator group.

Dosing was weight based and selected to provide the highest dose expected to be safe, with the liposomal bupivacaine dose chosen to produce systemic exposure comparable to that observed in adult infiltration studies. Before wound closure, surgeons injected the study drug in small increments into the deep and superficial tissue layers along the entire incision to promote uniform distribution, using standardized infiltration instructions. Intraoperative and postoperative opioids, acetaminophen, and nonsteroidal anti-inflammatory drugs were permitted according to each site’s standard of care, but administration of any additional local anesthetic was prohibited for 96 hours after liposomal bupivacaine.
Duration April 2, 2019, to September 24, 2019
Outcome Measures

Primary: Pharmacokinetics (Cmax, time to Cmax)

Secondary: Safety of liposomal bupivacaine
Baseline Characteristics   12 to < 17 years: Liposomal bupivacaine (n= 31) 12 to < 17 years: Bupivacaine HCl (n= 30) 6 to < 12 years: Spine surgery (n= 5) 6 to < 12 years: Cardiac surgery (n= 29)
Age, mean (SD), y 13.8 (1.3) 13.9 (1.3) 10.0 (1.7) 8.7 (1.8)
Female, n (%) 28 (90) 22 (73) 2 (40) 14 (48)
Hispanic/Latino, n (%) 10 (32) 7 (23) 0 (0) 9 (31)
White, n (%) 21 (68) 26 (87) 4 (80) 26 (90)
ASA physical status III, n (%) 1 (3) 4 (13) 2 (40) 27 (93)
Height, mean (SD), cm 158.8 (13.6) 160.9 (11.1) 141.5 (17.6) 134.2 (13.0)
Weight, mean (SD), kg 53.4 (11.5) 54.7 (13.4) 39.1 (14.7) 34.9 (12.6)
Results   12 to < 17 years: Liposomal bupivacaine (n= 15) 12 to < 17 years: Bupivacaine HCl (n= 15) 6 to < 12 years: Spine surgery (n= 2) 6 to < 12 years: Cardiac surgery (n= 21)
Cmax, ng/mL (SD) 357 (125) 564 (321) 320 447 (243)
tmax, median (range), h 1.1 (0.3–26.1) 0.9 (0.3–2.5) 7.4 22.7 (0.2–54.5)
AUC0-∞, ng/h/mL 14,246 (9119) 5709 (3282) 11,570 26,164 (28,038)
Adverse Events In age group 1 (12 to < 17 years), adverse events were comparable between liposomal bupivacaine (61%) and bupivacaine HCl (73%). In age group 2 (6 to < 12 years), 100% of patients undergoing spine surgery and 31% undergoing cardiac surgery experienced adverse events. Common adverse events included constipation, nausea, and vomiting. All adverse events were mild to moderate, with no discontinuations or deaths.
Study Author Conclusions Plasma bupivacaine levels following local infiltration with liposomal bupivacaine remained below the toxic threshold in adults across age groups and procedures. Adverse events were mild to moderate, supporting the safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery.
Critique The study was well-designed to assess pharmacokinetics and safety in a pediatric population, providing valuable data for FDA approval. However, the small sample size, especially in the younger age group undergoing spine surgery, limits the ability to generalize findings. The study was not powered to statistically compare adverse events between groups, which should be considered when interpreting safety data.
Table 2 References:
[3] Tirotta CF, de Armendi AJ, Horn ND, et al. A multicenter study to evaluate the pharmacokinetics and safety of liposomal bupivacaine for postsurgical analgesia in pediatric patients aged 6 to less than 17 years (PLAY). J Clin Anesth. 2021;75:110503. doi:10.1016/j.jclinane.2021.110503

 

Clinical and Economic Outcomes Associated With Use of Liposomal Bupivacaine Versus Standard of Care for Management of Postsurgical Pain in Pediatric Patients Undergoing Spine Surgery

Design

Retrospective cohort

N= 10,189

Objective

To examine the association of opioid-related and economic outcomes with postsurgical liposomal bupivacaine (LB) or non-LB analgesia in pediatric patients who received spine surgery

Study Groups

LB (n= 373)

Non-LB (n= 9,816)

Inclusion Criteria

Age 1-17 years who underwent inpatient primary spine surgery (including discectomy, lumbosacral fusion, other fusion, laminectomy, or other spine surgery); received either LB analgesia or did not receive LB analgesia for pain management following the procedure

Exclusion Criteria

Multiple records of the same primary surgery admission; if hospital costs were ≥ 3 standard deviations beyond the mean cost (considered outliers)

Methods

A retrospective analysis of the deidentified Premier Healthcare Database that contains administrative data from > 1,000 US hospitals and health-care systems was performed to identify patients who met inclusion criteria using International Classification of Diseases (ICD)-9 and ICD-10 codes. 

Inpatient opioid prescription was extracted from standard charge master codes for opioids and converted into total morphine milligram equivalents (MMEs). Opioid-related adverse events (ORAEs) included cardiovascular, central nervous system, gastrointestinal, respiratory, skin, and other complications. 

Duration

January 1, 2015 to September 30, 2019

Follow up: entire hospitalization period from admission to discharge

Outcome Measures

Primary: inpatient opioid prescription 

Secondary: length of stay (LOS), total cost of hospital care, ORAEs

Baseline Characteristics

  

LB (n= 373)

Non-LB (n= 9,816)

  

Age, years

 14.2 ± 2.6 12 ± 4.5  

Female

 63% 59.1%  

White

 66.5% 67.7%  

Quan-Charlson Comorbidity Index

0-1

> 1

 

92.2%

7.8%

 

82.3%

17.7%

  

Index surgery year

2015

2016

2017

2018

2019

 

16.1%

26.8%

21.2%

14.7%

21.2%

 

21.8%

25.5%

23.2%

16.8%

12.7%

  

PCA

 22% 15.1%  

Spine surgery type

Discectomy

Fusion (lumbosacral)

Fusion (other)

Laminectomy

Other

 

1.6%

11.3%

67.8%

1.1%

18.2%

 

1.7%

5.8%

51.1%

1.7%

39.7%

  

PCA, patient-controlled analgesia

Results

Endpoint

LB (n= 373)

Non-LB (n= 9,816)

Adjusted Rate Ratio (95% confidence interval [CI]); p-Value

In-hospital postsurgical opioid consumption, MMEs

 1,288 2,437 0.53 (0.45 to 0.61); p< 0.0001

Patients with ORAEs

 19.3% 23% 0.84 (0.65 to 1.08); p= 0.1791

LOS, days

 3.5 4 0.86 (0.8 to 0.94); p= 0.0003

Total hospital costs, US dollars

 29,790 32,284 0.92 (0.86 to 0.99); p= 0.0227

8% lower total costs with LB; cost savings mostly attributed to hospital stay cost by room and board ($6,312 vs. 7,395; 15% savings) and central supply cost ($8,267 vs. 9,370; 12% savings)

Adverse Events

See results section. 

Study Author Conclusions

Pediatric patients undergoing spine surgery who received LB had significantly reduced in-hospital postsurgical opioid consumption, LOS, and hospital costs compared with those who did not. 

InpharmD Researcher Critique

This study is limited by its retrospective design introducing the risk for selection bias, as well as the relatively small population in the LB group compared to the non-LB group. Data was pulled from an administrative database, so clinical information was limited including baseline opioid intake which may have affected the primary outcome results.  
Table 3 References:
[4] Ballock RT, Seif J, Goodwin R, Lin JH, Cirillo J. Clinical and Economic Outcomes Associated With Use of Liposomal Bupivacaine Versus Standard of Care for Management of Postsurgical Pain in Pediatric Patients Undergoing Spine Surgery. J Health Econ Outcomes Res. 2021;8(1):29-35. Published 2021 Apr 14. doi:10.36469/jheor.2021.21967

 

Efficacy of liposomal bupivacaine in pediatric patients undergoing spine surgery

Design

Single-center, retrospective matched cohort study

N= 141

Objective

To evaluate the use of liposomal bupivacaine in a cohort of pediatric patients undergoing multisegment spinal surgery to determine whether the use of liposomal bupivacaine reduces the amount of 72-hour postoperative opioid or other analgesic use

Study Groups

Control (n= 94)

Liposomal bupivacaine (n= 47)

Inclusion Criteria

Pediatric patients, underwent a surgical procedure involving posterior spinal fusion performed by a single surgeon at a single institution

Exclusion Criteria

 Patients with missing data, not matched with a patient who received liposomal bupivacaine

Methods

Patients were identified via the hospital's electronic medical record. Patients who received liposomal bupivacaine were matched 1:2 with patients who received plain bupivacaine (control) on type and extent of surgery and then on age and gender within 3 years. Postoperative pain management was at the discretion of the treating physician and, in general, included intravenous (IV) opioids administered by patient-controlled analgesia immediately post-operation, followed by a transition to oral opioid medication when tolerated. IV acetaminophen (APAP) and IV ketorolac were used either scheduled or as needed for breakthrough pain.

Duration

Surgery: February 2011 to May 2016

Data collection: up to 72 hours after procedure

Outcome Measures

Primary: difference in total amount of IV morphine equivalents per kg of weight used in postoperative period

Secondary: total amount of IV APAP per kg of weight and total IV ketorolac per kg of weight administered during postoperative period

Baseline Characteristics

  

Control (n= 94)

Liposomal bupivacaine (n= 47)

    

Age, years (range)

 14.02 (8.6 to 19.8) 14.30 (9.6 to 18.6)    

Male

 15 (15.9%) 7 (14.9%)    

Number of spinal segments fused

11-15

> 15

 

91

3

 

45

2

    

Results

Endpoint

Control (n= 94)

Liposomal bupivacaine (n= 47)

95% confidence interval

p-value

Morphine equivalents, mg/kg

 2.02 ± 0.98 1.76 ± 0.82 0.23 to 0.29 0.14

IV APAP, mg/kg

 58.6 ± 49.8 60.6 ± 54.8 - Not significant

IV ketorolac, mg/kg

 3.65 ± 2.8 3.3 ± 2.5 - Not significant

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Liposomal bupivacaine was not associated with reductions in postoperative opioid use in pediatric spinal surgery.

InpharmD Researcher Critique

This study is likely limited by confounding variables, including treatment bias, due to patients not being blinded to their treatment group.
Table 4 References:
[5] Cloyd C, Moffett BS, Bernhardt MB, Monico EM, Patel N, Hanson D. Efficacy of liposomal bupivacaine in pediatric patients undergoing spine surgery. Paediatr Anaesth. 2018;28(11):982-986. doi:10.1111/pan.13482

 

The Role of Liposomal Bupivacaine in Multimodal Pain Management following Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis: Faster and Farther with Less Opioids

Design

Single-center, retrospective review

N= 119

Objective

To evaluate the effect of intraoperative liposomal bupivacaine (LB) infiltration on post-surgical pain management in adolescent idiopathic scoliosis (AIS) patients

Study Groups

LB (n= 53)

Control (n= 66)

Inclusion Criteria

Age < 18 years, underwent primary posterior spinal fusion (PSF)

Exclusion Criteria

Non-AIS spine conditions, fusion to the pelvis, revision procedures, growing rod instrumentation

Methods

All patients received a multimodal weight-based perioperative pain management regimen per standard protocol, consisting of preoperative gabapentin, acetaminophen, and celecoxib as well as postoperative gabapentin, clonidine, and ketorolac (which was then transitioned to naproxen on postoperative day 1). Additionally, patients in the LB group received regional analgesia with intraoperative local infiltration of LB 4 mg/kg (maximum dose 266 mg) as an erector spinae block (ESB) into the erector spinae muscles prior to muscle closure. Patients in control group received only standard multimodal pain management protocol. 

Duration

Underwent procedure between January 2021 and September 2022

Outcome Measures

Postoperative opioid consumption, postoperative pain scores (visual analog scale [VAS]), ambulation, length of stay (LOS)

Baseline Characteristics

  

LB (n= 53)

Control (n= 66)

  

Age, years

 14.7 ± 2.41 14.3 ± 2.24  

Female

 43 53  

Cobb angle, degrees

 54.9 ± 9.78 55.7 ± 8.95  

Number of levels fused

 10.3 ± 2.31 10.7 ± 1.67  

Results

Endpoint

LB (n= 53)

Control (n= 66)

p-Value

Postoperative opioid consumption

Oral morphine equivalents

Oral opioids only

 

44.5 ± 29

43 (81.1%)

 

70.2 ± 30.3

27 (40.9%)

 

< 0.001

0.001

Postoperative pain score, VAS

POD 0

POD 1

POD 2

 

4.78 ± 2.06

4.76 ± 1.69

4.76 ± 1.48

 

5.25 ± 1.8

5.30 ± 1.54

5.03 ± 1.54

 

0.216

0.072

0.326

Total ambulation distance

POD 1

POD 2

 

282.3 ± 317.9

888.7 ± 651.8

 

149.71 ± 143.6

553.4 ± 246.5

 

0.003

0.002

LOS, days

Discharged on POD 2

2.42 ± 0.61

54.7%

2.74 ± 0.58

27.3%

0.005

0.002

Adverse Events

 N/A

Study Author Conclusions

This study confirmed the addition of intraoperative ESB with LB to the standard multimodal pain regimen demonstrated decreased total and IV opioid utilization to achieve the same degree of analgesia. The results suggest LB also is associated with decreased hospital LOS and greater mobility in terms of ambulation distance. Therefore, the use of a multimodal approach to pain management that includes LB is effective in opioid limitation and avoidance while improving ambulation postoperatively and decreasing LOS. 

InpharmD Researcher Critique

This small retrospective study is subject to inherent limitations of its study design and sample size, as well as being restricted to a single institution. 
Table 5 References:
[6] Changoor S, Giakas A, Sacks K, et al. The Role of Liposomal Bupivacaine in Multimodal Pain Management following Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis: Faster and Farther with Less Opioids [published online ahead of print, 2023 May 1]. Spine (Phila Pa 1976). 2023;10.1097/BRS.0000000000004702. doi:10.1097/BRS.0000000000004702

Ultrasound-guided paravertebral block with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after the Nuss procedure in children: A randomized clinical trial
Design

Randomized controlled trial

N= 109
Objective To evaluate the ability of liposomal bupivacaine to reduce postoperative opioid use among children undergoing the Nuss procedure
Study Groups

liposomal bupivacaine (LB; n= 54) 

Non-liposomal bupivacaine (nLB; n= 55)
Inclusion Criteria Children aged 6–18 years scheduled for elective Nuss procedures
Exclusion Criteria Congenital heart disease, arrhythmia, or other serious cardiovascular diseases; scoliosis deformities; allergies to local anesthetics or contraindications for nerve block; history of immunodeficiency diseases; use of immunosuppressants within 30 days before surgery; history of mental illness; communication barrier; history of chronic or visceral pain; abnormal liver or kidney function
Methods Patients were randomly assigned to receive ultrasound-guided paravertebral block with either liposomal bupivacaine (4 to 8 ml of 0.665% LB) or non-liposomal bupivacaine (4 to 8 ml of 0.25% bupivacaine) after anesthesia induction. The total volume of local anesthetics did not exceed 40 ml, and the LB dose did not exceed 4 mg/kg. Anesthesia was maintained with propofol infusion and sevoflurane inhalation. Postoperative pain was managed with patient-controlled intravenous analgesia (PCIA) using sufentanil.
Duration June to November 2024
Outcome Measures

Primary: Consumption of morphine equivalent during the first 72 h after surgery

Secondary: Maximum NRS pain score within 72 h, incidence of rebound pain within 72 h, NRS sleep score at 3 days
Baseline Characteristics   LB (n = 54) nLB (n = 55) P-value
Age, mean(SD), y 13.0(2.3) 13.4(2.3) 0.409
Male 44(81.5%) 43(78.2%) 0.668
Weight, mean(SD), kg 41.9(9.8) 43.8(11.1) 0.375
BMI, mean(SD) 16.5(2.0) 16.7(2.3) 0.685
ASA classification - I 41(75.9%) 42(76.4%) 0.957
ASA classification - II 13(24.1%) 13(23.6%) 0.957
History of surgical procedures 13(24.1%) 12(21.8%) 0.779
NRS of pain, at rest, median(IQR) 0(0–0) 0(0–0) 0.889
NRS of pain, with movement, median (IQR) 1(0–1) 1(0–1) 0.236
NRS of sleep, median(IQR) 1(0–2) 1(0–1.5) 0.203
Basal mean arterial pressure, median (IQR),mmHg 77.6 (69.5–82.3) 75.6 (69.3–82.2) 0.480
Basal heart rate, mean(SD), min−1 83.6(6.3) 82.7(7.3) 0.523
Haller index, mean(SD) 4.1(0.42) 4.1(0.41) 0.704
Exertion dyspnoea 5(9.3%) 7(12.7%) 0.836
Results   LB (n = 54) nLB (n = 55) RR or MD (95 %CI) P value
Postoperative morphine equivalent, median (IQR), mg - Within 72 h 78.6 (44.2–110.2) 101.7 (61.5–137.8) MD 23.1 (2.4–37.1) 0.023
Rebound pain 7(13.0%) 16(29.1%) RR 0.45 (0.20–0.96) 0.039
NRS of sleep, median (IQR) - Day 2 after surgery 3(2–5) 4(3–5) MD 1(0–1) 0.005
NRS of sleep, median (IQR) - Day 3 after surgery 2(2–3) 3(2–4) MD 1(0–1) 0.016
Adverse Events The incidence of adverse events was similar in both groups, and no patients experienced severe adverse events during the study period.
Study Author Conclusions Paravertebral block with liposomal bupivacaine reduces opioid use (a ~ 23% reduction) and the incidence of rebound pain in children after the Nuss procedure compared to the non-liposomal bupivacaine group.
Critique This study provided valuable insights into the use of liposomal bupivacaine for postoperative pain management in children undergoing the Nuss procedure. The randomized controlled design strengthens the validity of the findings. However, the single-center nature and the focus on a specific surgical procedure may limit the generalizability of the results. Additionally, while the study showed a reduction in opioid use and rebound pain, the incidence of moderate-to-severe pain remained high, indicating a need for further research into more effective analgesic regimens.
Table 6 References:
[7] Wu L, Wei SW, Chen Z, Jiang LD, Qu SQ, Du Z. Ultrasound-guided paravertebral block with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after the Nuss procedure in children: A randomized clinical trial. J Clin Anesth. 2025;106:111953. doi:10.1016/j.jclinane.2025.111953

Liposomal Bupivacaine Is Both Safe and Effective in Controlling Postoperative Pain After Spinal Surgery in Children
Design

Retrospective comparative cohort study

N= 323
Objective To evaluate: (1) pain relief efficacy; (2) opioid consumption; (3) length of stay (LOS); (4) discharge disposition (DD); and (5) safety and adverse effects of liposomal bupivacaine (LB) in pediatric patients who underwent spinal deformity correction
Study Groups

LB cohort (n= 195)

Control cohort (n= 128)
Inclusion Criteria Patients younger than or equal to the age of 18 years; patients who have undergone spinal deformity surgery through a posterior approach; patients who received locally injected LB before closure of the skin incision
Exclusion Criteria Patients older than the age of 18 years; patients who underwent deformity surgery correction through nonposterior surgical approach; patients with mental disability who were unable to communicate or articulate their level of pain or have altered mental status that precludes complying with a visual analog pain scale
Methods All procedures used a posterior midline approach with pedicle screw and rod fixation, with posterior column osteotomies performed when indicated. Before wound closure, up to 20 mL of liposomal bupivacaine was diluted 1:1 with normal saline. Using a 20-gauge needle, the solution was injected bilaterally into the paraspinal muscles along the fused vertebrae at sites approximately 1.5 cm apart, followed by similar infiltration into the subcutaneous fat along the incision. No other local anesthetic or vasoconstrictor, such as epinephrine, was added. Both groups received two epidural catheters delivering hydromorphone 1 to 2 mcg/kg/hour, generally tapered and discontinued over 48 hours, as well as ketorolac 0.5 mg/kg intravenously every 6 hours, acetaminophen 15 mg/kg orally every 6 hours, and oxycodone 5 to 10 mg orally every 4 hours as needed. Intravenous hydromorphone 0.5 to 2 mg every 2 hours was available for breakthrough pain, and oral diazepam 2.5 to 5 mg every 4 hours was available as needed for muscle spasms.
Duration July 2014 to August 2016
Outcome Measures Primary: Pain relief efficacy, opioid consumption, length of stay (LOS), discharge disposition (DD), safety and adverse effects
Baseline Characteristics   LB (N = 195) Control (N = 128) P
Age at surgery (y) 14.7 ± 2.1, (14.4–14.9) 14.4 ± 2.4, (13.9–14.8) 0.16
BMI 21.6 ± 5.1, (20.8–22.3) 21.1 ± 5.4, (20.1–22.03) 0.50
Length of incision 256 ± 93.6, (242.86–269.14) 246 ± 98, (229.02–262.98) > 0.05
Results   LB cohort Control cohort p-value
Pain scores POD 1 2 (0–5) 5 (2.5–7) < 0.001
Pain scores POD 2 3 (0–5) 4 (3–6) < 0.001
Opioid consumption (morphine mg equivalents) 78.2 129 0.0001
Length of stay (days) 3 (IQR= 3–4) 4 (IQR= 4–6) < 0.001
Discharge to home 98% 97%  
Adverse Events Complications were similar among the cohorts in superiority and 10% noninferiority analyses. Patients in the LB cohort had lower odds for complications (odds ratio = 0.77; 95% CI, 0.64–0.93; P = 0.009 and 0.67; 95% CI, 0.50–0.90; P = 0.008).
Study Author Conclusions This study demonstrated the safety and efficacy of LB when added to the current multimodal postoperative pain management regimens after pediatric spinal surgery.
Critique The study provides strong evidence for the efficacy and safety of LB in pediatric spinal surgery, showing significant reductions in pain scores, opioid consumption, and length of stay. However, the retrospective design and single-center nature may limit the generalizability of the findings. The lack of a priori power analysis and potential selection bias are also limitations, although the study's large sample size helps mitigate these concerns.
Table 7 References:
[8] Chughtai M, Sultan AA, Hudson B, et al. Liposomal Bupivacaine Is Both Safe and Effective in Controlling Postoperative Pain After Spinal Surgery in Children: A Controlled Cohort Study. Clin Spine Surg. 2020;33(10):E533-E538. doi:10.1097/BSD.0000000000000996

Incidence of adverse events attributable to bupivacaine liposome injectable suspension or plain bupivacaine for postoperative pain in pediatric surgical patients: a retrospective matched cohort analysis
Design

Retrospective, single-center, assessor-blinded cohort study

N= 924
Objective To describe the incidence of local anesthetic systemic toxicity (LAST) syndrome in pediatric surgical patients receiving liposomal bupivacaine compared to plain bupivacaine for surgical wound infiltration
Study Groups

Liposomal bupivacaine (n= 356)

Plain bupivacaine (n= 568)
Inclusion Criteria Pediatric patients between a gestational age of 37 weeks and 16 years who had open or laparoscopic surgical procedures and received surgical site infiltration with liposomal or plain bupivacaine during surgery at Cleveland Clinic from Feb 2013 to April 2017
Exclusion Criteria Not explicitly stated
Methods Retrospective review of pediatric surgical inpatients receiving wound infiltration with local anesthetics at Cleveland Clinic. Patients were matched 1:2 based on age, ASA physical status score, and procedure type. The incidence of LAST was assessed by two independent adjudicators blinded to the type of local anesthetic. 
Duration February 2013 to April 2017
Outcome Measures

Primary: Incidence of LAST syndrome

Secondary: Incidence of single signs/symptoms possibly related to local anesthetic administration
Baseline Characteristics   Liposomal bupivacaine (n= 356) Plain bupivacaine (n= 568)
Age, years 13 8.5
Median dose, mg (IQR) 266 (133 to 266) N/A
Results   Liposomal bupivacaine (n= 356) Plain bupivacaine (n= 568) p-value
Primary outcome (LAST) 0 0 >0.99
Single sign/symptom 3 2 0.38
Adverse Events

No cases of LAST syndrome were identified.

Few patients exhibited single signs or symptoms potentially related to local anesthetic toxicity (3 cases in the liposomal bupivacaine group vs. 2 cases in the plain bupivacaine group).
Study Author Conclusions In a cohort of pediatric surgical patients receiving wound infiltration with either plain or liposomal bupivacaine, no cases of LAST syndrome were identified, and only a few patients exhibited signs or symptoms potentially related to local anesthetic toxicity. Prospective evaluation in a larger cohort is required to provide additional safety data.
Critique The study is limited by its retrospective design and lack of sufficient power to detect differences in rare complications like LAST. The inability to match groups on all baseline characteristics, such as procedure category and duration of surgery, may introduce bias. Additionally, dosing data for the plain bupivacaine group was not captured, which could affect the comparability of the groups. Despite these limitations, the study provides valuable descriptive data on the safety profile of liposomal bupivacaine in pediatric patients.
Table 8 References:
[9] Cohen B, Glosser L, Saab R, et al. Incidence of adverse events attributable to bupivacaine liposome injectable suspension or plain bupivacaine for postoperative pain in pediatric surgical patients: A retrospective matched cohort analysis. Paediatr Anaesth. 2019;29(2):169-174. doi:10.1111/pan.13561

Use of bupivacaine liposomal injectable suspension in children aged 2 to 6 years undergoing cardiac surgery does not accelerate recovery
Design

Retrospective cohort study

N= 100
Objective To evaluate if intraoperative bupivacaine liposomal injectable suspension administration decreases postoperative opioid use, peak pain scores, and length of stay in children aged 2 to 6 years undergoing cardiac surgery via median sternotomy
Study Groups

BLIS group (n= 50)

Control group (n= 50)
Inclusion Criteria Children aged 2 to 6 years undergoing cardiac surgery using cardiopulmonary bypass from September 14, 2022, to September 1, 2023
Exclusion Criteria Patients who did not have a median sternotomy, remained intubated leaving the operating room or underwent postoperative reintubation, had incomplete BLIS dosage documentation, or remained hospitalized at the time of the query
Methods Patients received 4 mg/kg bupivacaine liposomal injectable suspension mixed with 0.25% bupivacaine hydrochloride and 0.9% sodium chloride via local infiltration at the conclusion of their procedure. Postoperative opioid use was converted into morphine milligram equivalents, and pain severity was measured using the Face, Legs, Activity, Cry, and Consolability scale. 
Duration September 14, 2022, to September 1, 2023
Outcome Measures

Primary: Postoperative opioid use

Secondary: ICU length of stay, hospital length of stay
Baseline Characteristics   BLIS (n= 50) Control (n= 50)
Age at surgery, years 3.9 (0.98) 3.9 (1.0)
Weight at time of surgery, kg 15.14 (2.6) 14.91 (2.4)
Results   BLIS (n= 50) Control (n= 50) p-value
Postoperative opioid exposure (MME/kg) 0.48 (0.3-0.66) 0.70 (0.46-0.98) 0.005
ICU length of stay, days 3.9 (2.2-5.1) 3.2 (2.0-5.7) 1.0
Total length of stay, days 8.0 (5.0-10.1) 7.9 (4.4-11.5) 0.2
Adverse Events No significant adverse events reported
Study Author Conclusions Intraoperative bupivacaine liposomal injectable suspension use in children aged 2 to 6 years undergoing cardiac surgery showed statistically but not clinically significant decreases in postoperative opioid use. It had no impact on intensive care unit or hospital length of stay but was substantially more expensive.
Critique The study provides valuable insights into the use of bupivacaine liposomal injectable suspension in young children undergoing cardiac surgery. However, the retrospective design and lack of randomization may introduce bias. The study's findings of reduced opioid use did not translate into clinically significant outcomes, and the high cost of BLIS may limit its practical application. Further prospective studies are needed to evaluate the clinical benefits and cost-effectiveness of BLIS in this population.
Table 9 References:
[10] Nitsche LJ, Devlin PJ, Bond SJ, et al. Use of bupivacaine liposomal injectable suspension in children aged 2 to 6 years undergoing cardiac surgery does not accelerate recovery. JTCVS Open. 2024;23:245-255. Published 2024 Dec 4. doi:10.1016/j.xjon.2024.11.013