A continuous peripheral nerve block (CPNB) consists of a percutaneously inserted catheter with its tip adjacent to a target nerve/plexus through which local anesthetic may be administered. Such a “perineural local anesthetic infusion” provides a prolonged peripheral nerve block that may be titrated to the desired effect.1 In the decades after its first report in 1946,2 a plethora of data relating to CPNB was published, much of which was examined in a 2011 Anesthesia & Analgesia review.1 The current update is an evidence-based review of the CPNB literature published in the interim. Because of publication limitations, the majority of information—including 364 citations—included in the previously published review is not repeated here.1 Consequently, the current update is most likely best utilized in concert with the previous review article to provide a complete overview of CPNB. Because there are literally thousands of CPNB-related publications, only those that provide the highest quality data (eg, randomized controlled trials [RCTs]) and/or are the most influential (eg, unique case reports and observational studies) are included.
In addition, a variety of novel, alternative analgesic modalities are currently under development/testing. These techniques are also reviewed and compared/contrasted with CPNB.
INDICATIONS AND INSERTION LOCATIONS
The overwhelming majority of recently published CPNB data involves providing analgesia after surgical procedures. Noteworthy exceptions include case reports/series using CPNB to treat chronic pain such as cancer-related pain,3–8 complex regional pain syndrome,9–12 ischemia-induced pain,13,14 ulcer-derived pain,15 and phantom limb pain (Table 1).16–18 Regarding the latter, the only available randomized data come from a very small pilot study (n = 3) but does strongly suggest that further research is warranted.19 Another randomized, placebo-controlled pilot study (n = 4) provides evidence that a 3-day, continuous interscalene nerve block dramatically improves shoulder range of motion both during and up to 12 weeks after manipulation for adhesive capsulitis.20 Also noteworthy, continuous paravertebral21–23 and intercostal24–26 catheters have been used to treat pain after traumatic rib fracture; and a randomized pilot study (n = 30) detected no differences between this CPNB technique and a thoracic epidural infusion with the exception of a greater incidence and degree of hypotension using epidural analgesia.27 Lastly, continuous transversus abdominis plane (TAP) and femoral blocks have been used to treat abdominal wall pain during pregnancy28 and femur fracture pain,29,30 respectively.
Recently, case reports and small series using CPNB to induce sympathectomy to improve transplantation success have been published.31,32 Similarly, a number of reports have been published, involving the use of continuous TAP blocks to treat postoperative pain after hernia repair,33 renal transplantation,34 and abdominal procedures.35 Unfortunately, this catheter location remains unvalidated with the only (negative) randomized, placebo-controlled trial underpowered (n = 20),33 and a different RCT comparing TAP and epidural catheters for upper abdominal surgery designed as a superiority trial yet detecting few differences between treatments (therefore, inconclusive).36 Bilateral continuous paravertebral blocks have also been used for abdominal surgery in the presence of mild coagulopathy instead of an epidural because of concern of epidural hematoma formation.37
Novel insertion sites include catheters adjacent to the lesser palatine,38 ulnar,39 superficial peroneal,40,41 and deep peroneal nerves.40 New interfascial catheter sites have also been described: interpectoral42,43 and quadratus lumborum44–46 for breast and abdominal analgesia, respectively.
However, adductor canal catheters are by far the most examined and potentially influential anatomic site described recently (Table 1).47 The adductor canal is an aponeurotic tunnel in the midthird of the thigh deep to the sartorius muscle that contains multiple afferent nerves innervating the knee, yet only a single efferent nerve innervating the medial part of the quadriceps femoris muscle.48,49 Therefore, local anesthetic administered in the canal induces dramatically less quadriceps weakness compared with deposition adjacent to the femoral nerve at the inguinal crease.50 Reflecting the concern regarding the association between continuous femoral nerve blocks and both falls51–56 and physical therapy limitations,57,58 adductor canal perineural infusion has garnered strong interest.59,60 Although this catheter site has been validated with a number of randomized, placebo-controlled trials,47,61–65 multiple issues remain in dispute66–71 or are unclear/unknown72,73 such as the relative analgesia afforded compared with a femoral infusion (see the following section on benefits).50,57–59,74
Although RCTs involving surgical pediatric populations remain the exception,75,76 series of patients continue to be published.77–83
Before the advent of ultrasound-guided regional anesthesia, CPNB-related clinical investigation focused on comparing nonstimulating and stimulating catheters inserted through an insulated needle used to localize a target nerve/plexus.84,85 With the subsequent widespread adoption of ultrasound to place a needle adjacent to a target nerve/plexus, the emphasis has shifted to comparing needle/catheter insertion using ultrasound versus electrical current.86 Since publication of the previous CPNB review,1 the preponderance of new evidence suggests benefits nearly exclusively in favor of catheter insertion using ultrasound guidance compared with electrical stimulation (passed via either the needle or the catheter). Catheter insertion success is higher using ultrasound guidance compared with nerve stimulation for most insertion sites, yet requires less time for placement, induces less procedure-related discomfort, and carries a lower risk of vascular penetration.87
The data are somewhat conflicting on whether catheters inserted using ultrasound guidance provide superior analgesia during the perineural infusion itself.87–92 Regarding this issue, the highest quality data are derived from an RCT involving over 450 subjects randomized to 3 different femoral catheter insertion techniques.93 Using electrical current to guide the inserting needle and/or stimulating catheter failed to provide superior analgesia or decrease opioid requirements (and vice versa). In addition, using electric current with either the needle or the catheter required a longer insertion time and ultimately proved more costly. With the number of CPNB-related RCTs involving nerve stimulation appearing to fall precipitously within the past few years,14,94–99 it subjectively appears there is now some consensus emerging regarding the ultrasound-versus-stimulation debate.86 Nonetheless, using electric current to supplement ultrasound guidance for difficult to visualize (eg, deep)100 or ambiguous (eg, inexperienced practitioners) neural targets may prove beneficial in challenging cases.1
Few RCTs have been published—recently or otherwise—to help guide practitioners regarding the specifics of ultrasound-guided catheter insertion.1,101,102 For example, imaging the target nerve in the short axis (a cross-section) is far easier103 and decreases total insertion time compared with imaging the long axis103,104; and nearly all publications report this transducer-to-nerve orientation. However, catheters may be inserted through a needle introduced either parallel or perpendicular to the target nerve.105 Few RCTs compare these “in-” and “out-“of-plane techniques106; and of those that do, results may agree (femoral)103,104 or conflict (interscalene).107,108 Although publication limitations of this review article preclude an in-depth discussion of these issues,109 readers are referred elsewhere for related information.105,110
Technologic innovations of the past few years offer possible improvements in CPNB application110 and include self-coiling catheters that curl immediately on exiting the needle, theoretically decreasing the catheter tip-to-nerve distance111–113; a catheter attached to a needle that is passed adjacent to the target nerve and then exited out of the body on the other side of the transducer (remaining in plane the entire trajectory)114,115; a 6-hole catheter to theoretically improve local anesthetic spread (failed in 1 RCT)116; a perineural catheter that is introduced over an insertion needle to theoretically decrease the incidence of leakage (similar to an intravenous catheter)30,117–120; and a novel needle-over-cannula set to also decrease leakage (successful in 1 RCT).121
Because flexible perineural catheters usually deviate from the ultrasound plane of view after exiting a rigid in-plane needle, evaluating the crucial catheter tip-to-nerve distance can be difficult.87 Various investigators have injected—under real-time ultrasound visualization—fluid, an agitated air/fluid admixture, or a small volume of air, although the relative benefits of each were previously uninvestigated.1 The “air test” was recently evaluated within a porcine–bovine model, but unfortunately there was no benefit over simply visualizing the catheter without air injection.122,123 Attempts to improve the echogenicity of perineural catheters have been somewhat equivocal124,125 with 1 RCT detecting no differences in visibility between the experimental echogenic and the standard stimulating catheters.126 Although visualizing catheter tip location using 3-dimensional ultrasound127,128 and catheter stylet “pumping” combined with color Doppler are promising techniques,129 neither has been validated.110
Long-acting local anesthetic remains the primary analgesic infused during CPNB,1 and there is minimal new information to help guide clinical practice: data suggest that ropivacaine, bupivacaine, and levobupivacaine provide similar analgesia130 with the main differences being ropivacaine’s shorter duration of action—presumably allowing easier titration yet added expense (at least within the United States).1 New data do support previously available evidence1 that total dose and not concentration/volume is the primary determinant of clinical effects for continuous interscalene,131 femoral,132 posterior lumbar plexus (psoas compartment),133 and popliteal sciatic nerve blocks134; although it remains unclear whether this relationship is valid for other brachial plexus,1 adductor canal,57,58 TAP, and paravertebral perineural infusions.135
Although there is recently published preclinical evidence involving perineural pregabalin infusion136 as well as the addition of clonidine, dexamethasone, and buprenorphine to perineural bupivacaine in a rat model,137 these data are preliminary and there remains no medication other than local anesthetic approved for continuous perineural administration by the US Food and Drug Administration (FDA).1 Randomized, controlled clinical trials have failed to detect benefits of adding clonidine or epinephrine to perineural infusions.1 There are sporadic RCTs reporting benefits of various opioids in a perineural infusion14,138–141; however, all but 1140 lacked an active systemic control group, precluding any determination on the importance of perineural (vs intravenous) administration. Unsurprisingly, the addition of opioids often resulted in an increased incidence of opioid-related side effects.14,139 Regardless, considering the absence of safety data,142 a dearth of evidence of perineural efficacy, reports of unacceptable side effects,14,139 and lack of Federal regulatory approval,143 no adjuvants can be recommended at this time; and CPNB with solely local anesthetic remains the infusate by general consensus as judged by published reports of the past 2 decades.1
LOCAL ANESTHETIC DELIVERY REGIMENS
The RCTs published in the past few years have done little to clarify the optimal mode of delivering perineural local anesthetic: as exclusively a basal infusion, solely repeated bolus doses, or a combination of the 2.1 A large body of relatively older evidence suggests that providing a basal infusion improves baseline analgesia, decreases the incidence and severity of breakthrough pain, and decreases sleep disturbances and supplemental analgesic requirements for interscalene, infraclavicular, subgluteal, and popliteal sciatic infusions.1 In contrast, recently published data indicate that few benefits—if any—are afforded with a basal infusion, as opposed to repeated boluses for catheters in these anatomic locations (Table 2).94,144–147 Contrary new data also exist for femoral CPNB: although previous data suggested that the delivery mode is irrelevant for femoral infusions,1 a recent RCT suggests that including a basal infusion improves analgesia for this catheter site.95
The conflicting results are most likely due to the heterogeneity of catheter designs (eg, nonstimulating vs stimulating), catheter insertion techniques (eg, ultrasound vs stimulating vs a combination), local anesthetic type (eg, ropivacaine vs bupivacaine) and concentration, basal infusion rates, bolus volumes, lockout times, surgical procedures, outcome measures evaluated, measurement sensitivity, and a multitude of other factors. Consequently, there is no evidence-based “ideal” delivery regimen,148 although investigators have provided clinical recommendations.143,149 Nevertheless, there are some clinical situations in which including bolus doses are theoretically beneficial such as to enable block reinforcement before potentially painful dressing changes150 or physical therapy.20 Virtually all RCTs providing patient-controlled boluses to 1 treatment group report a lower local anesthetic requirement, suggesting 3 possible benefits: (1) theoretically decreasing motor block by decreasing the required basal infusion rate (inadequately investigated to date)51,151,152; (2) decreasing the incidence of an insensate extremity153; and (3) increasing infusion/analgesia duration for outpatients discharged with a fixed local anesthetic reservoir volume.154,155
One technique variation has recently garnered increased interest: the use of mandatory/automatic bolus doses based on the theory that increasing the volume of local anesthetic introduced at a single time point might improve perineural spread compared with an equivalent volume/dose provided as a basal infusion.13 Continuous adductor canal blocks appear to require a higher basal rate of local anesthetic than their femoral counterparts; and a recent study demonstrated that even with a relatively high rate of 8 mL/h, local anesthetic spread remains somewhat limited.156 A subsequent investigation involving healthy volunteers found sensory perception and quadriceps femoris strength equivalent when administering ropivacaine 0.2% at 8 mL/h as either a continuous basal or hourly bolus doses.144 Similar results were reported for interscalene,145 femoral,152 and popliteal catheters.157 It would therefore be understandable to discount the concept of repeated bolus doses, except a new RCT did find analgesic benefit after thoracotomy in administering a relatively large volume of levobupivacaine (15 mL) via paravertebral catheters once every 6 hours compared with a continuous infusion.158 Although this study was somewhat confounded by the use of 2 different concentrations of levobupivacaine, it does raise the possibility that the strategy previously used—a repeated hourly bolus equivalent to the volume from 1 hour of a basal infusion comparator—could be improved by scheduling larger bolus volumes over a longer period of time. Additional investigation at other catheter sites and administering a higher volume of local anesthetic is required (ClinicalTrials.gov, NCT02662023 and NCT02539628).
Lastly, evidence accumulates that prolonged ropivacaine infusions—even at relatively high doses >40 mg/h—have an extraordinarily low incidence of inducing toxicity signs, symptoms, or plasma levels.159
PORTABLE INFUSION PUMPS
Little has changed regarding portable infusion pumps since they were last reviewed1,149,160 with 3 exceptions. First, more disposable pumps now allow a similar ability to adjust basal rates, bolus volume, and lockout times compared with their electronic, programmable counterparts.161 Second, a number of portable pumps now have the capability of delivering repeated bolus doses at intervals set by the provider.144 How useful this capability will prove to be remains under investigation (see the previous section).13 However, the development with potentially the most influence on clinical care is the new ability of health care providers to remotely communicate directly with electronic infusion pumps via the Internet.162 In a prospective cohort study of 59 hospitalized subjects undergoing CPNB over approximately 3 days, investigators were alerted by text message when the need for pump changes arose because of an insensate extremity, muscle weakness, or difficulty during physical therapy. The infusion pumps would query subjects and, based on the responses, then communicate directly with health care providers who could remotely control the device. The mean (standard deviation) time for pump setting adjustment from the initial alert was 15 (2) minutes with no associated adverse events, demonstrating at least the feasibility of this technique.
AMBULATORY PERINEURAL INFUSION
In contrast to the topic of portable infusion pumps, research involving ambulatory CPNB has been relatively prolific in recent years.4,6,7,19,23,33,78,79,116,153,163–175 Originally, the objective of ambulatory perineural infusion was to simply improve analgesia for patients who were never intended to be hospitalized overnight.149,155 Because enhanced pain control and its many derived benefits have been well documented in earlier RCTs (reviewed previously),1 nearly20,33,167,173,176,177 all recent investigation has centered on describing new applications or complications,4,6–8,19,23,171,174,175 optimizing perineural techniques (few major revelations),14,116,160 and reporting large series of cases (including over 1600 pediatric patients).78,79,165,168,169,178 Although most series were retrospective in design, 1 large multicenter effort prospectively enrolled over 1500 patients receiving ambulatory continuous interscalene nerve blocks at home.168 This study documented relatively few CPNB-related complications after discharge with a 1.5% catheter dislodgement rate and no catastrophic incidents. Whereas major problems outside the hospital are very rare,174 they can prove more challenging to treat than in hospitalized patients.171,174,179,180
However, with the collective experience and thousands of published cases in the past 15 years, the main arguments against ambulatory CPNB has shifted from a lack of validation and the risks of complications181 to instead the challenges of setting up and running an effective ambulatory service (“perineural catheter analgesia as a routine method after ambulatory surgery: effective but unrealistic”).182,183 This view is countered by others who contend that “rather than dismissing these techniques as too difficult, and settling for an unsubstantiated (but probably ineffective) alternative [wound infusion], future research should focus on facilitating the uptake of perineural infusions….”184 Indeed, there are published accounts specifically addressing practitioners’ successes185 and challenges186 in developing and implementing ambulatory infusion programs.172,187
A second goal of ambulatory infusion eventually developed: using improved pain control to allow patients—who would be expected to remain in the hospital—to be instead discharged earlier than otherwise possible.188,20,175 Theoretical benefits include improved patient satisfaction, decreased risk of nosocomial infection and health care provider error, and decreasing health care-related costs.170,189,190 Although multiple RCTs demonstrate that ambulatory CPNB reduces the time until discharge readiness,1 only 2 have demonstrated a shortening of actual hospitalization duration.191,192
Nevertheless, with interest growing in the “perioperative surgical home,” ambulatory CPNB is being viewed as a possible enabling intervention.193 One recent example is an investigation that randomized subjects (n = 38) undergoing complex arthroscopic elbow surgery accompanied by a 60-hour continuous infraclavicular (brachial plexus) nerve block to either remain hospitalized for the 3-day standard of care or be allowed discharge as early as the morning after surgery (Table 3).173 Both groups underwent continuous passive motion of the elbow for 14 days, and subjects discharged early had similar elbow range of motion after 2 weeks and 3 months compared with patients remaining hospitalized for at least 3 days. Furthermore, there were no statistically significant differences in pain scores, opioid requirements, patient satisfaction, and function-related questionnaires. Importantly, the cost of care for subjects remaining hospitalized was greater than for those allowed early discharge. Although there remains debate as to the significance of the degree of savings (15%),193 these data are supported by an additional clinical trial that permitted a total avoidance of hospital admission.194 This second investigation randomized subjects (n = 120) with a continuous popliteal nerve block having major orthopedic foot surgery to be discharged either after surgery or remain hospitalized for 2 nights (Table 3).194 Total costs of care were decreased 79% in the early discharge group, and no other differences between treatments were detected, including pain scores, complications, and readmission rates. These savings are not applicable to practices within the United States because the surgical procedures under investigation—osteotomies and hallux valgus corrections—are already nearly exclusively performed as outpatients procedures, regardless of the presence of CPNB. However, the strong interest in these investigations may be an indication of the direction ambulatory infusion research—and practice worldwide—will take over the coming decade.
Novel indications for CPNB have been published within the past few years, suggesting benefits for an even wider array of morbidities.13,15,20–24,28–36,47,61–65 New RCTs have provided evidence that adding a perineural infusion after a single-injection peripheral nerve block improves postoperative analgesia (and in most cases decreases supplemental analgesic requirements) using interscalene,163,176,195 paravertebral,167 adductor canal,47,61–65 femoral,196–199 and sciatic catheters (Table 3).96,97,200,201 Compared with epidural infusions,202 CPNB provides similar analgesia203 but improves hemodynamic stability (presumably by inducing less sympathectomy)27,204,205 and after knee arthroplasty shortens the time to achieve flexion goals, improves analgesia, and lowers supplemental analgesic requirements.198 Compared with intrathecal morphine, continuous posterior lumbar plexus blocks provide similar analgesia with lower supplemental opioid requirements and incidence of pruritis.206 Data continue to accumulate, demonstrating that CPNB provides superior analgesia compared with continuous wound infusions.99,207,208
Because of the association between continuous femoral nerve blocks and falling after knee arthroplasty,51,52,54 the past 5 years have seen a plethora of research validating adductor canal catheter effectiveness after major knee surgery47,61–65 based on the theory that any risk of falling will be decreased because of less induced quadriceps weakness compared with femoral infusion (Table 3).50,59 Of the 6 RCTs directly comparing continuous adductor canal and femoral nerve blocks,50,57–59,74,209 3 demonstrated dramatic improvements for subjects with adductor catheters in the ability to stand, sit, ambulate, and climb stairs.50,57,58,74 One study did not investigate ambulation209; but the 2 remaining RCTs failed to detect mobilization improvements using an adductor infusion—although they did document and quantify improved quadriceps femoris strength (52% vs 18% of baseline in one).50,59 It is noteworthy that these 2 latter studies provided solely a fixed basal infusion (8 mL/h) without either patient-controlled or repeated provider-administered bolus doses,50,59 which may have decreased adductor infusion effectiveness. In addition, 2 of the RCTs detected improved analgesia for subjects with femoral infusions at either rest (unicompartment arthroplasty)57 or with movement (tricompartment arthroplasty),58 whereas others failed to detect differences between the 2 catheter locations. Lastly, 1 of the investigations reported a decreased time until discharge favoring the adductor catheters (3.1 vs 3.9 days),74 although there were issues raised regarding its protocol/findings66–68 and a similar RCT detected no decrease in time until discharge readiness or actual discharge,58 albeit with slightly different criteria. What does appear likely is that continuous adductor canal blocks are associated with greater mobilization ability while providing similar analgesia compared with their femoral counterparts.60 What remains unclear is the ideal catheter insertion location/protocol,70,71 optimal method of local anesthetic delivery (eg, basal infusion vs repeated bolus doses, basal rate, bolus volume), and if an optimized delivery regimen can shorten hospitalization duration.144,210,211
In an effort to further improve analgesia after total knee arthroplasty,212,213 3 recent RCTs have investigated the effects of adding a continuous sciatic nerve block to a continuous femoral or posterior lumbar plexus (psoas compartment) block.96,97,201 All demonstrated lower pain scores and decreased supplemental analgesic consumption,96,97,201 and 1 detected a lower incidence of nausea and vomiting as well as improved knee flexion and ambulation.201 As has been previously opined, there are potential drawbacks to providing a continuous sciatic nerve block such as the extra time required to place a second catheter, an inability to fully evaluate sciatic nerve function postoperatively,214 and interference with physical therapy goals (eg, foot drop, leg weakness).215
Although there are relatively few demonstrated benefits of CPNB after catheter removal,1 there are significant additions to our knowledge base within recently published data. Two RCTs found that a 2- to 3-day postoperative continuous interscalene or femoral nerve block resulted in less pain,176,216 opioid requirements,176,216 and sleep disturbances176 on postoperative day 7 compared with a control group after shoulder and knee procedures, respectively. Similarly, 2 RCTs add to the previous evidence that a continuous femoral nerve block after total knee arthroplasty improves joint flexion for up to 6 months.198,216
However, it is the possibility of decreasing persistent postsurgical pain that has perhaps garnered the most attention and optimism.217,218 Four new RCTs add data to the single previous positive study that involved the addition of a femoral catheter to a popliteal infusion for major ankle surgery.219 One study reported that providing a continuous femoral nerve block after total knee arthroplasty reduced chronic pain at 3 and 6 months,216 and another involving the same surgical procedure found that providing a continuous sciatic nerve block in addition to a femoral infusion resulted in a reduction of dynamic pain at 3 months (no difference at 12 months for either trial).220 Finally, 2 RCTs investigating continuous paravertebral blocks after mastectomy detected improvements in analgesia up to a full year after surgery,177,221 including superior physical and mental health-related quality of life221 and decreased pain-related physical and emotional dysfunction.177
Probably the largest change in the CPNB literature of the past 5 to 6 years is the proportion of reports involving ultrasound guidance versus nerve stimulation with the former now eclipsing the latter to an overwhelming degree. This is undoubtedly multifactorial; but a predominant reason is probably that the risk of inaccurate and/or difficult catheter insertion is, on average, decreased with the use of ultrasound guidance.1,87 However, the incidence for all CPNB-related complications can vary dramatically, most likely because of heterogeneous catheter insertion equipment, techniques, anatomic locations, and infusion protocols. For example, the reported frequency of catheter failure over the past few years varies between 0.5% and 26%.79,222 Accordingly, precise complication rates will not necessarily be widely applicable. This section reviews reports of adverse events published since the previous review article,1 and readers are directed to that report for a complete examination of all possible complications.
Relatively few complications during insertion have been reported in recent years, perhaps because of the widespread adoption of ultrasound guidance (or possibly because all the adverse events had been previously published). However, new cases do include the inadvertent penetration of the epidural space113,223 and a catastrophic incident involving an unidentified intrathecal placement bolused on the wards.224,225 In addition, a single report describes the potential contamination of the surgical site caused by leakage from an interscalene catheter with the patient in a seated position.226 In contrast, reports of adverse events occurring during infusion are more common, including those reported previously such as hoarseness,227 dyspnea,169,228 and respiratory distress229 associated with continuous interscalene nerve blocks.168 Although 1 healthy-volunteer study reported a catheter dislocation rate of 25% and 5% for femoral and interscalene catheters, respectively, over a period of 5 hours,230 the incidence of dislodgement reported in both RCTs and large series is dramatically lower,77,168 even for ambulatory pediatric patients.79 Leakage at the catheter site continues to be an issue in a small minority of cases,79,168 but 2-octyl cyanoacrylate glue can decrease this problem by a factor of 10.231
One case report describes a patient with an ambulatory popliteal sciatic block who fractured a metatarsal 2 days into the infusion, which was recognized only after the catheter was removed the next day.174 In contrast, it is reassuring that there is 1 case of limb ischemia because of a surgically induced axillary artery injury and 3 reports of compartment syndrome all identified in a timely fashion by breakthrough pain not masked by the presence of a CPNB.232–235
Catheters have been accidentally cut during tunneling,236 suture removal,237 and for unknown reasons (most likely catheter withdrawal into the needle).238 Although it is common to leave a fractured epidural catheter remnant in situ, health care providers should be cognizant that many perineural catheters contain coiled wire, which is at risk for heating during subsequent magnetic resonance imaging.239 Catheter retention during withdrawal can also occur caused by a perineural loop,165 knot,240 kink,241,242 or adherence.171,179,243–247 Although multiple catheter designs have been involved with retained catheter reports,240,242 it is notable that within the past few years, 1 specific stimulating catheter (StimuCath; Teleflex, Morrisville, NC) has been overwhelmingly the predominant model described: 9 publications reporting a total of 18 separate cases.165,171,179,241,243–247 One investigator opined referring to these case reports, “While stimulating peripheral nerve catheters do have clinical utility, the expanding body of literature describing catheter entrapment is worrisome.”248
Regarding infusion-induced local anesthetic toxicity, both older1 and more recent evidence suggest that perineural infusion-induced local anesthetic toxicity is very rare.159,249 Similarly, major hematoma formation is extraordinarily infrequent and usually occurs in the presence of anticoagulation and/or comorbidity such as myeloproliferative thrombocytosis.250 There is limited new information regarding the concurrent use of anticoagulants and perineural catheters,251–253 and no new recommendations from the American Society of Regional Anesthesia and Pain Medicine have been published since the previous review article.254,255 Of note, some investigators have advocated replacing epidural with paravertebral or TAP catheters in certain situations256 based on the theoretical premise that a hematoma in the peripheral nervous system carries less risk of catastrophic nerve injury.35,37 Minimal information regarding CPNB-related infection has been published in recent years,77,79,168 other than the identification of diabetes and obesity as risk factors for catheter-associated infection257,258 and a few new cases of previously described related complications such as abscess formation.259–262 Of note, although the incidence of infection increases with infusion duration, there remains no “maximum” time period for a perineural catheter (although there are various regulations regarding the maximum duration of local anesthetic contained within a reservoir); and the longest reported infusion of 88 days was recently published.7
In contrast, there has been a significant amount of data published in the past few years involving neurologic risk in the presence of a CPNB.263 In most cases of postoperative neurologic symptoms (PONS), it is problematic assigning causality to the surgical procedure, CPNB, or simply perioperative injuries (eg, tourniquet or positioning injuries on an unrelated part of the body). Interpreting the available data is further complicated because of a lack of controls and/or randomization, which lead to multiple types of bias. An excellent example is a prospective, uncontrolled cohort study of patients with continuous popliteal sciatic nerve blocks (n = 151) after foot and ankle surgery reporting an alarming 41% incidence of PONS within 2 weeks, 24% at 34 weeks, and 4% after 48 weeks.264 A similar retrospective study (n = 157) found a 1.9% incidence of unresolved PONS at 11 months.265 These risks are an order of magnitude higher than previous estimates for popliteal infusions (0%–0.4%)266,267 and are most likely because of numerous biases, beginning with selection bias.
Another relatively new retrospective investigation of 1182 continuous interscalene and femoral nerve blocks identified 4 (0.3%) patients with PONS at any time point, with 1 of these cases resolving by 6 months.268 Of note, these investigators reported an increased incidence of PONS lasting >6 months among patients with continuous versus single-injection peripheral nerve blocks (0.24% vs 0.07%; P = .08).268 It is important to be aware of the very high risk of selection bias from this retrospective, nonrandomized cohort (eg, larger surgical procedures—with inherently higher neurologic risk—more represented in the catheter group). The most reliable, recently published data are derived from 2 prospective investigations of over 2500 interscalene and femoral catheters, reporting a PONS incidence of 4.9% to 5.3% resolving by 6 months with all but 0.3% to 0.7% of these resolving by 11 months.168,269 To emphasize, it is critical that practitioners are cognizant of the fact that these values approximate association and not necessarily causation: an unknown percentage of subjects with PONS would have experienced them without any regional analgesic because of the surgery itself or other factors. Unfortunately, the available data do not suggest that ultrasound guidance has a “meaningful impact on the incidence of PONS,” so switching from a different insertion technique is not expected to decrease the rate of PONS.270
The risk of falling after knee and hip arthroplasty has become better appreciated within the previous decade.271,272 Single-injection femoral nerve blocks do not appear to increase this risk273; but data from randomized, controlled trials suggest that a continuous femoral or psoas compartment block is associated with a 4 to 5 times increased risk of falling,51,54,274 although some investigators have questioned this correlation.275,276 Regardless of the relationship between CPNB and falls, this complication continues to occur even with the implementation of specific, intensive fall prevention programs.52,56,277,278 Although replacing continuous femoral nerve blocks with adductor canal infusions have been proposed as a method to decrease the risk of falling because of decreases induced quadriceps weakness,50,59 such an association has yet to be demonstrated.59,279
While perineural infusion has become accepted and now routine within anesthesiology, there are a number of novel, alternative analgesic modalities either currently available or under development/investigation. Although numerous analgesic possibilities are available,99,207,280–282 publication limitations prohibit inclusion of every option.182 The current article compares and contrasts 4 of the most novel analgesic alternatives to CPNB.
LOCAL ANESTHETIC ADJUVANTS
Single-injection peripheral nerve blocks have multiple benefits over their continuous infusion counterparts, including less time required for administration, management, follow-up; lower risk of infection; no risk of leakage, catheter dislodgement, or pump malfunction; and simply cost. Of course, the reason that CPNB is used despite these relative disadvantages is that the duration of treatment effects may be prolonged beyond the duration of a single-injection peripheral nerve block.1 However, a single-injection block with a similar duration to what is possible with CPNB would provide the benefits of a 1-shot block without the drawbacks of a perineural catheter and infusion.283 Toward this end, multiple medications—some in just the past few years—have been combined with (and without) local anesthetic, including opioids,284–287 clonidine,288,289 dexmedetomidine,290,291 dexamethasone,292–294 epinephrine, magnesium, midazolam, and tramadol.295
Unfortunately, most reported adjuvants prolong analgesia by fewer than 12 hours295,296 with even the most effective—buprenorphine and dexamethasone—reliably providing <24 hours of pain control.284–287,297 Many of the additives may increase the incidence of side effects such as pruritis,298 nausea/vomiting,287,298 hypotension,288 bradycardia,288,295 and sedation.288,295 Optimal doses remain unknown,299 and the risk of neurotoxicity remains a concern for multiple agents.295 Importantly, because systemic administration may result in similar or even superior300 prolongation of analgesic benefits versus perineural administration291,301–303—although there are exceptions286,304—and there is no adjuvant currently approved by the US FDA for perineural administration, the risk–benefit ratio of perineural administration remains in question at the time of this writing.
While there are no direct comparisons of CPNB and single-injection blocks including an adjuvant, it is unlikely that such studies will be conducted because most perineural catheters are inserted for use of at least 2 days,1 and no adjuvant given by any route of administration has been shown to reliably extend analgesia even 1 full day. The 2 techniques do not, in fact, “compete” but are instead complementary, depending on the desired duration of block effects.
LIPOSOME LOCAL ANESTHETIC
Liposomes consist of 2 hydrophobic tails and a hydrophilic head305 and can form vesicles to act as a medication “depot” (Figure 1).306,307 After administration, the liposomes gradually break down, resulting in an extended release of medication.308,309 Combining liposomes and a local anesthetic (lidocaine) was first proposed in 1979,310 initially used in humans in 1988,311 and first reported for postoperative analgesia in 1994.310,312 Although multiple subsequent reports were published,313–321 a liposome local anesthetic was not approved by the US FDA until 2011 (Exparel liposome bupivacaine; Pacira Pharmaceuticals, Parsippany, NJ) for administration at the surgical site to provide postoperative analgesia in adults.307
Two multicenter RCTs demonstrated superior postoperative analgesia of this approved medication compared with placebo wound infiltration after hemorrhoidectomy322 and bunionectomy.323 In contrast, when compared with bupivacaine HCl (“standard” bupivacaine), 10 of the 12 currently published RCTs were negative for their primary (and most secondary) analgesic end points.324–330 Of the 2 positive RCTs versus bupivacaine HCl, 1 involved hemorrhoidectomy,331 although another similar trial had negative results.324 The second positive RCT involved submuscular augmentation mammaplasty in which mean pain scores were reduced by <1 on the 0 to 10 numeric rating scale and the investigators concluded, “…it is our assertion that the additional cost of liposomal bupivacaine is unjustified for this particular use.”332 Some of these 14 RCTs were dose–response studies, not powered to be a conclusive test of efficacy; and when combined with the placebo-controlled trials, there were some detected positive associations for secondary endpoints such as pain scores at individual time points,333 opioid use (although differences were minimal),333 and duration until first use of opioid analgesics.324,333 However, considering the new medication costs an estimated 100 times that of bupivacaine HCl, it is incumbent on those proposing the conversion to produce data conclusively demonstrating superiority.330 Various large RCTs currently ongoing should provide much-needed data to help practitioners make evidence-based decisions involving this analgesic modality (ClinicalTrials.gov NCT02713490, NCT02111746, NCT02197273).
There are no RCTs directly comparing CPNB with liposome bupivacaine wound infiltration.334 The only direct comparison to a single-injection femoral nerve block after total knee arthroplasty suggests that liposome bupivacaine infiltration provides inferior analgesia during the duration of the peripheral nerve block without subsequent analgesic differences between the 2 treatments.335 Considering that there are now 4 negative published RCTs comparing liposome bupivacaine with bupivacaine HCl infiltration after total knee arthroplasty,324,326–328 and the literature is replete with positive studies involving CPNB,1 the evidence certainly does not suggest even equivalence between these 2 modalities.
In contrast to wound infiltration, recently published data from 1 RCT strongly suggest that liposome bupivacaine within a single-injection subcostal TAP block provides statistically and clinically superior analgesia to bupivacaine HCl up to 3 days after robotic-assisted hysterectomy.336 In a separate RCT, few differences were detected between a continuous subcostal TAP block and epidural infusion after open renal or hepatobiliary surgery,36 although this investigation was designed as a superiority study and the negative findings should be viewed as inconclusive and not equivalent. Therefore, a randomized comparison of a TAP with liposome bupivacaine bolus compared with either an epidural infusion or a perineural local anesthetic TAP infusion appears warranted.337,338 Of note, the US FDA recently revised the label for the single approved liposome bupivacaine formulation explicitly including, “infiltration into the transversus abdominis plane (TAP) which is a field block technique [is] covered by the approved indication for EXPAREL.”
Although no liposome local anesthetic is currently approved for use within the epidural space339 or peripheral nerve blocks, a great deal of related research has been completed (if not all published).307 Both preclinical toxicology and clinical data indicate that liposome bupivacaine has a safety profile at least as favorable as bupivacaine HCl.340–350 Although phase 1 to 3 clinical trials involving the use of liposome bupivacaine have been reported for intercostal and ankle blocks,306,307,340 the most published data may be found for femoral nerve blocks.351,352 No direct comparisons with CPNB are available, but liposome bupivacaine in a femoral nerve block produced over 72 hours of analgesia with an incomplete motor block in healthy volunteers351 and demonstrated analgesic activity for up to 72 hours versus placebo in subjects after total knee arthroplasty (albeit extraordinarily minimal analgesic differences after 24 hours).352 Further sizable RCTs involving adductor canal, brachial plexus, and femoral nerve blocks with liposome bupivacaine are ongoing (ClinicalTrials.gov NCT02607579, NCT02713230, NCT02713178).
Theoretical benefits over CPNB include the avoidance of catheter insertion (eg, less procedure time, no catheter management/removal), the lack of an infusion pump and anesthetic reservoir to purchase/carry, a lower risk of infection, and no risk of catheter dislodgement or leakage.353 It is emphasized that at the time of this writing, there are no liposome bupivacaine local anesthetics approved for use in the epidural space339 or peripheral nerve blocks (other than the possible exception of TAP blocks, depending on how this block is categorized).
Cryoneurolysis is the application of exceptionally low temperatures to reversibly ablate peripheral nerves, resulting in temporary analgesia termed “cryoanalgesia.”354 The first cryosurgical apparatus was described in 1961,355 and modern cryoprobes transmit a gas (usually nitrous oxide or carbon dioxide) at high pressure down their length, through a minute opening, and into the sealed distal tip at a lower pressure (Figure 2A).356 Explained by the Joule-Thomson effect, a large drop in temperature occurs when the gas moves from a high to low pressure inducing brisk expansion and absorption of heat.357 The gas is returned out of the body through a larger diameter (low pressure) cylinder in the middle of the shaft. This closed circuit ensures that all gas exits the body. The intense cold temperature at the probe tip produces Wallerian degeneration—a reversible breakdown of the nerve axon—subsequently inhibiting transmission of afferent and efferent signals. However, because the temperature resulting in irreversible degeneration—approximately −100°C—is colder than the boiling point of the gas (carbon dioxide: −79°C; nitrous oxide: −88°C), the remaining endoneurium, perineurium, and epineurium remain intact and the axon regenerates at a rate of approximately 1 to 2 mm/d.356
Cryoneurolysis has been used via the surgical incision to treat acute pain after thoracotomy,358–374 tonsillectomy,375 and herniorrhaphy.376,377 Alternatively, ultrasound may be used to guide378,379 a percutaneously inserted probe to a peripheral nerve to provide analgesia and has been described for various chronic pain conditions.380–385 The combination of ultrasound and newly designed, FDA-approved handheld cryoneurolysis devices386,387 may now make percutaneous cryoanalgesia a valuable postoperative analgesic alternative to CPNB (Figure 2B).354 The largest limiting factors when applying this technique to acute pain states are (1) the inhibition of efferent signals effectively paralyzing innervated muscles; and (2) the relatively unpredictable duration of action measured in multiple weeks and often months. Therefore, the modality has historically been used to target sensory-only nerves,388 although mixed motor–sensory nerves have been cryoablated to treat spasticity,389 and preclinical studies found no lasting changes to the structure or function of motor nerves after remyelination.386,387
Surgical procedures possibly amenable to cryoneurolysis include iliac crest bone harvesting (superficial superior cluneal nerves), total knee arthroplasty (anterior femoral cutaneous and infrapatellar saphenous nerves), various thumb surgeries (superficial branch of the radial nerve), rotator cuff repair (suprascapular nerve), and digit/limb amputations, among others.354,356 Although there are available cryoneurolysis devices currently approved by the US FDA for relief of pain, the use of cryoanalgesia to treat acute pain requires a great deal of further investigation with both RCTs and large series. It remains undetermined whether the duration of denervation can be shortened (eg, decreasing the freezing interval or number of cycles) and the incidence of adverse events such as neuralgias after thoracotomy.372–374 Direct comparisons with CPNB are unavailable, but some theoretical benefits of cryoneurolysis include an ultralong duration of action, no catheter management/removal, the lack of an infusion pump and anesthetic reservoir to carry, a lower risk of infection, and no risk of local anesthetic toxicity, catheter dislodgement, or leakage.
PERCUTANEOUS PERIPHERAL NERVE STIMULATION
Electric current applied in both the central and the peripheral nervous systems induces analgesia. There are numerous theories regarding the mechanism of action,390 but most are usually based on “gate control theory” by Melzack and Wall391: current activates large-diameter myelinated afferent peripheral nerves which then—within the spinal cord—impede pain signal transmission from small-diameter pain fibers to the central nervous system.392,393 Implanted spinal cord and peripheral nerve stimulators have since been used to treat multiple chronic pain states.394–398 In contrast, the use of peripheral nerve stimulation to treat acute/postoperative pain is extraordinarily rare,399–401 in no small part because of cutaneous pain fiber activation with transcutaneous electrical nerve stimulation392 and the invasive requirement of surgically implanting/removing peripheral nerve electrodes/leads.402,403
Electrical leads are now available with a diameter small enough to allow passage through a needle, allowing percutaneous insertion (Figure 3A).404–409 Precise placement is possible using ultrasound guidance410,411 and has been reported to treat chronic pain.412–415 More recently, postoperative pain was treated using ultrasound-guided percutaneous peripheral nerve stimulation.416–416c In one report, femoral—and in 2 cases sciatic—leads were inserted in subjects (n = 5) 8 to 58 days after total knee arthroplasty.416 Percutaneous peripheral nerve stimulation decreased pain an average of 93% at rest (reduced from a mean of 5.0 to 0.2 on a 0–10 numeric rating scale) with 4 of 5 subjects experiencing complete resolution of pain. During passive and active knee motion, pain decreased an average of 27% and 30%, respectively. Neither maximum passive nor active knee range of motion was consistently affected in this small cohort of subjects.
There are no direct comparisons with CPNB, but theoretical benefits of percutaneous peripheral nerve stimulation are numerous.416d Leads function optimally when inserted 0.5 to 3.0 cm from a target peripheral nerve, negating the importance of location within a particular facial plane. Electrical generators are now so minute that their footprint is smaller than a business card and may be literally adhered to a patient’s limb, so there is no large portable infusion pump or local anesthetic reservoir to carry (Figure 3B). Helically coiled leads are designed to minimize the risks of migration and fracture and decrease the infection risk to approximately 0.03 per 1000 indwelling days (or 1 infection for approximately every 33,000 indwelling days).416c These characteristics permit a dramatically long duration of lead retention—well over a year in some cases417–419—raising the possibility of preoperative insertion and continued postoperative stimulation for the entire interval of surgically related pain.417–421 There are theoretically no induced sensory, proprioception, or motor deficits, enabling full engagement in physical therapy and likely lacking any association with an increased falling risk. Obviously, there is no risk of local anesthetic toxicity or leakage. Conversely, practical implementation of percutaneous peripheral nerve stimulation to treat acute pain states is dependent on multiple factors that are currently undetermined: the time required for lead insertion, clinical efficacy and applicability, adverse event rate, the cost of leads and electrical generators, the maximum provided analgesia, and the future commercial availability of US FDA-approved equipment specifically approved for the treatment of acute pain.415,422
Although the recently published evidence presented in this review helps to clarify questions previously unanswered, many unknown aspects of CPNB persist. Although the data demonstrating perineural local anesthetic infusion’s many benefits continue to grow in quality, breadth, and depth, both older280,282,298,423 and novel307,352,354,424 analgesic alternatives must be considered and investigated. Only through persistent, unbiased investigation will we be able to optimize analgesia for patients, whether from CPNB or an alternative modality.425
The author thanks Elan Ilfeld for his rendering of Figure 2A, Haley Chung for her rendering of Figure 3B, and Anya Morgan, MA, research coordinator extraordinaire (University of California San Diego, San Diego, California) for her assistance with the myriad of articles used in this review.
Name: Brian M. Ilfeld, MD, MS.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Conflicts of Interest: Brian M. Ilfeld’s university has received research funding from Smiths Medical, Teleflex Medical, Summit Medical, Pacira Pharmaceuticals, Myoscience, SPR Therapeutics, and Infutronics. In addition, he was a consultant to Pacira Pharmaceuticals through March 2015.
This manuscript was handled by: Richard Brull, MD, FRCPC.
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