Systematic review of the systemic concentrations of local anaesthetic after transversus abdominis plane block and rectus sheath block

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1 British Journal of Anaesthesia, 118 (4): (2017) doi: /bja/aex005 Review Article Systematic review of the systemic concentrations of local anaesthetic after transversus abdominis plane block and rectus sheath block J. Rahiri 1, *, J. Tuhoe 2, D. Svirskis 3, N. J. Lightfoot 4, P. B. Lirk 5 and A. G. Hill 1 1 Department of Surgery, South Auckland Clinical Campus, The University of Auckland, Auckland, Otahuhu, New Zealand, 2 Tiakina Te Ora, Auckland, Papakura, New Zealand, 3 School of Pharmacy, The University of Auckland, Auckland, New Zealand, 4 Department of Anaesthesiology, University of Amsterdam, Amsterdam 1105AZ, The Netherlands and 5 Department of Anaesthesia and Pain Medicine, Counties Manukau Health, Middlemore Hospital, Auckland, New Zealand *Corresponding author. j.rahiri@auckland.ac.nz Abstract Background. Safe and efficacious modalities of perioperative analgesia are essential for enhanced recovery after. Truncal nerve blocks are one potential adjunct for analgesia of the abdominal wall, and in recent years their popularity has increased. Transversus abdominis plane block (TAPB) and rectus sheath block (RSB) have been shown to reduce morphine consumption and improve pain relief after abdominal. These blocks typically require large volumes of local anaesthetic (LA). We aimed to synthesize studies evaluating systemic concentrations of LA after perioperative TAP and RSB to enhance our understanding of systemic LA absorption and the risk of systemic toxicity. Methods. An independent literature review was performed in accordance with the methods outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. An electronic search of four databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and PubMed) was conducted. Primary articles measuring systemic concentrations of LA after single-shot bolus TAPB or RSB were included. Results. Fifteen studies met the inclusion criteria. Rapid systemic LA absorption was observed in all studies. Of a total of 381 patients, mean peak concentrations of LA exceeded toxic thresholds in 33 patients, of whom three reported mild adverse effects. The addition of epinephrine reduced systemic absorption of LA. No instances of seizure or cardiac instability were observed. Conclusions. Local anaesthetic in TAPB and RSB can lead to detectable systemic concentrations that exceed commonly accepted thresholds of LA systemic toxicity. Our study highlights that these techniques are relatively safe with regard to LA systemic toxicity. Key words: anaesthetics, local; drug toxicity; nerve block Safe and effective modalities of perioperative analgesia are essential for enhancing recovery after. Optimal regimens of analgesia seek to improve patient comfort and mobilization whilst minimizing the risk of complications that may inhibit postoperative recovery. 1 Severe pain after open and laparoscopic abdominal remains a significant clinical VC The Author Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com 517

2 518 Rahiri et al. problem. As surgical techniques change and length of inpatient stay decreases, it is important to offer safe and reliable methods of analgesia that may be delivered in both hospital and outpatient settings. Regional anaesthesia has become an important addition to multimodal regimens of analgesia for postoperative pain. The block of pain impulses by local anaesthetic (LA) provides effective pain relief for abdominal, either on its own or as part of a multimodal analgesic regimen. 2 With the development of ultrasound imaging techniques that enable precise target identification, truncal blocks, such as transversus abdominis plane block (TAPB) or rectus sheath block (RBS), are becoming popular after abdominal. 34 Previous clinical trials have shown that the addition of truncal blocks to multimodal regimens of analgesia significantly reduces pain and opioid consumption after. 5 7 Transversus abdominis plane block and RSB are compartmental blocks, which require large volumes of LA to optimize the spread within a fascial plane towards a target nerve or group of nerves. 8 Despite the increasing interest in truncal blocks, little is known about systemic concentrations of LA after truncal nerve block. The large doses of LA required raise the potential issue of LA systemic toxicity. Local anaesthetic systemic toxicity is characterized by central nervous system and cardiac instability ranging from dizziness to seizures, and from mild arrhythmia to cardiovascular collapse and death, respectively Systemic concentrations of LA are correlated with the vascularity of the tissue, LA pharmacodynamic properties and effects of potential additives, and patient conditions such as pregnancy or sepsis. 11 After a single bolus injection of LA, peak concentrations are greatest after intrapleural or intercostal administration followed in decreasing order by caudal, epidural, brachial plexus, and lower limb blocks. 12 The systemic absorption of LA after epidural and brachial plexus applications has been well characterized and discussed in the literature The aim of this review was to synthesize data from studies assessing perioperative LA systemic concentrations after single bolus TAPB and RSB and define the plasma concentrations to be expected. Methods A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement where possible. 15 Two authors (J.R., J.T.) independently performed a series of electronic searches of four databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and PubMed). With the assistance of a subject librarian, the first author (J.R.) collated a list of keywords and search terms to incorporate into strategies adapted for each database. The search terms combined local anaesthetics, anterior abdominal wall blocks, systemic concentrations, and pharmacokinetics of local anaesthetics. Language limitation was not applied. Truncated search terms were used to increase the hit rate. Search results were downloaded and managed with RefWorks citation management software (ProQuest LLC, Ann Arbor, MI, USA). Study selection Abstracts were screened and full-text papers obtained to identify primary research studies reporting serum concentrations of LA agents used in ultrasound-guided (USG) anterior abdominal wall blocks (TAPB and RSB) in adult patients for any indication. The primary outcome of interest was serum concentrations of LA agents in the first 24 h after. All human clinical trials, whether randomized, quasi-randomized, or non-randomized, that primarily evaluated serum concentrations of LA agents after TAPB or RSB were included. Exclusion criteria included studies that did not evaluate serum concentrations of LA agents, studies on infants and children (<18 yr of age), and those articles for which full-text publications were not available (e.g. conference abstracts). Two reviewers (J.R., J.T.) independently performed the searches and examined titles and abstracts to exclude irrelevant reports and produce a list of studies for full-text review in an iterative process. Any disagreement over inclusion or exclusion was discussed with the senior author (A.G.H.) and a consensus reached. Additional articles and abstracts were retrieved by manually examining reference lists of relevant publications. The last search was performed on July 16, Data abstraction Data extraction was performed independently by the first author and entered in predesigned electronic tables. Tables recorded patient characteristics, operative characteristics, LA dose and type, and LA serum concentrations, including pharmacokinetic parameters (C max and T max ), where C max refers to the maximal serum concentration that a drug achieves and T max refers to the time at which C max is observed. Data were reported as the mean (SD) where possible, and only recorded if stated in the text, tables, graphs, or figures of the articles. The median score was used as an estimate of the mean where the latter was not reported. Standard deviation measures were attempted based on the methods described in the Cochrane Handbook of Systematic Reviews of Interventions, where attempts to contact authors for clarification were unsuccessful (up to two s). 16 Variations in the timing of outcome measures, procedure type, and study cohorts limited meaningful synthesis of the data. Pharmacokinetic modelling was not attempted because of study heterogeneity and differences in LA detection method and anaesthetic regimens. The data are therefore presented as a narrative review. Assessment of risk of bias Two reviewers (J.R., J.T.) independently applied the Newcastle Ottawa Scale (NOS), which assesses the methodological quality of non-randomized aspects of study design, including patient selection, comparability of study groups, and assessment of outcomes. 17 The tool uses a scoring system with a maximum of nine stars, and studies that achieve five or more stars are considered high quality. Results The literature search identified 206 records in the initial database search. A PRISMA flow diagram for the systematic review is presented in Fig. 1. Fifteen clinical studies met the inclusion criteria and were included in the review Three studies were excluded, where two studies were abstracts from conference proceedings, and multiple LA applications were used in the remaining study (Table 3). The majority of the included studies used ropivacaine as their chosen LA agent One study used lidocaine, and three studies used levobupivacaine. Among 381 participants included for analysis in all 15 studies, there were 33 reported instances where systemic LA concentrations exceeded toxic threshold parameters (as defined

3 Concentrations of LA after truncal nerve block 519 Included Eligibility Screening Identification 206 records identified through database searching 112 records after duplicates removed 112 records screened by title and abstract 18 full-text articles assessed for eligibility 15 studies included in qualitative synthesis (n=381) 84 records excluded Fig 1 PRISMA flow diagram of the study selection process. 3 full-text articles excluded: 1 concomitant truncal blocks/local infiltration 2 conference abstracts pregnant women undergoing Caesarean section. This was the only study where participants (n¼3) reported instances of mild systemic toxicity with symptoms of perioral and tongue paraesthesia, a metallic taste, and slurred speech. One study used lidocaine in patients undergoing laparoscopic. 24 Individual C max values ranged from 2.7 to 5.5 mg ml 1 (Table 2). No adverse effects were reported. The effect on the systemic absorption of ropivacaine, lidocaine, or levobupivacaine after bilateral USG TAPB with the addition of epinephrine was not assessed. A graphical representation of LA systemic absorption after bilateral TAPB in several of the studies is shown in Fig. 2. Rectus sheath block Four studies measured systemic concentrations of LA, of which three used ropivacaine and one used levobupivacaine One study exclusively measured LA systemic concentrations after bilateral USG RSB. 29 The remaining studies compared changes in the systemic concentrations of LA between patients receiving bilateral USG RSB and TAPB Mean peak concentration (C max ) and T max were lower in the RSB groups compared with the TAPB groups. Dose-dependent increases in mean peak systemic concentrations were also observed and are shown in Table 3. Additives The effect of epinephrine on LA absorption was assessed in one study. 30 Although no significant findings were observed in the RSB group, the addition of epinephrine to ropivacaine after TAPB led to a decreased C max and delayed T max. There were no reported instances of LA systemic toxicity despite predefined toxic thresholds being exceeded in three patients. The systemic absorption of LA after bilateral USG RSB is depicted in Fig. 3. by the publication authors). Of these instances, three patients exhibited subjective symptoms of mild LA systemic toxicity. 21 Symptoms were limited to perioral and tongue paraesthesia, a metallic taste, and slurred speech. No instances of severe neurotoxicity (seizures) or persistent cardiovascular instability were observed. Transversus abdominis plane block Eleven studies measured systemic concentrations of LA agents after bilateral USG TAPB (Table 2). Abdominal or pelvic was performed in eight studies, while in the remaining three studies participants were healthy volunteers who did not undergo any Eight of the 11 studies used ropivacaine Peak systemic concentrations of ropivacaine were dose dependent, with mean doses of ropivacaine ranging from 50 to 200 mg, and weight-based doses ranging from 1.9 to 4.2 mg kg 1. Four studies concurrently measured free concentrations of ropivacaine Mean pharmacokinetic C max and T max variables for each study are shown in Table 2. Twenty-nine instances among all included TAPB studies exceeded systemic concentration thresholds for ropivacaine as defined by the respective study authors There is some variation in the LA systemic thresholds used in the included studies, as shown in Table 2. The highest mean individual peak systemic concentration of ropivacaine observed was in a study by Griffiths and, 20 who measured concentrations in Discussion This review identified 15 studies investigating systemic concentrations of LA after TAPB and RSB It is the first systematic review to collate primary studies assessing the safety of LA after anterior abdominal wall blocks. Although a significant number of patients in the included trials exceeded potentially toxic thresholds (33 of 381 patients) of LA as defined by previous clinical trials and case studies, only three patients reported mild symptoms of LA systemic toxicity. This highlights the somewhat arbitrary nature of typical LA systemic toxic thresholds. Furthermore, we note that even using widely accepted LA dosages, TAPB and RSB can lead to plasma concentrations in excess of predefined thresholds of toxicity. However, all instances observed in the present study were associated with only mild neurotoxicity, and no cardiovascular instability was observed. Local anaesthetics inhibit the central nervous system in a dose-dependent manner through blockage of sodium channel function and cessation of action potential propagation. 36 They also have anti-inflammatory, anti-thrombotic, anti-microbial, anti-adhesion-forming, and neuroprotective properties It is not possible to monitor systemic concentrations of LA in clinical practice, so we are guided by studies that, to the best of our knowledge, inform safe dosing of LA agents. Generally, high volumes of LA are required for TAPB and RSB. Systemic absorption of LA from injected tissues depends on several factors, including LA dose, spread of injected solution, tissue vascularity, and the physiological state of the patient. 39 Local anaesthetic binds to

4 520 Rahiri et al. Table 1 Summary of included studies measuring systemic concentrations of local anaesthetics after transversus abdominis plane block. Cmax, maximal serum concentration that a drug achieves; LA, local anaesthetic; LC, liquid ; MS/MS, tandem mass spectrometry; n, number of study participants; T max, time at which C max is observed; USG, ultrasound guided; (1) (3), group one to three. *P < 0.05, **P < 0.01 Study Procedure LA volume, type, concentration (total dose) n Block, time given Time points (min) Method of analysis Total C max (mgml 1 ) Tmax (min) Toxic threshold, patients exceeded (n) Toxicity (n) Griffiths and Open gynaecologi- (2010) 18 cal Torup and Open abdominal (2012) 19 and pelvic 40 ml, ropivacaine, 3mgkg 1 (201 mg) 40 ml, ropivacaine, 0.5% (200 mg) Griffiths and Caesarean section 40 ml, ropivacaine, (2013) mg kg 1 (199 mg) Kitayama and Open retropubic (2014) 21 prostatectomy 20 ml, ropivacaine (1) 0.25% (2) 0.5% (3) 0.75% Kumar and Laparotomy 40 ml, ropivacaine, (2014) % Toju and Open upper (2015) 23 abdominal Kato and Laparoscopic (2009) 24 gynaecological Ishida and Open gynaecologi- (2015) 25 cal 3mgkg 1, ropivacaine, 0.45% 40 ml, lidocaine, 1% (400 mg) 40 ml per side, levobupivacaine, 0.25% (100 mg) Børglum and None 60 ml, ropivacaine, (2012) % (225 mg) Corvetto and None 20 ml, levobupivacaine, (2012) % with or without (E) 5 mg ml 1 28 Bilateral USG TAPB, after induction 18 Bilateral USG TAPB, pre-induction 30 Bilateral USG TAPB, after wound closure 39 Bilateral USG TAPB, after intubation 12 Bilateral USG TAPB, during 12 Bilateral USG TAPB, after intubation 12 Bilateral USG TAPB, after intubation 40 Bilateral USG TAPB, after intubation 15, 30, 45, 60, 90, 120, 180, 240, 720, , 10, 30, 60 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 0, 15, 30, 45, 60, 90, 120, 180 0, 15, 30, 45, 60 Arterial: 15, 30, 45, 60, 90, 120 1, 5, 15, 30, 60, 120 Arterial: 5, 10, 15, 30, 60, 120, Classic TAPB and upper intercostal 0, 30, 120, 240, Unilateral TAPB Arterial: 2, 5, 10, 30, 45, 60, (0.8) mg ml mg ml (0.05) 30 n¼10 HPLC-MS/MS Not reached Not reached 2.2 mg ml (0.7) 0.07 (0.034) (1) 0.41 (0.14) (2) 0.89 (0.55)* (3) 1.56 (0.50)** 35.5 (15.7) not reported (1) 23.0 (15.8) (2) 23.1 (4.5) (3) 20.8 (11.5) n¼6 2.2 mg ml 1 n¼ mg ml 1 n¼1 (0.75%) HPLC 2.1 (0.8) mg ml (0.02) 24.6 LC-MS/MS 1.9 (0.8) 31.3 (16.7) 4.3 (0.6) mg ml 1 Fluorescence polarization 3.6 (0.7) 30 (15 60) 5 mg ml 1 n¼1 immunoassay LC-MS/MS 1.0 (0.4) mg ml 1 UPLC 1.4 (0.3) 35.0 (7.0) None reported HPLC Arterial: 0.6 (95% CI, ) 3 Not reported None reported Latzke and None 20 ml, ropivacaine, (2012) mg ml 1 (150 mg) 8 USG TAP block 0, 5, 10, 20, 30, 60, 90, 120, 150, 180, 210, 240, 300, 360 HPLC Total: 1.9 (0.4) 0.11 (0.02) Total: 0.4 (0.4) Not determined None reported

5 Concentrations of LA after truncal nerve block 521 Table 2 Summary of included studies measuring systemic concentrations of local anaesthetics after rectus sheath block. C max, maximal serum concentration that a drug achieves; (E), epinephrine; HPLC, high performance liquid ; LA, local anaesthetic; LC, liquid ; MS/MS, tandem mass spectrometry; n, number of study participants; RSB, rectus sheath block; TAPB, transversus abdominis plane block; (1) (3), group one to three. *P < 0.05, **P < 0.01 Study Procedure LA volume, type, concentration (total dose) n Block, time given Time points (min) Method of analysis Total C max (mgml 1 ) T max (min) LA toxic threshold, patients exceeded (n) Toxicity (n) RSB Wada and (2012) 29 RSB and TAPB Kitayama and (2014) 30 Murouchi and (2015) 31 Yasumura and (2016) 32 Open abdominal 20 ml, ropivacaine, (1) 0.25% (2) 0.5% (3) 0.75% Laparotomy and open retropubic prostatectomy Laparoscopic ovarian Laparoscopic gynaecological 20 ml, ropivacaine, 0.5% with and without (E) 30 ml, ropivacaine, 0.5% 40 ml, levobupivacaine, 2.5 mg kg 1 39 Bilateral USG RSB, after induction 52 Bilateral USG TAPB (1) and RSB (2), after intubation 22 Bilateral TAPB (1) and RSB (2) 50 Bilateral USG TAPB (1) and RSB (2), after induction Arterial: 0, 15, 30, 45, 60, 90, 120, 180 Arterial: 0, 15, 30, 45, 60, 90, 120, 180 Arterial: 0, 10, 20, 30, 45, 60, 90, , 30, 60, 120 (1) 0.5 (0.2) (2) 1.1 (0.4)* (3) 1.5 (0.8)** (1) 1.0 (0.3) (2) 1.4 (0.3) HPLC (1) 1.8 (0.4) (2) 1.8 (0.3) HPLC and LC-MS/MS (1) 1.0 (2) 1.0 (1) 49.6 (21.6) (2) 48.5 (28.8) (3) 38.1 (14.5) (1) 18.5 (6.6) (2) 36.9 (9.9) (1) 35.0 (12.0) (2) 53.0 (16.0) (1) 32.4 (2) mgml mg ml 1 n¼ mgml 1

6 522 Rahiri et al. Systemic level (µg ml 1 ) mg 22 50mg mg mg mg mg 20 (L) 400mg 24 (LB) 100mg mg mg Time (min) Fig 2 Systemic absorption of ropivacaine, lidocaine (L) and levobupivacaine (LB) after bilateral ultrasound-guided (USG) transversus abdominis plane block (TAPB). plasma proteins, primarily a 1 -acid glycoprotein and albumin. Plasma protein concentrations are directly influenced by surgical trauma, pregnancy, and disease states, such as cardiac, renal, and liver disease. The process of plasma binding reduces pharmacologically active free concentrations of LA and attenuates crossing of the blood brain barrier and binding of cardiac channels, causing central nervous system or cardiac toxicity, respectively. 40 Thresholds of LA systemic toxicity have been defined in older studies but not cross-validated for truncal blocks or patients with different conditions. Ropivacaine possesses intrinsic vasoconstrictive properties and is thought to have a safer side-effect profile This narrative is reflected by the predominant selection of ropivacaine for truncal blocks among the included studies in this review. A study of volunteers receiving titrated i.v. infusions of ropivacaine until occurrence of clinical signs of central nervous system toxicity showed symptom onset at a mean total venous concentration of 2.2 mg ml 1 and an unbound concentration of 0.15 mg ml 1. 9 Given the paucity of information to suggest otherwise, these ropivacaine thresholds are generally accepted. This is somewhat evident in the use of these parameters in the majority of the included studies using ropivacaine for TAPB or RSB. Single bolus anterior abdominal wall blocks were assessed in healthy participants undergoing abdominal or pelvic. In response to the stress of, studies have observed increased concentrations of a 1 -acid glycoprotein that in turn lower free concentrations of LA Latzke and 28 measured total and free concentrations of ropivacaine after bilateral USG TAPB in healthy volunteers. Two studies included in this review assessed patients undergoing laparotomy in a similar manner In comparison, Latzke and 28 observed higher free concentrations of ropivacaine and a notably lower C max. Another study in healthy volunteers also demonstrated a lower C max after concomitant classic TAPB and upper intercostal block despite higher volumes of ropivacaine. 26 This occurrence highlights the potential physiological differences that can exist in surgical patients and how this can influence the resorption kinetics of LA. The TAPB aims to produce anaesthesia and analgesia of the lower abdominal wall below the umbilicus. 44 Generally, a large volume of LA is injected in the neurovascular plane between the transversus abdominis (deep) and internal oblique muscles of the abdominal wall to block segmental thoraco-abdominal nerves. Systemic toxic thresholds of LA were predominantly exceeded in patients who received bilateral USG TAPB. Symptomatic patients were reported in a single study that prospectively assessed healthy women undergoing elective Caesarean section for LA systemic toxicity after bilateral TAPB. 20 Mean body weight of symptomatic patients was greater compared with asymptomatic patients, resulting in higher mean doses of ropivacaine. Importantly, pregnancy is a peculiar physiological state, which results in reduced concentrations of a 1 -acid glycoprotein. 45 This increases the likelihood of systemic toxicity as a result of high circulating concentrations of free LA. 46 These phenomena are more than likely to have contributed to the high mean total C max and instances of LA systemic toxicity. The addition of a vasopressor, such as epinephrine, to LA solution can reduce peak concentrations of LA and delay systemic absorption. 47 Interestingly, Kitayama and observed this effect with epinephrine only in the TAPB group and not in the RSB group. 30 In general, the RSB groups appeared to have delayed T max when compared with the TAPB groups. Despite this, no significant differences of C max were observed between various truncal blocks using the same LA. The RSB is achieved by LA agent administrated to block the terminal branches of the ninth, 10th, and 11th intercostal nerves and

7 Concentrations of LA after truncal nerve block 523 Table 3 Excluded studies of interest. CI, confidence interval; C max, maximal serum concentration that a drug achieves; (E), epinephrine; HPLC, high performance liquid ; IIB, ilioinguinal block; LA, local anaesthetic; LC, liquid ; MS/MS, tandem mass spectrometry; n, number of study participants; Tmax, time at which Cmax is observed; RSB, rectus sheath block; TAPB, transversus abdominis plane block; USG, ultrasound guided; (1) (5), group one to five Study Procedure LA volume, type, concentration (total dose) n Block, time given Time points (min) Serum analysis Total Cmax (mg ml 1 ) ETmax (min) LA systemic toxicity Reason for exclusion Kitayama and (2009) 33 Kitayama and (2010) 34 Wulf and (2001) 35 Lower abdominal Open retropubic prostatectomy Inguinal hernia repair 20 ml, ropivacaine: (1) 0.25% (2) 0.5% (3) 0.75% (4) 0.5% with (5) 0.5% with (E) 20 ml, ropivacaine: (1) 0.25% (2) 0.5% (3) 0.75% (4) 0.5% and lidocaine (5) 0.5% with (E) 60 ml, ropivacaine, 0.5% 50 Bilateral RSB Arterial: 15, 30, 45, 60, 90, 120, Bilateral TAPB Arterial: 15, 30, 45, 60, 90, 120, IIB, genitofemoral block plus local infiltration 10, 20, 30, 45, 60, 90, 120, (0.2) (0.4) 1.4 (0.6) (0.3) 1.1 (0.4) 0.41 (0.14) 0.89 (0.55) 1.56 (0.50) 0.64 (0.27) 1.01 (0.33) 42.0 (30 60) 39.0 (15 90) 40.2 (15 60) 42.0 (15 120) 38.2 (30 45) 23 (15 60) 23 (15 60) 21 (15 45) 44 (15 90) 18 (15 30) None reported Conference abstract None reported Conference abstract HPLC 1.50 (0.60) 45 (30 60) None reported Additional iliac crest block and LA wound infiltration

8 524 Rahiri et al. 2 Systemic level (µg ml 1 ) (LB) 136.4mg 32 (R) 50mg 29 (R) 100mg 29 (R) 150mg 29 (R) 100mg Time (min) Fig 3 Systemic absorption of ropivacaine (R) and levobupivacaine (LB) after bilateral ultrasound-guided (USG) rectus sheath block (RSB). provides sensory block to the midline of the abdomen. 48 Anatomical studies demonstrate the relationship between the location of LA administration and the desired region of anaesthesia, where exposure to large vascular surface areas provides ideal conditions for rapid LA systemic absorption. 49 Therefore, delayed C max and ineffective vasopressor activity after bilateral RSB could be attributed to a relatively avascular fascial plane, possibly accounting for a more rapid systemic absorption of LA observed after TAPB. Traditionally, LA amounts were high and administration was highly unselective because of blind techniques that may have led to block of adjacent nerves. Since the initial description of truncal blocks, the introduction of ultrasound guidance has provided the advantage of reliably depositing LA under realtime imaging. 6 This has in effect improved block success rates and minimized the potential for harm. Numerous modifications to block techniques have seen the evolution from single injection blind techniques to improved USG techniques With further advances of interest, including surgical or anaesthetic placement of wound catheters for LA infusions, enhancing our understanding of LA systemic concentrations after abdominal wall block is important. 52 This systematic review has a number of limitations. First, as a result of the lack of individually reported data, pharmacodynamic or pharmacokinetic modelling was not possible. Study heterogeneity was present, and the lack of adequate pharmacological attention in the presented studies meant that meaningful synthesis was limited. Another limitation was the low number of RSB studies. This made it difficult to make robust comparisons between the profiles of LA agents as applied to the two different anterior abdominal wall block studies. In conclusion, LA use in anterior abdominal wall blocks can lead to detectable systemic concentrations that exceed commonly accepted thresholds of LA systemic toxicity. Dosing regimens for truncal blocks have been tested only in healthy subjects. In the absence of patient studies determining safe doses for LA in truncal blocks, providers should take LA dose, patient co-morbidities/conditions, and site of injection into account whenever performing TAPB or RSB, and remain vigilant for systemic toxicity at all times. Under these premises, our study shows that the site of injection in TAPB and RSB is associated with a relatively slow absorption, and therefore, the safety profile can be considered good. Authors contributions Study design and writing the manuscript: J.R. Electronic search, study selection, and data analysis: J.R., J.T. Critical revision of drafts and final manuscript: D.S., N.J.L., P.B.L., A.G.H. Acknowledgements The authors sincerely thank Anne Wilson, Subject Librarian from the Counties Manukau Health Library, for assistance with the search strategies. Declaration of interest None declared. Funding Health Research Council of New Zealand (grant number 16/449 to J.R.). References 1. Andreae MH, Andreae DA. Local anaesthetics and regional anaesthesia for preventing chronic pain after. Cochrane Database Syst Rev 2012; 10: CD Holte K, Kehlet H. Epidural anaesthesia and analgesia: effects on surgical stress responses and implications for postoperative nutrition. Clin Nutr 2002; 21:

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