Novel Methodologies in

Regional Anesthesia for

K n e e A r t h ro p l a s t y
Rodney A. Gabriel, MD, MAS (Clinical Research),
Brian M. Ilfeld, MD, MS (Clinical Investigation)*

KEYWORDS
 Knee arthroplasty  Cryoanalgesia  Cryoneurolysis  Neuromodulation
 Peripheral nerve stimulation

KEY POINTS
 Combined with the rising expertise of ultrasound imaging among anesthesiologists, ubiq-
uitous availability of ultrasound devices, and availability of portable cryodevices, cryoanal-
gesia is now a realistic intervention for acute pain management.
 Although a single application of ultrasound-guided percutaneous cryoneurolysis provides
weeks to months of analgesia, careful selection of candidates is required given the poten-
tial prolonged motor block if mixed motor-sensory nerves are targeted.
 Ultrasound-guided percutaneous peripheral nerve stimulation offers a novel intervention
to provide post–knee arthroplasty analgesia without the major limitations of opioids and
continuous peripheral nerve blockade.
 Before ultrasound-guided percutaneous cryoanalgesia and percutaneous peripheral
nerve stimulation may be routinely practiced, robust clinical trials documenting their risks
and benefits in managing acute and subacute postoperative pain should be conducted.

Disclosures: R.A. Gabriel’s institution has received funding and product for his research from
Myoscience and Epimed; infusion pump manufacturer Infutronics; perineural catheter manu-
facturer Ferrosan Medical; and a manufacturer of a peripheral nerve stimulation device, SPR
Therapeutics. B.M. Ilfeld’s institution has received funding and product for his research from
Myoscience and Epimed; infusion pump manufacturer Infutronics; perineural catheter manu-
facturer Ferrosan Medical; a manufacturer of a peripheral nerve stimulation device, SPR Ther-
apeutics; and, manufacturers of long-acting bupivacaine formulations, Pacira Pharmaceuticals
and Heron Pharmaceuticals.
Department of Anesthesiology, University of California, San Diego, 200 West Arbor Drive, MC
8770, San Diego, CA 92103, USA
* Corresponding author.
E-mail address: bilfeld@ucsd.edu

Anesthesiology Clin 36 (2018) 387–401

https://doi.org/10.1016/j.anclin.2018.05.002 anesthesiology.theclinics.com
1932-2275/18/Published by Elsevier Inc.
388 Gabriel & Ilfeld

INTRODUCTION

Maximizing analgesia is critical following joint arthroplasty because postoperative pain

is a major barrier to adequate participation in physical therapy, which is in itself central
to optimizing functional recovery. Both single-injection and continuous peripheral
nerve blocks (PNB) provide pain control following knee arthroplasty1 and are
often considered the gold standard for postoperative analgesia.2 However, limitations
of these techniques have limited their general use,3,4 and alternatives could
improve the risk-benefit ratio and increase their application worldwide following
knee arthroplasty.
One of the major issues of local anesthetic-based analgesics is their duration
measured in only a few hours or days. The pain following total knee arthroplasty
(TKA) usually far outlasts this analgesic duration. The duration of continuous PNB
catheters is limited by the risk of infection and dislodgement.5 Perineural infusions
also induce motor, sensory, and proprioception deficits that potentially increase the
risk of falling.4 A further disadvantage of continuous PNB in ambulatory patients is
the burden of carrying an infusion pump and local anesthetic reservoir bag. Percuta-
neous cryoneurolysis and peripheral nerve stimulation (PNS) are two modalities
approved by the Food and Drug Administration (FDA) for use in treating acute pain;
yet they have been nearly absent from the acute pain literature.6–8 This article reviews
these analgesic methods and their application to acute pain states, specifically for
knee arthroplasty.

CRYOANALGESIA

Cryoanalgesia, also termed cryoablation, cryoneuroablation, or cryoneurolysis, is a

method in which peripheral nerves are reversibly ablated by extremely cold tempera-
tures leading to analgesia in the distribution of the nerve for multiple weeks to months.
It was first reported in 1961 using liquid nitrogen to create temperatures at 190 C to
ablate nerves.9,10 Lloyd and colleagues11 coined the term “cryoanalgesia” 15 years
later after describing its use for the management of pain. Since then, its clinical appli-
cation expanded mainly to treat various chronic pain conditions.12 In the few cases
cryoneurolysis was used to treat acute pain, it was almost exclusively applied intrao-
peratively by surgically exposing the target nerves and applying the cannula under
direct visualization.13–25 More recently, cryoneurolysis was administered using a blind
percutaneous approach using landmarks,18 and subsequently using a percutaneous
ultrasound-guided approach.6,7 Most studies have involved application to sensory-
only nerves. Although mixed sensory-motor nerve treatment was reported without
negative sequelae in preclinical26,27 and clinical28 settings, its safety and therapeutic
profile have yet to be determined with adequately designed and powered trials.
Mechanism of Action
The modern cryoprobe consists of a hollow tube with a smaller inner tube. Highly pres-
surized gas (usually nitrous oxide or carbon dioxide) travels from the proximal part of
the tube to its distal portion where it is released from a larger outer tube through a nar-
row annulus, allowing the gas to rapidly expand in the closed tip (Fig. 1). Because of
the Joule-Thompson effect, a drop of temperature to approximately 70 C accom-
panies the drop in pressure, creating an ice ball at the tip of the probe.29 The gas itself
is vented back proximally through the outer tube. This mechanism ensures that no gas
enters or remains in the patient’s tissues.
Wallerian degeneration (a breakdown of the axon) occurs distal to the point of treat-
ment, resulting in a complete sensory, motor, and proprioception conduction block.
 Regional Anesthesia for Knee Arthroplasty 389

Fig. 1. A cryoneurolysis probe produces extremely cold temperature at its tip because of the
Joule-Thomson effect, which results in gas flowing from a high to low pressure chamber.
(Courtesy of B. Ilfeld, MD, MS, San Diego, CA.)

Fortunately, at temperatures warmer than 100 C, the endoneurium, perineurium,

and epineurium all remain intact, permitting regeneration of the nerve of approximately
2 mm/d in a proximal-to-distal direction along the remaining nerve skeleton.12 Cryo-
neurolysis using nitrous oxide or carbon dioxide has inherent safety because the
freezing point of each is approximately 90 C and 80 C, and therefore each reaches
a solid state before reaching 100 C, which is associated with neural and stromal
destruction. Such extremely low temperatures can cause irreversible nerve injury,
potentially leading to neuroma formation.30

Application to Acute Pain

Until recently, cryoanalgesia for acute pain management has been limited to invasive
approaches that require surgical exposure of the target nerves.24,25,31 Most of these
examples target post-thoractomy pain, in which cryoanalgesia was applied to inter-
costal nerves by the surgeon intraoperatively.14–17,19,20,22,23 However, technical ad-
vances now allow percutaneous administration, specifically hand-held devices with
cryoprobes easily visualized with ultrasound-guidance and cleared by the FDA
(Fig. 2).29 Other portable devices exist that allow percutaneous administration with ul-
trasound guidance (Fig. 3). Combined with the rising expertise of ultrasound imaging
among anesthesiologists and ubiquitous availability of ultrasound devices, cryoanal-
gesia is now a realistic intervention for acute pain management. Advantages over
continuous PNB techniques include longer duration with a single application; avoid-
ance of the risk of local anesthetic toxicity; theoretically decreased risk of infection;
a lack of infusion pump malfunction, catheter migration/dislodgement, and leakage

Fig. 2. A hand-held cryoneurolysis device with a 5.5-cm, 22 cryoprobe. (Courtesy of B. Ilfeld,

MD, MS, San Diego, CA.)
390 Gabriel & Ilfeld

Fig. 3. A portable cryoneurolysis device with built-in nerve stimulator (PainBlocker). (Cour-
tesy of B. Ilfeld, MD, MS, San Diego, CA and Epimed, Dallas, TX.)

complications; and no burden of carrying an infusion pump and local anesthetic

reservoir.
Dasa and colleagues18 were the first to analyze the efficacy of a percutaneous
approach to cryoanalgesia for management of post-TKA pain. Cryoneurolysis was
performed at an office visit to the surgeon days before the scheduled surgery. A blind
approach used landmarks to apply percutaneous cryoanalgesia along two treatment
lines to treat the anterior femoral cutaneous nerve and the infrapatellar branch of the
saphenous nerve (Fig. 4).32 Both nerves provide purely sensory innervation to the
anterior aspect of the knee and lie in a predictable and superficial location in the
proximity of the knee capsule. The anterior femoral cutaneous nerve innervating
the superior knee lies within the fascia above the quadriceps tendon as it crosses
a horizontal line the width of the patella approximately 7 cm above the superior
aspect of the patella. The infrapatellar branch of the saphenous nerve innervating
the inferior knee lies along the joint capsule and crosses a vertical line from the infe-
rior aspect of the patella to the tibial tubercle approximately 5 cm medial to the pa-
tella. Because of the superficial and predictable locations of each of these nerves,
applying cryoanalgesia using landmark techniques is possible. To block these two
nerves with cryoneurolysis, Dasa and colleagues18 applied superficial treatment
with a hand-held cryodevice to produce a 0.5-cm cold zone under the skin. A treat-
ment cycle consisted of a period of cooling then warming of the probe, lasting
approximately 50 seconds. Each treatment line required approximately six treatment
cycles to cover the entire length (total procedural duration to freeze both nerves was
15 minutes).
 Regional Anesthesia for Knee Arthroplasty 391

Fig. 4. Treatment lines (green bars) used to apply cryoneurolysis via a “blind” superficial
approach to target anterior femoral cutaneous nerve and the infrapatellar branch of the
saphenous nerve. (Courtesy of B. Ilfeld, MD, MS, San Diego, CA.)

This retrospective study of 100 patients reported the use of preoperative cryoneur-
olysis was associated with a reduced incidence of prolonged hospitalization duration
and opioid consumption up to 12 weeks postoperatively in patients undergoing TKA.18
Similarly, this blind approach using landmark techniques was used to treat
392 Gabriel & Ilfeld

nonsurgical pain associated with knee osteoarthritis.33 In this randomized, double-

blind, sham-controlled multicenter study, the infrapatellar branch of the saphenous
nerve was targeted with cryoneurolysis. The study population consisted of 180 pa-
tients, in which those in the treatment group had statistically significant decreases
from baseline Western Ontario and McMaster Osteoarthritis Index (an instrument
measuring functioning) and pain scores at 30, 60, and 90 days after treatment when
compared with the control group.
The use of ultrasound guidance combined with a percutaneous cryoprobe offer the
ability to target far more peripheral nerves than the blind approach that is appropriate
exclusively for cutaneous nerves. An ultrasound-guided percutaneous technique has
been recently described but is currently limited to short series of cases.6,7 Preopera-
tive ultrasound-guided percutaneous cryoanalgesia for use in treating acute postop-
erative pain in the orthopedic population has also been reported.7 Like the
previously described reports, the infrapatellar branch was targeted by preoperative
cryoneurolysis in patients planned for TKA. In contrast to prior studies, this approach
used ultrasound-guidance to target the nerve versus a blind landmark technique. The
case series also reports use of ultrasound guidance to visualize cryoprobe positioning
and treatment of the suprascapular nerve just superior to the suprascapular notch for
patients undergoing rotator cuff repair. All patients in this case series experienced
excellent postoperative analgesia and had decreased opioid consumption compared
with historical control subjects. No adverse events were reported.
In another report, ultrasound-guided percutaneous cryoanalgesia was used post-
operatively or postinjury to treat the (1) intercostal nerve to provide multiple weeks
of analgesia to a patient with refractory back pain associated with a surgical incision
from a nephrolithotomy procedure; (2) subcostal and intercostal nerves to provide
weeks of analgesia to a patient with hip pain following iliac crest bone grafting; and
(3) the saphenous, sural, posterior tibial, and superficial peroneal nerves to help
manage pain in a patient with burn injury to the foot.6 In all cases, patients reported
adequate analgesia for at least 2 weeks following treatment with no subsequent nerve
injury or neuropathic pain. No other adverse events occurred in relation to
cryoanalgesia.

Potential Risks
Compared with other invasive analgesic modalities, cryoanalgesia has few contraindi-
cations and risks. Relative contraindications include Reynaud syndrome, cryoglobuli-
nemia, and cold urticaria.34 The associated prolonged total sensory, motor, and
proprioception block combined with an unpredictable duration of action (weeks to
months) is not appropriate in most clinical scenarios involving acute pain with the
one potential exception being the treatment of the anterior femoral cutaneous and
infrapatellar branch of the saphenous nerve for knee surgery, such as knee
arthroplasty.18,32
Similar to traditional needle-based percutaneous regional anesthesia techniques,
potential complications of cryoneurolysis include bleeding, bruising, and infection.
Additional risks include injury to the nerve or surrounding tissue if the cannula is
retracted before resolution of the ice ball, and cutaneous discoloration if the ice ball
reaches the skin.29 Therefore, when treating superficial nerves it is important to use
a cannula designed specifically for this area with heating units at and below the skin
to protect against inadvertently involving the dermis and epidermis.
Of note, cryoneurolysis has been in clinical use for more than five decades without a
single published case of permanent nerve injury or neuroma28 and no evidence of
long-term changes to nerve function.26,30 However, two randomized, controlled
 Regional Anesthesia for Knee Arthroplasty 393

clinical trials reported an increase in neuropathic pain associated with cryoneurolysis

when administered via the surgical incision during thoracotomy.16,19 One study
compared epidural infusion alone with a combination of epidural infusion and inter-
costal cryoanalgesia and identified a higher incidence of neuropathic-type pain
(mainly allodynia) at 8 weeks, but resolving by 6 months.16 Furthermore, this study re-
ports that patients who had received cryoneurolysis had higher pain scores at various
time points (12 hours, 2 days, and 8 weeks). Of note, the statistical significance for this
analysis was not adjusted for multiple comparisons and these results are, therefore,
inconclusive. The second investigation compared epidural infusion alone with inter-
costal cryoanalgesia alone.19 They reported an increased incidence of allodynia for
subjects who had received cryoneurolysis at 6 and 12 months. However, statistical
significance was not adjusted for multiple comparisons. Furthermore, it remains un-
known if the difference in treatments was caused by an increased risk of cryoneurol-
ysis or a protective effect from the epidural infusion.
For both studies, cryoanalgesia was applied via surgical exposure and possible
nerve retraction. This is significant because preclinical evidence suggests that
any physical manipulation of the nerve at the time of cryoneurolysis may be a miti-
gating factor in producing a sustained chronic pain condition.35 Although not
perfectly understood, the nerve manipulation before the freeze is hypothesized
to produce an afferent barrage that sets up the central sensitization such that
when axonal regeneration occurs following cryoneurolysis, the fiber activity is
perceived as dysesthetic.36 Although this issue certainly deserves further investi-
gation, it is relevant that most clinical reports identified no increased risk involving
thoracotomy or any other surgical procedure,6,7,18,20,21,23–25,31,37,38 and percuta-
neous application does not involve nerve manipulation. Lastly, preclinical data sug-
gest that a partial nerve injury (inducing Wallerian degeneration of only a portion
of nerve fibers) results in hyperalgesia, whereas a complete ablation does not.35
It is therefore possible that incomplete neurolysis could explain why two trials
found an association between cryoanalgesia and allodynia in contrast to most
similar investigations.

Summary of Cryoanalgesia
There are currently far more unresolved questions than conclusive answers regarding
the use of cryoneurolysis to treat post–knee arthroplasty pain. Remaining undeter-
mined is the optimal number of cryoneurolysis applications for each target nerve,
the duration of treatment, the duration of thawing before subsequently moving the
cannula, and specific apparatus and cannula design. For example, there are preclin-
ical data suggesting that the duration of analgesia/anesthesia is directly correlated
with the duration of cryoneurolysis application (30–120 seconds),22 suggesting that
the ultimate treatment duration may be better controlled than currently realized. How-
ever, additional laboratory studies have demonstrated that partial nerve injury
(inducing Wallerian degeneration of only a portion of nerve fibers) results in hyperalge-
sia.35 Most importantly, outcome data from randomized, controlled clinical trials are
required to identify and quantify any improvement in outcomes and associated risks.
This technique should be compared with local anesthetic-based analgesic modalities;
however, the optimal pain control method may involve a combination of PNBs and cry-
oneurolysis for short- and long-term analgesia, respectively. Nonetheless, the use of
cryoanalgesia for TKA patients seems promising because of the combination of few
contraindications, easy technical application, new portable cryoneurolysis devices
and disposable cannulas, few apparent risks, and prolonged duration that in many
cases outlasts the surgical pain itself.
394 Gabriel & Ilfeld

PERIPHERAL NEUROMODULATION

The concept of using electricity to induce analgesia is not new, having originated with
the ancient Romans using living torpedo fish.39 Since the first device designed to pro-
vide electroanalgesia became available in the early twentieth century,40 neuromodu-
lation has mainly evolved for the management of chronic pain through implanted
spinal cord and PNS devices.41,42 Use of PNS to treat acute postoperative pain has
been limited primarily because of the invasive and time-consuming nature of the avail-
able technology.43 Although transcutaneous delivery of electrical current has been re-
ported, the analgesic ceiling caused by triggering pain fibers in the skin significantly
limits the degree of postoperative analgesia benefit.44 The development and FDA
clearance of a lead that is inserted percutaneously through a needle has now removed
the limitation of invasive surgical implantation and extraction, thus opening the possi-
bility of applying neuromodulation to treat postoperative pain (Fig. 5).
Extremely small, insulated electrical leads (Fig. 6) have been developed that allow
rapid placement via a percutaneous approach through an introducer needle.45,46 An
ultrasound-guided percutaneous approach using these extremely small leads has
been used for various chronic pain states47,48; but, its potential for acute postoperative
pain management remains primarily unexplored. Using ultrasound, these leads are
placed via an introducer needle proximal to nerve (about 1–2 cm away). Unlike tradi-
tional PNB techniques, needle placement does not need to be in contact with the
nerve to ensure appropriate local anesthetic spread. Stimulation is subsequently
tested and if appropriate paresthesias or motor stimulation is elicited, the introducer
needle is removed and lead left remaining in situ. The proximal portion of the lead is
then attached to a small external stimulator, which can easily be affixed to the patient’s
skin (Fig. 7).8

Mechanism of Action
The definitive mechanism of neuromodulation’s effect on pain remains unknown,
although multiple theories have been proposed. The most commonly noted is “gate
control theory,” in which electrical activation of large-diameter myelinated afferent pe-
ripheral nerve fibers inhibits pain signals from the small-diameter pain fibers to the
central nervous system.49 The resultant effect is analgesia while preserving motor,
sensory, and proprioception.

Peripheral Nerve Stimulation and Acute Pain

Ultrasound-guided percutaneous PNS offers a novel intervention to provide post–
knee arthroplasty analgesia without the major limitations of opioids and continuous
PNB.8 Just one example is the associated motor, sensory, and proprioception deficits

Fig. 5. A small diameter (0.2-mm), open-coiled, helical electrical lead with an anchoring wire
preloaded within a 12.5-cm, 20-gauge insertion needle for percutaneous application. (Cour-
tesy of B. Ilfeld, MD, MS, San Diego, CA.)
 Regional Anesthesia for Knee Arthroplasty 395

Fig. 6. A small diameter (0.2-mm), open-coiled, helical electrical lead. (Courtesy of B. Ilfeld,
MD, MS, San Diego, CA.)

from the local anesthetic that may increase the risk of falling after joint replacement.4
Therefore, neuromodulation has important potential implications for use in total joint
surgeries because this intervention potentially may provide effective analgesia while
also preserving complete motor function and proprioception, both of which are
required to optimize postoperative rehabilitation and safety.
Recent preliminary studies provide data regarding the use of ultrasound-guided
percutaneous lead placement and subsequent PNS in the management of acute post-
operative pain following TKA.50,51 In one pilot study, leads were placed in five subjects
(femoral and/or sciatic nerve) who experienced uncontrolled postoperative pain with
oral analgesics between 8 and 58 days following TKA.50 Following lead insertion,
pain scores were recorded before and after the stimulators were activated. Immediate
analgesia was experienced by all subjects and decreased resting pain by an average

Fig. 7. Setup for a percutaneous peripheral nerve stimulator of the femoral nerve. (Courtesy
of B. Ilfeld, MD, MS, San Diego, CA.)
396 Gabriel & Ilfeld

of 93%, in which four of the five patients reported complete resolution of pain. Pain
during passive and active knee motion was reduced by 27% and 30%, respectively,
whereas maximum passive or active knee range-of-motion were only minimally
affected. A second study involving another small series of subjects reported similar
findings using an identical protocol between 8 and 97 days following TKA.52
Only a single report has been published describing the use of percutaneous PNS to
treat pain in the immediate postoperative period.53 Femoral and sciatic leads were
inserted preoperatively in seven patients and remained for up to 6 weeks. During
the first 2 weeks, pain was well controlled in 88% of the patients, four of whom did
not require addition opioids after this time period. Of the five subjects with data on
opioid use, the median time to complete opioid cessation was only 8 days, with
100% of subjects opioid-free 1 month following surgery. This is a dramatic improve-
ment compared with the typical median time to cessation of nearly 2 months (vs
8 days)54–57 with a 1-month opioid-independence rate of 11% to 33% (vs 100%) for
patients having the same surgical procedure within the United States.58 The average
6-minute-walk-test distance was 97% and 124% of patients’ preoperative distances
at 2 weeks and at 3 months, respectively. Importantly, there were no falls, motor block,
or infections reported.

Potential Risks and Concerns

Potential risks associated with percutaneous PNS are, theoretically, minimal relative to
current local anesthetic-based techniques; however, there have been no confirmatory
large-scale clinical trials involving this novel modality. As with any implanted foreign
body, there is a risk of infection. Yet the risk seems to be exceedingly low, with fewer
than one infection per 3000 indwelling days,59 orders of magnitude smaller than for
perineural catheters.60 This improvement is most likely because of the helical coil
lead design, which encourages tissue ingrowth between the coils sealing the passage
through the skin, and allowing stretching/compression of the lead avoiding “pistoning”
that draws bacteria into the body (Fig. 8). Additional risks include migration, dislodge-
ment, and fracture. As with infections, the helical coil lead design theoretically mini-
mizes migration and dislodgement by allowing the lead to stretch and compress,
unlike perineural catheters. As a result, the helical coil design permits long duration
of lead retention from multiple weeks to more than a year.61–63
Fracture of the 2-mm diameter lead occurs in approximately 7.5% of subjects, usu-
ally during extraction, but sometimes simply during use.8 In more than 200 patients
with a fractured lead, the lead remnants were uniformly left in situ without any

Fig. 8. Illustration showing how (A) electrical lead (B) when at rest and (C) when applied
traction causes an opening of the helical coil, which prevents pistoning through the skin
and dislodgment. (Courtesy of B. Ilfeld, MD, MS, San Diego, CA.)
 Regional Anesthesia for Knee Arthroplasty 397

subsequent negative sequelae.8 Importantly, the remnants themselves do not pre-

clude subsequent MRI.64 Although not reported to date, there is the risk of nerve injury
as with any invasive procedure. However, this risk is theoretically far lower than for
local anesthetic-based PNBs considering the lead, and therefore insertion needle,
do not require the lead and nerve to be in direct contact (unlike traditional PNB). Allow-
ing for a remote distance from the nerve promotes selective stimulation of the required
larger-diameter myelinated sensory neurons65 without activating motor or smaller-
diameter sensory neurons that induce muscle contraction and discomfort, respec-
tively.8 After 50 years of clinical use, we are unaware of any reports of nerve injury
caused by the electric current of neuromodulation.66 Many of the risks of continuous
PNB do not apply to percutaneous PNS, such as local anesthetic toxicity and sensory,
motor, and proprioception blockade (which may increase risk of falls). Finally, because
the required external stimulator for percutaneous PNS is small and requires no medi-
cation bag to hold local anesthetic, this burden is no longer an issue with percuta-
neous PNS.

SUMMARY

With increased awareness of opioid overuse after surgery and the current worldwide
opioid epidemic, it is timely to introduce and study novel interventions that may aid in
long-term management of postsurgical pain to decrease opioid requirements. Also
noteworthy is that during the first few days following knee arthroplasty, adequate anal-
gesia improves ambulation, which is associated with shorter hospital length of stay
and lower hospitalization costs.67 Improved analgesia during the weeks to months
following knee arthroplasty will theoretically aid in improved physical therapy partici-
pation and reduce opioid requirements at home.
Before ultrasound-guided percutaneous cryoanalgesia and percutaneous PNS
may be more widely practiced, robust clinical trials demonstrating their efficacy in
managing acute and subacute postoperative pain should be completed. Further-
more, other hospital metrics should be examined including hospital length of stay,
opioid consumption, incidence of adverse events, and health care expenditures.
Lastly, until the costs of percutaneous PNS systems are better defined, a cost-
benefit analysis will remain inconclusive. Nevertheless, given the need to improve
postoperative analgesia, decrease opioid requirements because of the current
opioid epidemic, shorten hospitalization duration, improve postoperative functional
outcomes, and lessen analgesic-associated patient risks, such as falling,
ultrasound-guided percutaneous cryoanalgesia and PNS deserve further consider-
ation and investigation.

ACKNOWLEDGMENTS

The authors thank Elan Ilfeld for his rendering of Figs. 1 and 8.

REFERENCES

1. Kopp SL, Borglum J, Buvanendran A, et al. Anesthesia and analgesia practice

pathway options for total knee arthroplasty: an evidence-based review by the
American and European societies of regional anesthesia and pain medicine.
Reg Anesth Pain Med 2017;42(6):683–97.
2. Terkawi AS, Mavridis D, Sessler DI, et al. Pain management modalities after total
knee arthroplasty: a network meta-analysis of 170 randomized controlled trials.
Anesthesiology 2017;126(5):923–37.
398 Gabriel & Ilfeld

3. Gabriel RA, Ilfeld BM. Use of regional anesthesia for outpatient surgery within the
United States: a prevalence study using a nationwide database. Anesth Analg
2018;126(6):2078–84.
4. Ilfeld BM, Duke KB, Donohue MC. The association between lower extremity
continuous peripheral nerve blocks and patient falls after knee and hip arthro-
plasty. Anesth Analg 2010;111(6):1552–4.
5. Ilfeld BM. Continuous peripheral nerve blocks: an update of the published evi-
dence and comparison with novel, alternative analgesic modalities. Anesth Analg
2017;124(1):308–35.
6. Gabriel RA, Finneran JJ, Asokan D, et al. Ultrasound-guided percutaneous cryo-
neurolysis for acute pain management: a case report. A Case Rep 2017;9(5):
129–32.
7. Ilfeld BM, Gabriel RA, Trescot AM. Ultrasound-guided percutaneous cryoneurol-
ysis providing postoperative analgesia lasting many weeks following a single
administration: a replacement for continuous peripheral nerve blocks? A case
report. Korean J Anesthesiol 2017;70(5):567–70.
8. Ilfeld BM, Grant SA. Ultrasound-guided percutaneous peripheral nerve stimula-
tion for postoperative analgesia: could neurostimulation replace continuous pe-
ripheral nerve blocks? Reg Anesth Pain Med 2016;41(6):720–2.
9. Gage AA. History of cryosurgery. Semin Surg Oncol 1998;14(2):99–109.
10. Cooper IS, Grissman F, Johnston R. A complete system for cytogenic surgery. St
Barnabas Hosp Med Bull 1962;1:11–6.
11. Lloyd JW, Barnard JD, Glynn CJ. Cryoanalgesia. A new approach to pain relief.
Lancet 1976;2(7992):932–4.
12. Trescot AM. Cryoanalgesia in interventional pain management. Pain Physician
2003;6(3):345–60.
13. Graves C, Idowu O, Lee S, et al. Intraoperative cryoanalgesia for managing pain
after the Nuss procedure. J Pediatr Surg 2017;52(6):920–4.
14. Ba YF, Li XD, Zhang X, et al. Comparison of the analgesic effects of cryoanalge-
sia vs. parecoxib for lung cancer patients after lobectomy. Surg Today 2015;
45(10):1250–4.
15. Sepsas E, Misthos P, Anagnostopulu M, et al. The role of intercostal cryoanalge-
sia in post-thoracotomy analgesia. Interact Cardiovasc Thorac Surg 2013;16(6):
814–8.
16. Mustola ST, Lempinen J, Saimanen E, et al. Efficacy of thoracic epidural anal-
gesia with or without intercostal nerve cryoanalgesia for postthoracotomy pain.
Ann Thorac Surg 2011;91(3):869–73.
17. Keller BA, Kabagambe SK, Becker JC, et al. Intercostal nerve cryoablation
versus thoracic epidural catheters for postoperative analgesia following pectus
excavatum repair: preliminary outcomes in twenty-six cryoablation patients.
J Pediatr Surg 2016;51(12):2033–8.
18. Dasa V, Lensing G, Parsons M, et al. Percutaneous freezing of sensory nerves
prior to total knee arthroplasty. Knee 2016;23(3):523–8.
19. Ju H, Feng Y, Yang BX, et al. Comparison of epidural analgesia and intercostal
nerve cryoanalgesia for post-thoracotomy pain control. Eur J Pain 2008;12(3):
378–84.
20. Yang MK, Cho CH, Kim YC. The effects of cryoanalgesia combined with thoracic
epidural analgesia in patients undergoing thoracotomy. Anaesthesia 2004;
59(11):1073–7.
 Regional Anesthesia for Knee Arthroplasty 399

21. Gwak MS, Yang M, Hahm TS, et al. Effect of cryoanalgesia combined with intra-
venous continuous analgesia in thoracotomy patients. J Korean Med Sci 2004;
19(1):74–8.
22. Moorjani N, Zhao F, Tian Y, et al. Effects of cryoanalgesia on post-thoracotomy
pain and on the structure of intercostal nerves: a human prospective randomized
trial and a histological study. Eur J Cardiothorac Surg 2001;20(3):502–7.
23. Bucerius J, Metz S, Walther T, et al. Pain is significantly reduced by cryoablation
therapy in patients with lateral minithoracotomy. Ann Thorac Surg 2000;70(3):
1100–4.
24. Robinson SR, Purdie GL. Reducing post-tonsillectomy pain with cryoanalgesia: a
randomized controlled trial. Laryngoscope 2000;110(7):1128–31.
25. Callesen T, Bech K, Thorup J, et al. Cryoanalgesia: effect on postherniorrhaphy
pain. Anesth Analg 1998;87(4):896–9.
26. Hsu M, Stevenson FF. Reduction in muscular motility by selective focused cold
therapy: a preclinical study. J Neural Transm (Vienna) 2014;121(1):15–20.
27. Hsu M, Stevenson FF. Wallerian degeneration and recovery of motor nerves after
multiple focused cold therapies. Muscle Nerve 2015;51(2):268–75.
28. Kim PS, Ferrante FM. Cryoanalgesia: a novel treatment for hip adductor spasticity
and obturator neuralgia. Anesthesiology 1998;89(2):534–6.
29. Ilfeld BM, Preciado J, Trescot AM. Novel cryoneurolysis device for the treatment
of sensory and motor peripheral nerves. Expert Rev Med Devices 2016;13(8):
713–25.
30. Connelly NR, Malik A, Madabushi L, et al. Use of ultrasound-guided cryotherapy
for the management of chronic pain states. J Clin Anesth 2013;25(8):634–6.
31. Wood GJ, Lloyd JW, Bullingham RE, et al. Postoperative analgesia for day-case
herniorrhaphy patients. A comparison of cryoanalgesia, paravertebral blockade
and oral analgesia. Anaesthesia 1981;36(6):603–10.
32. Hu E, Preciado J, Dasa V, et al. Development and validation of a new method for
locating patella sensory nerves for the treatment of inferior and superior knee
pain. J Exp Orthop 2015;2(1):16.
33. Radnovich R, Scott D, Patel AT, et al. Cryoneurolysis to treat the pain and symp-
toms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-
controlled trial. Osteoarthritis Cartilage 2017;25(8):1247–56.
34. Ilfeld BM, Gabriel RA, Trescot AM. Ultrasound-guided percutaneous cryoneurol-
ysis for treatment of acute pain: could cryoanalgesia replace continuous periph-
eral nerve blocks? Br J Anaesth 2017;119(4):703–6.
35. Myers RR, Heckman HM, Powell HC. Axonal viability and the persistence of ther-
mal hyperalgesia after partial freeze lesions of nerve. J Neurol Sci 1996;139(1):
28–38.
36. Wagner R, DeLeo JA, Heckman HM, et al. Peripheral nerve pathology following
sciatic cryoneurolysis: relationship to neuropathic behaviors in the rat. Exp Neurol
1995;133(2):256–64.
37. Miguel R, Hubbell D. Pain management and spirometry following thoracotomy: a
prospective, randomized study of four techniques. J Cardiothorac Vasc Anesth
1993;7(5):529–34.
38. Katz J, Nelson W, Forest R, et al. Cryoanalgesia for post-thoracotomy pain. Lan-
cet 1980;1(8167):512–3.
39. Tsoucalas G, Karamanou M, Lymperi M, et al. The "torpedo" effect in medicine. Int
Marit Health 2014;65(2):65–7.
40. Gildenberg PL. History of electrical neuromodulation for chronic pain. Pain Med
2006;7(1):S7–13.
400 Gabriel & Ilfeld

41. Long DM. Electrical stimulation for relief of pain from chronic nerve injury.
J Neurosurg 1973;39(6):718–22.
42. Deer TR, Mekhail N, Provenzano D, et al. The appropriate use of neurostimulation
of the spinal cord and peripheral nervous system for the treatment of chronic pain
and ischemic diseases: the Neuromodulation Appropriateness Consensus Com-
mittee. Neuromodulation 2014;17(6):515–50 [discussion: 550].
43. Hassenbusch SJ, Stanton-Hicks M, Schoppa D, et al. Long-term results of pe-
ripheral nerve stimulation for reflex sympathetic dystrophy. J Neurosurg 1996;
84(3):415–23.
44. Yu DT, Chae J, Walker ME, et al. Comparing stimulation-induced pain during
percutaneous (intramuscular) and transcutaneous neuromuscular electric stimu-
lation for treating shoulder subluxation in hemiplegia. Arch Phys Med Rehabil
2001;82(6):756–60.
45. Deer TR, Levy RM, Rosenfeld EL. Prospective clinical study of a new implantable
peripheral nerve stimulation device to treat chronic pain. Clin J Pain 2010;26(5):
359–72.
46. Yu DT, Chae J, Walker ME, et al. Percutaneous intramuscular neuromuscular
electric stimulation for the treatment of shoulder subluxation and pain in patients
with chronic hemiplegia: a pilot study. Arch Phys Med Rehabil 2001;82(1):20–5.
47. Huntoon MA, Burgher AH. Ultrasound-guided permanent implantation of periph-
eral nerve stimulation (PNS) system for neuropathic pain of the extremities: orig-
inal cases and outcomes. Pain Med 2009;10(8):1369–77.
48. Chan I, Brown AR, Park K, et al. Ultrasound-guided, percutaneous peripheral
nerve stimulation: technical note. Neurosurgery 2010;67(3 Suppl Operative):
ons136–9.
49. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150(3699):
971–9.
50. Ilfeld BM, Gilmore CA, Grant SA, et al. Ultrasound-guided percutaneous periph-
eral nerve stimulation for analgesia following total knee arthroplasty: a prospec-
tive feasibility study. J Orthop Surg Res 2017;12(1):4.
51. Ilfeld BM, Ball ST, Gabriel RA, et al. Perioperative percutaneous peripheral nerve
stimulation utilizing preoperative lead placement for the treatment of postopera-
tive pain [abstract]. Reg Anesth Pain Med 2017;(3603).
52. Ilfeld BM, Grant SA, Gilmore CA, et al. Neurostimulation for postsurgical anal-
gesia: a novel system enabling ultrasound-guided percutaneous peripheral
nerve stimulation. Pain Pract 2017;17(7):892–901.
53. Ilfeld BM, Gilmore CA, Chae J, et al. Percutaneous peripheral nerve stimulation
for the treatment of postoperative pain following total knee arthroplasty [abstract].
North American Neuromodulation Society conference. 2016(19:10562).
54. Namba RS, Inacio MC, Pratt NL, et al. Postoperative opioid use as an early indi-
cation of total hip arthroplasty failure. Acta Orthop 2016;87(Suppl 1):37–43.
55. Hah JM, Mackey S, Barelka PL, et al. Self-loathing aspects of depression reduce
postoperative opioid cessation rate. Pain Med 2014;15(6):954–64.
56. Carroll I, Barelka P, Wang CK, et al. A pilot cohort study of the determinants of
longitudinal opioid use after surgery. Anesth Analg 2012;115(3):694–702.
57. Rozet I, Nishio I, Robbertze R, et al. Prolonged opioid use after knee arthroscopy
in military veterans. Anesth Analg 2014;119(2):454–9.
58. Goesling J, Moser SE, Zaidi B, et al. Trends and predictors of opioid use after to-
tal knee and total hip arthroplasty. Pain 2016;157(6):1259–65.
 Regional Anesthesia for Knee Arthroplasty 401

59. Ilfeld BM, Gabriel RA, Saulino MF, et al. Infection rates of electrical leads used for
percutaneous neurostimulation of the peripheral nervous system. Pain Pract
2017;17(6):753–62.
60. Capdevila X, Bringuier S, Borgeat A. Infectious risk of continuous peripheral
nerve blocks. Anesthesiology 2009;110(1):182–8.
61. Onders RP, Elmo M, Khansarinia S, et al. Complete worldwide operative experi-
ence in laparoscopic diaphragm pacing: results and differences in spinal cord
injured patients and amyotrophic lateral sclerosis patients. Surg Endosc 2009;
23(7):1433–40.
62. Shimada Y, Matsunaga T, Misawa A, et al. Clinical application of peroneal nerve
stimulator system using percutaneous intramuscular electrodes for correction of
foot drop in hemiplegic patients. Neuromodulation 2006;9(4):320–7.
63. Marsolais EB, Kobetic R. Implantation techniques and experience with percuta-
neous intramuscular electrodes in the lower extremities. J Rehabil Res Dev
1986;23(3):1–8.
64. Shellock FG, Zare A, Ilfeld BM, et al. In vitro magnetic resonance imaging evalu-
ation of fragmented, open-coil, percutaneous peripheral nerve stimulation leads.
Neuromodulation 2017;21(3):276–83.
65. Grill SE, Hallett M. Velocity sensitivity of human muscle spindle afferents and
slowly adapting type II cutaneous mechanoreceptors. J Physiol 1995;489(Pt 2):
593–602.
66. Mekhail NA, Cheng J, Narouze S, et al. Clinical applications of neurostimulation:
forty years later. Pain Pract 2010;10(2):103–12.
67. Pua YH, Ong PH. Association of early ambulation with length of stay and costs in
total knee arthroplasty: retrospective cohort study. Am J Phys Med Rehabil 2014;
93(11):962–70.