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Abstract
Introduction Early diagnosis of acute extremity compartment syndrome is crucial to timely surgical management. Pain is commonly used as an early diagnostic sign for acute extremity compartment syndrome, making regional anesthesia after lower extremity surgery controversial. This randomized study tested whether different concentrations of local anesthetics, or combinations of nerve blocks, would differentially impact the perception of acute extremity compartment syndrome-like pressure and ischemic pain.
Methods Healthy volunteers underwent quantitative sensory testing, including determination of pressure pain thresholds and prolonged pressure/ischemic pain in the leg using a variable cuff inflation system. Subjects were randomized to receive (1) adductor canal block alone (ACB), (2) ACB with low-concentration sciatic nerve block (ACB +LC SNB), or (3) ACB with high-concentration SNB (ACB +HC SNB). For the primary outcome, we assessed block-induced increases in pressure threshold to reach 6/10 pain, and compared the degree of increase between the three groups. The main secondary outcome was a comparison of average pain score during a 5 min hold at the 6/10 pressure pain threshold between the three groups.
Results All blocks raised pressure pain threshold and decreased ischemic pain, but to variable extents. Specifically, the amount the block increased pressure pain threshold was significantly different among ACB, ACB+LC SNB, and ACB+HC SNB groups (mean±SD: 24±32 mm Hg, 120±103 mm Hg, 159±93 mm Hg; p=0.002), with post hoc testing revealing ACB as less than the other two groups. Similarly, average pain scores during a prolonged/ischemic cuff hold differed among the groups (4.2±1.4, 1.4±1.7, 0.4±0.7; p<0.001), with post hoc testing revealing ACB as significantly higher.
Discussion This study suggests the possible utility of titrating regional anesthesia, to provide some analgesia while still allowing acute extremity compartment syndrome detection.
Trial registration number NCT04113954.
- pain perception
- lower extremity
- anesthesia, local
- pain, postoperative
- acute pain
Data availability statement
Data are available on reasonable request.
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What is already known on this topic
The use of regional anesthesia after lower extremity fracture and surgery has been controversial due to the concern of masking acute extremity compartment syndrome (AECS).
What this study adds
This randomized, controlled study modeling AECS pain in healthy volunteers provided evidence that pressure and ischemic pain induced by a leg cuff is differently impacted by adductor canal nerve block (ACB) alone or ACB with different concentrations of sciatic nerve block.
How this study might affect research, practice, or policy
Clinical provision of analgesia by application of partial or lower concentration blockade may represent a more nuanced approach in patients after lower extremity surgery, when there is concern for AECS, and allow less reliance on opioid-based analgesia.
Introduction
Acute extremity compartment syndrome (AECS) is a surgical emergency, where time to diagnosis is crucial to avoid morbidity and mortality.1 Pain is often the first symptom of compartment syndrome, even though it has a low positive predictive value (11%–15%),2 and compartment syndrome can occur in the absence of pain.3 Well-timed regional anesthesia (RA) has the potential to decrease acute postoperative pain and opioid consumption after fracture surgery,4–6 but there is concern that this may also mask developing AECS and delay diagnosis.7 The debate regarding whether nerve blocks should be avoided to facilitate AECS diagnosis has been long-standing.7 8
A suggested middle ground is the idea of less dense peripheral nerve blockade, either by blocking only some of the nerves to an area (eg, saphenous nerve using an adductor canal block (ACB) for tibial plateau fracture), or by using lower concentrations of local anesthetics without adjuncts.8 The degree to which such variations may provide analgesia has not been systematically tested.
The goal of this study was to investigate whether varying the concentration of local anesthetics, or specific constellations of nerve blocks, would decrease pain perception in a human model of early AECS using administration of cuff pressure to the leg. Specifically, we aimed to determine whether ACB alone, or the use of a lower concentration in a sciatic nerve block (ACB +LC SNB) would impact pressure and ischemic pain less than higher concentration SNB (ACB +HC SNB). The primary outcome examined was the block-induced increase in pressure pain threshold, compared between the three block groups. The main secondary outcome was average pain score during a 5 min cuff hold (ischemic pain), compared between the three groups. We hypothesized that both ACB alone, or addition of a lower concentration sciatic block (ACB +LC SNB), would impact leg pain to a lesser degree than addition of a ACB +HC SNB.
Methods
Patient selection and recruitment
Participants were recruited using online advertisements and underwent a video-based informed consent process with demonstration of study procedures prior to being scheduled for the study. Inclusion criteria were 18–65 years of age and body mass index <35 kg/m2. Exclusion criteria included chronic pain and/or opioid use, neuropathy, diabetes, peripheral artery disease or limb loss, coagulation disorder, skin breakdown in lower extremities, pregnancy, smoking/vaping, or illicit substance use. Subjects who received at least one nerve block received financial compensation for their participation in the study.
Baseline assessment
In order to characterize baseline differences in factors known to modulate pain, participants used an encrypted iPad to complete self-reported, validated questionnaires. These included a survey of baseline pain (Brief Pain Inventory 9), widespread pain (Fibromyalgianess questionnaire,10 and catastrophic thinking about pain (Pain Catastrophizing Scale11), which assesses trait catastrophizing.
Quantitative sensory testing of pain in absence and presence of blocks
General pain sensitivity
Using a subset of previously validated quantitative sensory tests (QST),12 psychophysical sensitivity to standardized painful stimuli were performed to assess baseline differences in pain sensitivity between groups. A handheld algometer assessed general pressure pain threshold and tolerance at extremity (forearm) and truncal (trapezius) sites, and weighted pinprick probes assessed temporal summation of pain and painful after sensations after repeated pain stimuli, measures of pain centralization.12 13 A verbal Numeric Rating Scale (from 0 to 10) was used by participants to rate pain scores during testing procedures.
Leg pain testing
Pressure pain (primary outcome) and ischemic pain (secondary outcome) were induced using a Hokanson rapid cuff inflator with a pneumatic cuff centered around the largest diameter of the gastrocnemius muscle, approximately 2 cm below the tibial tuberosity, with marking between trials to ensure consistency of placement. This cuff inflation system applies a carefully titrated amount of pressure pain to the leg and has been used by our group in previous studies with chronic pain patients.14 15 Additionally, previous studies using a leg cuff have demonstrated measured ischemia under these conditions.16 Participants were blinded to pressure readings.
To determine cuff pressure pain threshold, the cuff was gradually inflated (~20 mm Hg/second) until the subject reported that the pressure first turned to pain (1/10 pain). The cuff pressure was then released. The cuff was then gradually reinflated (~20 mm Hg/second), and cuff pressures were noted when the subject reported pain reaching levels of 4/10, 6/10, 8/10 and 10/10. Once the participant indicated pain level was 10/10, the cuff pressure was released. This pressure ramp was applied three times on each leg, with a 1 min break between each round of testing. Pressure values to achieve each target pain level (4, 6, 8, 10/10 pain) were measured in three trials and averaged for each individual participant. Pressure threshold testing was repeated on the leg 20 min after ACB placement and 40 min after SNB (figure 1). We then assessed the amount of increase in pressure needed to achieve the same targeted pain threshold, compared with the baseline pressure values. To avoid any possible tissue damage, we limited cuff pressures to 400 mm Hg.
Study flow diagram. ACB, adductor canal block; BL, baseline; BMI, body mass index; HC, high concentration; LC, low concentration; PPT, pressure pain threshold; SNB,sciatic nerve block; SPCS, situational pain catastrophizing.
For the prolonged pressure/ischemic pain assessment, each participant’s averaged pressures to achieve 4, 6, 8 and 10/10 pain at baseline were applied to the leg. The leg cuff was rapidly inflated to the target pressure and then held for 5 min. Pain ratings (numeric rating scale, 0–10) were verbally gathered every 30 s. This procedure was performed four times, using pressures that induced 4, 6, 8 and 10/10 pain, with a 1 min break between each test. Subjects were repeatedly reminded that they could choose to have the cuff deflated prior to the end of the 5 min hold at any point. If the subject could not complete the 5 min hold, a pain score of ‘10’ was recorded for any time point between time of cuff deflation to the end of 5 min. Prolonged pressure/ischemic pain assessment were conducted first on the unblocked, then on the blocked leg. All QST procedures were completed by one of three trained behavioral testers (KLS, KMF, CAC). The order of cuff pressure pain testing and prolonged/ischemic pain testing in relation to block placement is depicted in figure 1.
Nerve blocks
Subjects were randomized into equal groups receiving ACB, ACB+LC SNB or ACB+HC SNB. Within each group, nerve blocks were randomized to the left or right leg, using the randomization function in REDCap. Prior to nerve block placement, a 20-gage intravenous catheter was placed in the hand, and continuous pulse oximetry, 5-lead EKG, and intermittent (5 min) non-invasive blood pressure cuff monitoring was applied. Nerve blocks were performed by specialty-trained experienced regional anesthesiologists (KLS, PL). The subject, QST tester, and anesthesiologist placing the nerve block were blinded to the SNB local anesthetic concentration. Nerve blocks were placed under sterile technique with chlorhexidine after the skin was anesthetized with 1 cc of 1% lidocaine, and a 21-gage 10 cm block needle (SonoPlex II Facet, PAJUNK) under ultrasound guidance (Sonosite Edge) using a HFL50x Linear Transducer Probe. Baseline strength and sensory testing was performed before and after blocks to ascertain successful nerve block placement.
For the ACB, the needle was advanced under ultrasound guidance at mid-thigh in-plane toward the saphenous nerve in the adductor canal, lateral to the superficial femoral artery, as previously described.17 After negative aspiration for blood, 1 cc of 0.9% normal saline was injected to confirm correct needle tip location, after which 10 cc of 1.5% mepivacaine was deposited around the saphenous nerve.
For the SNB, beginning in the popliteal fossa, ultrasound scanning was performed to identify the point of bifurcation of sciatic into common peroneal and tibial nerves. The needle was advanced in-plane toward the site of bifurcation. After negative aspiration for blood, 1 cc of 0.9% normal saline was injected to confirm correct needle tip location, after which 15 cc of either 0.375% mepivacaine (low-concentration) or 1.5% mepivacaine (high concentration) was deposited around the sciatic nerve. The order of nerve block placement in relation to pressure pain testing and ischemic pain testing can be seen in figure 1.
Outcomes
The primary outcome was the impact of block on pressure pain; specifically, block-induced increase in pressure pain threshold (mm Hg) to achieve 6/10 pain, compared between the three block groups (ACB, ACB +LC SNB, ACB +HC SNB). The main secondary outcome was the average pain score reported during the 5 min prolonged pressure/ischemic pain-induced hold at the 6/10 targeted pressure, compared between the three block groups. Other secondary/supplementary outcomes included the assessment of impact of blocks on other pressure pain thresholds and pain scores during prolonged/ischemic holds at other (4, 8, and 10/10) targeted pain levels.
Statistical analysis
All outcomes were assessed for normality of distribution and parametric or non-parametric testing used accordingly. Analysis of variance or Kruskal-Wallis tests were used to determine whether there was a difference among the ACB, ACB+LC SNB, and ACB+HC SNB groups for demographic information, psychosocial and pain profiles, block-induced increase in pressure threshold to reach pain thresholds, and average pain score during a 5 min cuff pressure holds. When significant, post hoc pairwise comparisons were performed. Paired t-tests were used to compare blocked and unblocked conditions within participants. Data analysis was conducted using SPSS (V.27). A p<0.05 was considered significant. Based on preliminary testing in a pool of volunteer test subjects, a sample size estimation was calculated using a mean of 160 mm Hg and SD of 70 mm Hg, which showed that to detect a 50% difference in cuff pressure pain thresholds at the 6/10 pain level, with 80% power and alpha 0.05, a sample size of 13 subjects per group was required.
Results
Participants (n=14 in each group) included 23 women and 19 men. Participants’ characteristics, including demographics, baseline pain sensitivity, and pain catastrophizing, were generally balanced between groups (table 1). Details of screening, enrolment, and study visit flow and testing procedures are shown in figure 1.
Baseline demographic, psychosocial and pain sensitivity characteristics
Effect of nerve blocks on cuff pressure pain threshold
The cuff pressure needed to produce 6/10 pain (6/10 pressure pain threshold) was tested before and after block(s), and shown to increase after all three nerve block combinations, but to varying degrees (ACB alone: increase of 24±32 mm Hg, ACB+LC SNB: increase of 120±103 mm Hg, and ACB+HD-SNB: increase of 159±93 mm Hg (figure 2, see also online supplemental appendix table A for paired testing results). For our primary outcome, we compared the amount of increase in 6/10 pressure pain threshold between the three groups (ie, change in pressure pain sensitivity), which revealed a significant overall group difference (p=0.004). Post hoc pairwise comparisons showed that the ACB group had significantly less increase in pressure pain threshold (ie, was more pain sensitive) compared with the ACB+LC SNB group (p=0.028) and the ACB+HC SNB group (p=0.001). There was no significant difference in increase of pressure pain threshold between the ACB+LC SNB and ACB+HC SNB groups (p=0.306). Supplemental findings of group comparisons of block-induced increase in pressure to produce 4, 8, and 10/10 pain are reported in online supplemental appendix table B.
Supplemental material
Impact of blocks on pressure pain threshold. Pain threshold pressures were compared before and after ACB, ACB +LC SNB, and ACB +HC SNB in the same leg, allowing calculation of the increase in cuff pressure to reach 6/10 pain. (A) Comparison of increase in pressure pain thresholds between groups. Each circle represents an individual participant, with bar height showing group mean and error bars SD. (B) Kruskal-Wallis test was used to compare the extent of increase in pressure pain threshold between groups. ACB, Adductor canal nerve block; ACB +LC-SNB, Adductor canal nerve block with low-concentration sciatic nerve block; ACB +HC-SNB, Adductor canal nerve block with high-concentration sciatic nerve block.
Effect of nerve blocks on prolonged pressure ischemic pain
In all three block groups, decreased pain scores were reported in the block leg compared with the control leg during prolonged/ischemic pain holds (figure 3). Our main secondary outcome was a comparison between the three groups on the average pressure pain reported during the 6/10 pressure hold in the presence of a block. We observed significant between-block-group differences in the average pain scores (4.2±1.4, 1.4±1.7, 0.4±0.7, p<0.001) (figure 4). Post hoc pairwise comparisons showed a significant difference in average pain scores between the ACB and ACB +LC SNB (p<0.001), and the ACB and ACB +HC SNB (p=0.001), but not between the ACB +LC SNB and ACB +HC SNB (p=0.21). Supplemental findings of group comparisons of pain scores at the 4, 8, and 10/10 holds are reported in online supplemental appendix table C.
Pain scores during prolonged cuff pressure/ischemic holds. Participants rated pain during 5 min sustained leg cuff pressure holds at the pressure needed to induce 4,6,8, and 10/10 pain at baseline, and rated pain every 30 s. Graphs show group mean and SD. Average difference between blocked and unblocked condition, and results of within subject paired t-test are shown for each block type and targeted pain level. ACB, Adductor canal nerve block; ACB +LC-SNB, ACB with low-concentration sciatic nerve block; ACB +HC-SNB, ACB with high-concentration sciatic nerve block.
Impact of Blocks on Prolonged Pressure/Ischemic Pain: Group comparisons. Participants rated pain every 30 s during a 5 min hold at the pressure needed to induce 6/10 pain at baseline, and average pain across 5 min was calculated.(A) Comparison of average pain in the blocked leg during a prolonged pressure/ischemic hold between groups. Each circle represents an individual participant, with bar height showing group mean and error bars SD. (B) Kruskal-Wallis was used to compare pain scores between groups. ACB, Adductor canal nerve block; ACB +LC-SNB, Adductor canal nerve block with low-concentration sciatic nerve block; ACB +HC-SNB, Adductor canal nerve block with high-concentration sciatic nerve block.
Discussion
In this human volunteer study, we sought to assess the influence of varying peripheral nerve block types and local anesthetic concentrations on pressure and ischemic pain in the leg. Our results suggest that ACB alone results in a small increase in the pressure pain threshold and decrease in ischemic pain. The addition of a low-concentration sciatic block further increased pressure pain threshold and decreased ischemic pain substantially more than ACB alone, as did addition of a high-concentration (full-strength/surgical) sciatic block.
The systematic investigation of these various block combinations allowed quantitative distinction of the analgesic effect of ACB (pain scores decreasing by about one point compared with baseline, which may be considered clinically significant),18 supporting the hypothesis that ACB alone provides mild pain relief in the lower leg. Since AECS is difficult to study in a clinical setting, and literature about AECS pain breaking through RA is limited to case reports, we believe that these findings in a human experimental model provide insight into the variable effects of different applications of RA on pressure and ischemic pain. In the case of AECS, most commonly occurring in the anterior compartment (de facto anterolateral), innervation is provided predominantly by the sciatic nerve. In addition, however, the saphenous nerve provides sensory innervation to the skin and subcutaneous tissues of the anteromedial aspect of the leg down to the ankle and foot, including partial innervation of the periosteum in the area of the medial malleolus. Therefore, while a dense SNB may significantly alter the clinical presentation of AECS, blocking the saphenous nerve should provide analgesia without altering AECS presentation. Although there appeared to be a graphical trend toward relatively larger impact on both pressure pain threshold and prolonged pressure/ischemic pain in the HC-SNB than the LC SNB, these were not statistically different. These differences appeared greater at the highest tested pain levels (pressure to induce 10/10 and ischemic holds at this pressure, online supplemental appendix tables B and C), potentially suggesting that the most severe pain, as would occur with AECS, would in fact break through a milder, low-concentration SNB faster than through a high-concentration SNB, but future studies with a larger sample size and broader range of local anesthetic concentrations are needed to explore this. The clinical relevance of these findings is that low-concentration nerve block is less likely to obscure AECS than a high-concentration nerve block, while still providing relief from pressure and ischemic pain.
The mechanism of ischemic pain remains poorly understood, although it is thought to be more similar to visceral pain than cutaneous incisional pain.19 Afferent fibers that detect ischemic metabolites in muscle tissue20 also carry deep tissue pressure sensation and have been shown to be poorly blocked with conventional peripheral nerve blocks,21 especially in the case of acidosis.20 22 While it is unlikely to completely block ischemic pain, RA is an effective tool to reduce acute pain and opioid administration after lower extremity fracture and surgery4 23 24 and may also impact the development of chronic postsurgical pain.25 26 Despite the drawbacks of frequent clinical examination or compartment pressure measurement in at risk patients,7 their use is likely superior to a reliance on pain as a clinical sign. Taken together, clinical practice guidelines and case reports suggest that vigilance and possibly using other methods of diagnosing AECS, rather than avoidance of a certain type of analgesia, is required to protect patients. A risk–benefit discussion about use of RA between the surgical and anesthesia team should be employed in patients with lower extremity fractures and high clinical suspicion for AECS.27
Limitations
Ethical and practical considerations limited us to a relatively brief, external application of high pressure to induce pressure and ischemic pain, and thus, the stimuli used in this experimental model of AECS are different in nature, timing, and sense of control to the insidious onset of pressure experienced clinically with AECS. As a healthy volunteer study, self-selection bias was likely present in our volunteer subjects, given that they were willing to receive a nerve block, potentially representing a group of individuals who were less anxious and more pain tolerant. Another limitation of the study was that only two concentrations of the shorter-acting mepivacaine were tested, again for practical reasons. We extrapolate that these doses are the equivalent of 0.375% and 0.1% bupivacaine,28 but future testing of local anesthetics that are more commonly used (bupivacaine), as well as lower concentrations of LA, is needed to explore an optimal balance of provision of analgesia and retention of ischemia detection.
Conclusion
Experimentally induced pressure and ischemic pain were inhibited by all block types, but the degree of block of ACB alone was significantly less than when either the low- or high-concentration SNB was added. At higher levels of induced pain, a trend toward greater separation of analgesic effect was observed between the low and high-concentration sciatic block conditions, but this was not statistically significant. The extent to which either of these block modifications could reduce delay in detecting a rapid AECS-related increase in pain in clinical practice remains unknown. Future clinical studies employing graded degree of neural blockade in patients with lower extremity fractures, occurring over the longer period (days) of clinical care, are needed to assess the clinical utility of such block modifications.
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
Written and informed consent were obtained from each participant. This study was conducted between October 2020 and April 2021 at Brigham and Women’s Hospital in Boston, Massachusetts, USA.
Acknowledgments
James Gosnell and Svetlana Gorbatov contributed to initial screening of participants.
References
Footnotes
Twitter @Jose_L_Zeballos
Contributors Y-YKC: funding acquisition, study conception and design, investigation, data collection, data curation, analysis and interpretation of results, draft manuscript preparation (writing—original draft and writing—review and editing), data visualization. PL: study conception and design, data collection, investigation, manuscript preparation (writing—original draft and writing—review and editing). KMF: study conception and design, data collection, data curation, analysis and interpretation of results, draft manuscript contribution (writing—original draft and writing—review and editing), data visualization. CAC: study conception and design, data collection, data curation, draft manuscript preparation (writing—review and editing). JMW: draft manuscript preparation (writing—original draft and writing—review and editing). JZ: study conception and design, draft manuscript preparation (writing—review and editing). AVK: draft manuscript preparation (writing—original draft and writing—review and editing). KEB: draft manuscript preparation (writing—review and Editing). KV: study conception and design, draft manuscript preparation (writing—original draft and writing—review and editing). KLS: study conception and design, investigation, data collection, analysis and interpretation of results, draft manuscript preparation (writing—original draft and writing—review and editing), supervision, guarantor.
Funding This study was supported by Brigham and Women’s Hospital Department of Anesthesiology, Perioperative and Pain Medicine Seed 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.