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Abstract
Introduction The ultrasound-guided interpectoral-pectoserratus plane block is a fascial plane block for superficial surgery of the anterolateral chest wall. This technique involves injecting a relatively large volume of local anesthetics (typically 30 mL of 0.25%–0.50%, ie, 75–150 mg ropivacaine) underneath the major and minor pectoral muscles of the anterior thoracic wall. There is a potential risk of toxic serum concentrations of local anesthetics due to systemic absorption.
Methods 22 patients scheduled for elective unilateral breast cancer surgery were included in this study. All surgery was performed with general anesthesia and an ultrasound-guided interpectoral-pectoserratus plane block with 2.5 mg/kg ropivacaine. Ten venous blood samples were collected at 0 (two samples) 10, 20, 30, 45, 60, 90 and 120 min and at 4 hours after performing the block. Free and total ropivacaine levels were measured at each time point. Albumin and alpha-1-acid-glycoprotein were measured to monitor shifts between the free and bound fraction of ropivacaine.
Results Samples of 20 patients were analyzed. The mean dose of ropivacaine was 172.8 (22.5) mg. In 50% of the patients, the potentially toxic threshold of 0.15 µg/mL free ropivacaine concentration was exceeded. Mean peak serum concentration occurred at 20 min postinjection.
Conclusions This pharmacokinetic study demonstrated that a 2.5 mg/kg ropivacaine interpectoral-pectoserratus plane block may result in exceeding the threshold for local anesthetic systemic toxicity.
- Drug-Related Side Effects and Adverse Reactions
- Pharmacology
- REGIONAL ANESTHESIA
Data availability statement
Data are available on reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Plasma concentration levels of local anesthetics following fascial plane injections can exceed the threshold for local anesthetic systemic toxicity.
Plasma concentrations following an interpectoral-pectoserratus plane block have not yet been established.
WHAT THIS STUDY ADDS
In 50% of the patients, the potentially toxic threshold of 0.15 µg/mL free ropivacaine concentration was exceeded.
Mean peak serum concentration occurred at 20 min postinjection.
Exceedances of the potential toxic threshold occurred up to 90 min after injection.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Maintain standard American Society of Anesthesiologists monitoring minimum 90 min after injection of local anesthetics.
Be cautious when performing a bilateral block and when combing the interpectoral-pectoserratus plane block with other regional anesthesia techniques and/or local infiltration.
Use NaCl 0.9% for hydrodissecting the planes to minimize the use of local anesthetics outside of the target planes.
Introduction
In 2012, the ultrasound-guided interpectoral-pectoserratus plane block was introduced for superficial surgery of the anterolateral chest wall. This regional anesthesia technique involves the injection of local anesthetics in two separate high-volume boluses, one between and one underneath the pectoralis muscles of the anterior thoracic wall. It has rapidly gained popularity in breast surgery due to its simplicity, safety and efficacy. Typically, a unilateral block is performed with 30 mL of 0.25%–0.50%, that is, 75–150 mg ropivacaine or comparable local anesthetic.1
High doses of local anesthetics might increase the risk of local anesthetic systemic toxicity (LAST). Potentially toxic concentrations of local anesthetics have been described in other fascial plane blocks, such as the transverse abdominal plane block.2 This observational study aims to assess the absorption of local anesthetics by quantifying the free and total ropivacaine, alpha-1-acid-glycoprotein and albumin concentrations in venous serum over 4 hours after injection of an ultrasound-guided interpectoral-pectoserratus plane block using ropivacaine 2.5 mg/kg total body weight.
Methods
Between June 7, 2021 and May 18, 2022, 22 adult female patients assigned an American Society of Anesthesiologists (ASA) physical status class 1–3, undergoing a mastectomy or lumpectomy with axillary clearance or a mastectomy with sentinel node biopsy were recruited at the AZ Turnhout hospital in Belgium. Patients were informed about the study by their surgeon during their final preoperative consultation. They were informed in more detail by one investigator (BV) 1 week before surgery. When patients were willing and eligible to participate, they received a booklet with information about the study and the informed consent document.
Inclusion criteria were as follows: (1) age 18 or older, (2) body mass index between 17 and 35 kg/m2, (3) scheduled for elective unilateral mastectomy or lumpectomy with axillary clearance or a mastectomy with sentinel node biopsy, and (4) written informed consent. Patients (1) with known allergies or sensitivity to local anesthetics, (2) who were pregnant, or (3) who had renal and/or hepatic impairment that compromised normal drug metabolism were excluded. Patients’ demographical data were collected on successful inclusion. Subjects could leave the study at any time for any reason without any consequences. The investigators were authorized to withdraw a subject from the study for urgent medical reasons.
On arrival in the operating room, standard ASA monitoring was applied and regular intravenous access was obtained at the upper extremity contralateral to the surgical site.After completion of the sign-in procedure, general anesthesia was induced with sufentanil and propofol. If needed, muscle relaxation (rocuronium) was used to facilitate endotracheal intubation. Anesthesia was maintained with volatile anesthetics (sevoflurane). Additional intermittent boluses of sufentanil were administered at the discretion of the attending anesthesiologist.
After induction of general anesthesia, an additional venous canula connected to a three-way stopcock valve was placed in the greater saphenous vein at the level of the ankle. This cannula was exclusively used for blood sampling. Next, the ultrasound-guided interpectoral-pectoserratus plane block was performed using an 8–15 MHz linear array transducer (GE LogiqE, GE Health-106 care, Little Chalfont, UK). We diluted ropivacaine 0.5% or 0.75% with NaCl 0.9% to create a 30 mL solution of 2.5 mg/kg ropivacaine total body weight. This solution was injected with a 50 mm needle (22 G, Stimuplex Ultra 360; B. Braun Melsungen AG, Germany) following the technique as described by Blanco et al.3 A 20 mL was injected underneath the pectoralis minor muscle and the remaining 10 mL was injected between the pectoralis major and minor muscles. The procedure was completed after confirming lateral spread of the injected fluid in the correct intermuscular planes and was designated as time zero. All nerve blocks were performed by the attending anesthesiologists (BV or KV) who are skilled in performing ultrasound-guided interpectoral-pectoserratus plane blocks. Surgery started about 10 min after finalizing the block. The attending anesthesiologist collected all data.
Ten blood samples were obtained from each participant. Two blood samples were obtained immediately after placement of the second intravenous access as one of these samples was used to determine albumin and alpha-1-acid-glycoprotein levels and one was used as the baseline. The eight other blood samples were obtained at 10, 20, 30, 45, 60, 90, 120 and 240 min after performing the block. Before a 5 mL sample was collected, a 2 mL of blood was aspirated which was disregarded. To ensure clean samples, the three-way stopcock valve was flushed with 2 mL of NaCl 0.9% after each collection.
Each sample was sent to the laboratory of AZ Turnhout where they were centrifuged at 1800 g for 10 min within 30 min after sampling. Serum samples were stored at −20°C at AZ Turnhout until all samples were collected after which they were transported on dry ice to the University Hospital Antwerp for analysis.
Samples were temperature equilibrated at 37°C for 1 hour before being processed. The separation of free and bound ropivacaine was performed using Rapid Equilibrium Dialysis. After 16 hours of dialysis, 50 µL of the serum fraction and 50 µL of the buffer fraction were taken and an internal standard (Ropivacaine 2 H7) was added prior to sample cleanup. Samples were vortexed and liquid-liquid extracted. The measurement was performed using ultra-high-pressure liquid chromatography and tandem mass spectrometry.
We selected the serum concentration as the primary outcome. The maximum free and total serum concentrations were compared with the generally accepted reference value for toxicity: 0.15 µg/mL and 2.2 µg/mL for free and total ropivacaine, respectively.4
Results
We recruited 22 adult female patients. Two patients were excluded due to protocol violations regarding the ropivacaine dosing, that is, our standard dosage of 30 mL ropivacaine 0.5% was administered (figure 1). Table 1 illustrates their demographics. Eleven patients underwent mastectomy with sentinel node biopsy, 9 patients underwent mastectomy with axillary clearance and 0 patients underwent lumpectomy with axillary clearance. Three, 14 and 3 patients had ASA physical status classes 1, 2 and 3, respectively.
Consolidated Standards of Reporting Trials (CONSORT) flow diagram.
Patient demographics
Patients had a mean alpha-1-acid-glycoprotein physiological concentration of 0.8 (0.3) g/L and a mean albumin concentration of 41.6 (2.8) g/L. All patients had values which are in the range of the reference values for healthy adults.5 6 The mean dose of ropivacaine administered was 172.8 (22.5) mg.
The time course of total and free serum ropivacaine concentrations are shown in figures 2 and 3.
Box plot of the total serum ropivacaine concentrations at different time points. The central mark is the median; the edges of the box are the 25th and 75th percentiles. The whiskers extend to the most extreme data points not considered outliers (percentiles 0–100). Outliers are plotted individually (
).
Box plot of the free serum ropivacaine concentrations at different time points. The central mark is the median; the edges of the box are the 25th and 75th percentiles. The whiskers extend to the most extreme data points not considered outliers (percentiles 0–100). Outliers are plotted individually (
).
The mean peak total serum ropivacaine concentration was 1.3 µg/mL, which occurred at the 20 min measurement. The highest individual total peak serum ropivacaine concentration was 3.1 µg/mL and measured 45 min after injection. Total mean concentrations remained under a potentially toxic threshold of 2.2 µg/mL during the course of the study. However, 4 patients (20% of the population) had concentrations above the potentially toxic threshold of 2.2 µg/mL. These exceedances occurred between 20 and 45 min after injection.
The mean peak free ropivacaine concentration was measured at 20 min and was 0.15 µg/mL. The highest individual free ropivacaine concentration was 0.38 µg/mL. Ten patients (50% of the population) exceeded the potentially toxic threshold concentration of 0.15 µg/mL at some point of measurement. These exceedances occurred between 10 and 90 min after injection.
Subgroup analysis based on the total dosage (ie, ≤170 mg (n=10) vs >170 mg (n=10) ropivacaine administered) was also performed to investigate the impact of exceeding the potentially toxic threshold of free ropivacaine. In both groups, 50% of the patients reported a peak free ropivacaine concentration higher than the threshold of 0.15 µg/mL.
While we did not prospectively assess for symptoms or clinical signs of neurological toxicity and the block was performed after the induction of general anesthesia, there were no severe cardiovascular complications observed in any patient.
Discussion
This study prospectively assessed the risk of toxic serum concentrations in patients undergoing breast cancer surgery with a 2.5 mg/kg ropivacaine unilateral interpectoral-pectoserratus plane block. In 50% of the patients, the potentially toxic threshold of 0.15 µg/mL free ropivacaine concentration was exceeded. This result is surprising as we administered a dosage below the internationally recommended maximum dosage of ropivacaine (225 mg),7 adhered to strict inclusion and exclusion criteria, and found no outliners in terms of alpha-1-acid-glycoprotein and albumin physiological concentrations. It must be noted that, while we did not actively assess for clinical symptoms of toxicity, we did not observe seizures or persistent cardiovascular instability in any patient. Seizures may have been obscured by the induction agents, muscle relaxants or inhalational agents.
This potentially toxic threshold is based on the work of Knudsen and colleagues.8 They studied volunteers receiving titrated intravenous infusions of ropivacaine and concluded that the maximum tolerated free plasma concentration of ropivacaine was 0.15 (0.08) μg/mL. This threshold was based on the onset of neurological symptoms. It is important to note that the reported onset symptoms were very mild and included tingling, perioral numbness, dizziness, paresthesia and light-headedness. Moreover, they found a wide range (0.01–0.24 µg/mL) of free ropivacaine concentrations producing these neurological symptoms. This might explain why we could not identify any case reports of local anesthetics overdosing or LAST in patients receiving the interpectoral-pectoserratus plane block.
The mean peak total and free serum ropivacaine concentration were observed 20 min after injection which is slower than in the paravertebral block,9 interscalene block,10 and awake craniotomy,11 where the peak concentration occurred at 7.5, 10, and 15 min, respectively, but faster than the transversus abdominis plane block12 which occurred at 30 min. Indeed, the anatomical location influences the pharmacokinetic characteristics affecting toxicity. Therefore, we agree with Rosenberg et al7 who proposed that rather than publishing a single maximum safe dose of local anesthetics, dosage recommendations should be location or block-specific.
The majority of the reported trials investigating the clinical efficacy of the interpectoral-pectoserratus plane block used 30 mL of 0.25%–0.50% ropivacaine.1 This pharmacokinetic study investigated a dosage of 172.8 (22.5) mg which is on the one hand higher than the typical dosage of a unilateral interpectoral-pectoserratus plane block, that is, 75–150 mg ropivacaine but on the other hand below the internationally recommended maximum dosage of ropivacaine (225 mg).7
While the official product description of Naropin (Fresenius SE, Bad Homburg vor der Höhe, Germany) reports that ‘addition of epinephrine to ropivacaine has no effect on limiting systemic absorption of ropivacaine’,13 recent research challenges this claim. The third ASRA Practice Advisory on LAST recommends the use of an intravascular marker such as epinephrine when injecting potentially toxic doses of local anesthetic.14 Research by El-Boghdadly et al15 confirms the ASRA guidelines and found that the maximum dose of ropivacaine can be 50 mg higher when using epinephrine (200 mg plain and 250 mg with epinephrine).
Based on the results of this study, we recommend clinicians to (1) apply standard ASA monitoring for 90 min after injection of local anesthetics as concentrations might exceed the potentially toxic threshold, (2) be cautious when performing a bilateral block and when combing the interpectoral-pectoserratus plane block with other regional anesthesia techniques and/or local infiltration, (3) use a fixed volume of 30 mL and dilute the local anesthetic to avoid higher concentrations of local anesthetics and hence prevent potential LAST, (4) use NaCl 0.9% for hydrodissecting the plane to minimize the use of local anesthetics outside of the target planes, and (5) add epinephrine when administrating doses of 200–250 mg ropivacaine.
This study has three limitations. First, we did not collect arterial samples which reflects the more accurate concentration of local anesthetic delivered to the brain and heart.9 Second, generalization of this study may be hindered because men, patients with a body mass index lower than 17 or higher than 35 kg/m2, pregnant patients and patients under the age of 18 years were excluded. Third, all serum samples were stored at −20°C until all samples were collected which may have a limited impact on serum concentrations compared with immediate analysis.16
Conclusions and recommendations
This pharmacokinetic study demonstrated that a 2.5 mg/kg ropivacaine interpectoral-pectoserratus plane block may result in exceeding the threshold for LAST.
Based on the results of this study, we recommend clinicians to (1) apply standard ASA monitoring for 90 min after injection of local anesthetics as concentrations might exceed the potentially toxic threshold, (2) be cautious when performing a bilateral block and when combing the interpectoral-pectoserratus plane block with other regional anesthesia techniques and/or local infiltration, (3) use a fixed volume of 30 mL and dilute the local anesthetic to avoid higher concentrations of local anesthetics and hence prevent potential LAST, (4) use NaCl 0.9% for hydrodissecting the plane to minimize the use of local anesthetics outside of the target planes, and (5) add epinephrine when administrating doses of 200–250 mg ropivacaine.
Supplemental material
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Ethics Committee of AZ Turnhout hospital authorized on March 26, 2020 with identifier OG 192 and Ethics Committee of University Hospital Antwerp authorized on January, 18 2021 with identifier 20/42/551. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors sincerely thank Ki-Jinn Chin MD PhD for his valuable input on the methodology of this study. We thank Isabelle Cadron MD PhD, Natacha Ruyssers MD, Dirk Servaes MD and Ingrid Vandeput, MD PhD for welcoming and supporting this serum concentration study in the breast surgery practice. We gratefully acknowledge all contributions of the anesthesiology department, the post anesthesia care unit and the medical laboratory technicians of the AZ Turnhout Hospital and all contributions of the medical laboratory technicians of the University Hospital Antwerp.
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @barbaraversyck, @KVermeylen
Contributors BV led the research team including study conception and design, participated and supervised the performance of the study, participated in data analysis, and participated in the preparation of the manuscript. BV accepts full responsibility for the finished work. KV participated in the study conception and design, performance of the study, data analysis, and preparation of the manuscript. GJVG, IL and FS participated in the study conception and design, and preparation of the manuscript. JW and SD participated in the study conception and design, prepared the samples for analysis, and preparation of the manuscript. SD analyzed the samples and participated in the preparation of the manuscript. LR participated in the study conception and design, supervised and participated in the analysis of samples, and preparation of the manuscript. All authors gave final approval to the submitted manuscript.
Funding We thank the Belgian Association for Regional Anesthesia (BARA) for their generous research grant.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.