Clinical trial NCT04298099
Conditions: Anesthesia, Local
Keywords: Ropivacaine Erector spinae plane block Pediatric
Sponsor: Baylor College of Medicine
Start date: 2020-12-18; Completion date: 2021-03-29
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary aim of this study is to evaluate the pharmacokinetics of serum ropivacaine concentrations following erector spinae plane peripheral nerve blocks in the pediatric population.

Secondary outcomes will assess the efficacy of the block with perioperative morphine equivalent consumption and pain scores.

Detailed description:
This pilot study will enroll patients at Texas Children's Hospital, aged 6 months to \<18 years scheduled to undergo a clinically indicated thoracic surgery with the adjunct of an erector spinae plane block for perioperative pain. A single shot erector spinae plane block is commonly offered for unilateral video-assisted thoracoscopic surgery (VATS) and unilateral chest tube insertions. Following parental consent and child assent to the block, participants will be assigned sequentially to either ropivacaine 0.2% at 0.3ml/kg or ropivacaine 0.5% at 0.3ml/kg. This pilot study poses no additional risk to the patient and the thoracic surgical procedures outlined are those for which an erector spinae plane block would be offered. Furthermore, the block dosing of 0.3ml/kg volumes with ropivacaine 0.2% or 0.5% are not outside of the standard of care or accepted dosages for peripheral nerve blocks.

Venous sample serum ropivacaine levels will be collected prior to ESP block and at 30, 60, 90-minutes and 2, 4, 6 -hours from intravenous access in situ. A baseline alpha-1 acid glycoprotein (AGP) test will be collected and processed by TCH Pathology. Amide local anesthetics are predominantly protein bound to AGP. It is the unbound form that is active. While this study seeks to understand the pharmacokinetics of ropivacaine following a single shot erector spinae plane block, correlate of the AGP will simultaneously ascertain the free vs bound portion.

Samples will be analyzed for the total and free serum ropivacaine concentrations. Pain scores will be collected from nursing records starting from arrival in the Post-Anesthesia Care Unit every 4 hours (up to 12 hours after arrival in PACU). Pain will be measured using The Face, Legs, Activity, Cry, Consolability scale (FLACC), the Wong-Baker FACES Pain Rating Scale (FACES), and the Visual Analogue Scale (VAS).

Arms: arm 1: Ropivacaine 0.2% at 0.3ml/kg arm 2: Ropivacaine 0.5% at 0.3ml/kg
Interventions: intervention 1: Ropivacaine
Intervention descriptions: intervention 1: Given the reproducible efficacy of the erector spinae plane block for thoracic procedures, this pilot study will recruit patients scheduled to undergo thoracic surgery with the adjunct of an erector spinae plane block for perioperative pain. Participants will be assigned sequentially to either ropivacaine 0.2% at 0.3ml/kg or ropivacaine 0.5% at 0.3ml/kg.

Protocol documents:
SAP_002.pdf: 
Pharmacokinetic Modeling of Ropivacaine Following Single Shot Erector Spinae Plane 
Block in Anesthetized Children 
 
 
 
NCT:  04298099 
 
 
 
Date: 2/17/2021 (date of original analysis document) 
 
 
 


Statistical Analysis: 
Prior investigations have suggested that a 1-compartment model with an absorption rate constant 
best describes the pharmacokinetic profile of Ropivacaine.12,13   Therefore, population 
pharmacokinetic analysis was performed with NONMEM v.7.412,13 (Icon, PLC; Dublin, Ireland) 
and PDx-Pop 5.2 (Icon, PLC, Dublin, Ireland) using first-order conditional estimation with 
interaction (FOCE-I). One- and two-compartment models with an absorption rate constant (Ka-1) 
and various error structures were evaluated, and the final model was selected based upon a 
significant reduction in the objective function value (p<0.05), in conjunction with standard 
subjective evaluation of graphical representations of model fit.  Models were generated for both 
total and free Ropivacaine concentrations.  After the final models were generated, simulation 
(n=1000) of serum concentrations (total and free Ropivacaine) was performed using 1, 1.5, 2, and 
2.5 mg/kg/dose in a patient with a median weight value from the dataset. 
 
REFERENCES: 
1. Richebé P, Capdevila X, Rivat C. Persistent Postsurgical Pain: Pathophysiology and 
Preventative Pharmacologic Considerations. Anesthesiology. 2018; 129(3):590-607.  
2. Lönnqvist PA, Ecoffey C, Bosenberg A, et al. The European society of regional anesthesia and 
pain therapy and the American society of regional anesthesia and pain medicine joint 
committee practice advisory on controversial topics in pediatric regional anesthesia I and II: 
what do they tell us? Curr Opin Anaesthesiol. 2017; 30(5):613-620.  


3. Taenzer AH, Herrick M, Hoyt M, et al. Variation in pediatric local anesthetic dosing for 
peripheral nerve blocks: an analysis from the Pediatric Regional Anesthesia Network (PRAN). 
Reg Anesth Pain Med. 2020; 45(12):964-969.  
4. Suresh S, De Oliveira GS Jr. Local anaesthetic dosage of peripheral nerve blocks in children: 
analysis of 40 121 blocks from the Pediatric Regional Anesthesia Network database. Br J 
Anaesth. 2018; 120(2):317-322. 
5. L Long JB, Birmingham PK, De Oliveira GS Jr, et al. Transversus abdominis plane block in 
children: a multicenter safety analysis of 1994 cases from the PRAN (Pediatric Regional 
Anesthesia Network) database. Anesth Analg. 2014; 119(2):395-9.  
6. Knudsen K, Beckman Suurküla M, Blomberg S, et al. Central nervous and cardiovascular 
effects of i.v. infusions of Ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 
1997; 78(5):507-14.  
7. Forero M, Adhikary SD, Lopez H, et al. The Erector Spinae Plane Block: A Novel Analgesic 
Technique in Thoracic Neuropathic Pain. Reg Anesth Pain Med. 2016; 41(5):621-7.  
8. Suresh S, De Oliveira GS Jr. Blood Bupivacaine Concentrations After Transversus Abdominis 
Plane Block in Neonates: A Prospective Observational Study. Anesth Analg. 2016; 122(3):814-
7.  
9. Yasumura R, Kobayashi Y, Ochiai R. A comparison of plasma levobupivacaine concentrations 
following transversus abdominis plane block and rectus sheath block. Anaesthesia. 2016; 
71(5):544-9.  
10. Berde CB, Yaster M, Meretoja O, et al. Stable plasma concentrations of unbound Ropivacaine 
during postoperative epidural infusion for 24-72 hours in children. Eur J Anaesthesiol. 2008; 
25(5):410-7.  


11. Arvidsson T, Eklund E. Determination of free concentration of Ropivacaine and bupivacaine 
in blood plasma by ultrafiltration and coupled-column liquid chromatography. J Chromatogr 
B Biomed Appl. 1995; 668(1):91-8.  
12. Ollier E, Heritier F, Bonnet C, et al. Population pharmacokinetic model of free and total 
Ropivacaine after transversus abdominis plane nerve block in patients undergoing liver 
resection. Br J Clin Pharmacol. 2015; 80(1):67-74.  
13. Walker BJ, Long JB, Sathyamoorthy M, et al. Complications in Pediatric Regional Anesthesia: 
An Analysis of More than 100,000 Blocks from the Pediatric Regional Anesthesia Network. 
Anesthesiology. 2018; 129(4):721-732.  
14. Aarons L, Sadler B, Pitsiu M, et al. Population pharmacokinetic analysis of Ropivacaine and 
its metabolite 2',6'-pipecoloxylidide from pooled data in neonates, infants, and children. Br J 
Anaesth. 2011; 107(3):409-24. 
15.  Bo¨senberg AT, Thomas J, Cronje L, et al. Pharmacokinetics and efficacy of Ropivacaine for 
continuous epidural infusion in neonates and infants. Paediatr Anaesth. 2005; 15: 739–49. 
 
 

Prot_001.pdf: 
Pharmacokinetic Modeling of Ropivacaine Following Single Shot Erector Spinae Plane 
Block in Anesthetized Children 
 
 
 
NCT: 04298099 
 
 
Date: 1/20/2021 (original protocol document date) 
 
 
 
 


Protocol  
 
This pilot study was a prospective, observational investigation approved by the Baylor College of 
Medicine IRB (H-4638).  In compliance with the EQUATOR network, all reporting was conducted 
under the STROBE guidelines. Written informed consent (with assent where applicable) was 
obtained by the parent(s) or legal guardian(s) for all enrolled participants.  Eligibility criteria 
included patients aged 6 months to 18 years weighing more than 4kg, scheduled to undergo 
minimally invasive video-assisted thoracoscopic surgery at Texas Children’s Hospital.  Exclusion 
criteria included allergy to local anesthetics, liver or renal dysfunction, pre-existing 
hypoalbuminemia, tumor or infection/abscess at the injection site, and a BMI > 95th percentile.    
 
Patients received an inhalational or intravenous induction with a general endotracheal tube 
anesthesia at the discretion of the attending anesthesiologist.  After the airway was secured, 
patients were placed in the lateral decubitus position and a single-shot unilateral ultrasound-guided 
ESP block, as all the procedures were unilateral incisions, was performed as previously described 
1-2 dermatomal levels above the surgical incision site.7  All patients received Ropivacaine 0.5% 
at 0.3ml/kg (1.5mg/kg) in the fascial plane deep to the erector spinae muscle.  Since there are no 
standardized dosing guidelines for ESP blocks in children, we chose a slightly higher dose from 
the previously published Ropivacaine dosing for TAP blocks of 0.25-0.75mg/kg but remaining 
within the consensus maximum dosing of 1.5mg/kg for peripheral nerve blocks.2,8  Post-anesthesia 
care unit (PACU) dermatomal assessments to ice were performed to validate ESP block accuracy.  
Intraoperative morphine equivalents (mg/kg) were additionally collected. Total and free serum 
Ropivacaine concentrations were obtained at baseline and the following time point after block 


injection: 30, 60, and 90-minutes and 2, 4, and 6-hours. These time-points reflect those previously 
noted in the literature, recognizing that serum capture of Ropivacaine is likely undetectable beyond 
6-hours.8-10 A baseline alpha-1 acid glycoprotein (AAG) was also collected.      
 
Samples were centrifuged for 15-minutes at 1100G within 2-hours of collection and the plasma 
was frozen at -80°C for processing at Lab ExperTox Inc.  We applied the same laboratory analysis 
as previously described, demonstrating the reproducibility of total and free  Ropivacaine levels 
with liquid chromatography/mass spectroscopy (LC-MS/MS).8-12 The LC-MS/MS analysis was 
performed with the Agilent Technologies 6460 mass spectrometer connected with the Agilent 
1200 series HPLC system via electrospray ionization mode.  The samples were analyzed in 
positive ionization mode with the voltage set at 3000V.  Data acquisition and data analysis were 
performed with the Agilent Mass Hunter software (Version B.07.00).  The total Ropivacaine 
concentrations were measured after protein precipitation in methanol.  The free Ropivacaine 
concentrations were measured with the same technique after ultracentrifugation of the samples 
with Vivaspin 2, 10 KDa molecular weight cut-off Concentrators (GE Healthcare, UK).  The assay 
was validated by spiking negative serum with known concentrations of Ropivacaine.  The assay 
method was linear over the concentration range 5 -3000 ng/mL, with a limit of detection of 1 
ng/mL and a limit of quantification of 5 ng/ml.  
 
REFERENCES: 
1. Richebé P, Capdevila X, Rivat C. Persistent Postsurgical Pain: Pathophysiology and 
Preventative Pharmacologic Considerations. Anesthesiology. 2018; 129(3):590-607.  


2. Lönnqvist PA, Ecoffey C, Bosenberg A, et al. The European society of regional anesthesia and 
pain therapy and the American society of regional anesthesia and pain medicine joint 
committee practice advisory on controversial topics in pediatric regional anesthesia I and II: 
what do they tell us? Curr Opin Anaesthesiol. 2017; 30(5):613-620.  
3. Taenzer AH, Herrick M, Hoyt M, et al. Variation in pediatric local anesthetic dosing for 
peripheral nerve blocks: an analysis from the Pediatric Regional Anesthesia Network (PRAN). 
Reg Anesth Pain Med. 2020; 45(12):964-969.  
4. Suresh S, De Oliveira GS Jr. Local anaesthetic dosage of peripheral nerve blocks in children: 
analysis of 40 121 blocks from the Pediatric Regional Anesthesia Network database. Br J 
Anaesth. 2018; 120(2):317-322. 
5. L Long JB, Birmingham PK, De Oliveira GS Jr, et al. Transversus abdominis plane block in 
children: a multicenter safety analysis of 1994 cases from the PRAN (Pediatric Regional 
Anesthesia Network) database. Anesth Analg. 2014; 119(2):395-9.  
6. Knudsen K, Beckman Suurküla M, Blomberg S, et al. Central nervous and cardiovascular 
effects of i.v. infusions of Ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 
1997; 78(5):507-14.  
7. Forero M, Adhikary SD, Lopez H, et al. The Erector Spinae Plane Block: A Novel Analgesic 
Technique in Thoracic Neuropathic Pain. Reg Anesth Pain Med. 2016; 41(5):621-7.  
8. Suresh S, De Oliveira GS Jr. Blood Bupivacaine Concentrations After Transversus Abdominis 
Plane Block in Neonates: A Prospective Observational Study. Anesth Analg. 2016; 122(3):814-
7.  


9. Yasumura R, Kobayashi Y, Ochiai R. A comparison of plasma levobupivacaine concentrations 
following transversus abdominis plane block and rectus sheath block. Anaesthesia. 2016; 
71(5):544-9.  
10. Berde CB, Yaster M, Meretoja O, et al. Stable plasma concentrations of unbound Ropivacaine 
during postoperative epidural infusion for 24-72 hours in children. Eur J Anaesthesiol. 2008; 
25(5):410-7.  
11. Arvidsson T, Eklund E. Determination of free concentration of Ropivacaine and bupivacaine 
in blood plasma by ultrafiltration and coupled-column liquid chromatography. J Chromatogr 
B Biomed Appl. 1995; 668(1):91-8.  
12. Ollier E, Heritier F, Bonnet C, et al. Population pharmacokinetic model of free and total 
Ropivacaine after transversus abdominis plane nerve block in patients undergoing liver 
resection. Br J Clin Pharmacol. 2015; 80(1):67-74.  
13. Walker BJ, Long JB, Sathyamoorthy M, et al. Complications in Pediatric Regional Anesthesia: 
An Analysis of More than 100,000 Blocks from the Pediatric Regional Anesthesia Network. 
Anesthesiology. 2018; 129(4):721-732.  
14. Aarons L, Sadler B, Pitsiu M, et al. Population pharmacokinetic analysis of Ropivacaine and 
its metabolite 2',6'-pipecoloxylidide from pooled data in neonates, infants, and children. Br J 
Anaesth. 2011; 107(3):409-24. 
15.  Bo¨senberg AT, Thomas J, Cronje L, et al. Pharmacokinetics and efficacy of Ropivacaine for 
continuous epidural infusion in neonates and infants. Paediatr Anaesth. 2005; 15: 739–49.