Effects of adding a combined femoral and sciatic nerve block with levobupivacaine and clonidine to

general anaesthesia in femoropopliteal bypass surgery

A randomised, double-blind, controlled trial

BACKGROUND Adding a regional block to general anaesthesia can prevent postoperative pain and
improve peripheral circulation.
OBJECTIVE To seek improved postoperative analgesia and care due to a long-acting combined femoral
and sciatic nerve block in patients undergoing femoropopliteal bypass surgery.
DESIGN A randomised, double-blind, controlled trial.
SETTING Vascular surgery unit of a French university hospital.
PATIENTS Forty-four adults scheduled for bypass surgery under general anaesthesia.
INTERVENTION Patients were allocated to receive either an active nerve block with 20 ml of 0.375%
levobupivacaine and clonidine 0.5mg kg–1, or a simulated (sham) block only, but with local anaesthesia
of the skin, before general anaesthesia. General anaesthesia was standardised with propofol, then
sevoflurane and sufentanil adjusted according to clinical need. Postoperative analgesia was standardised
with paracetamol 1 g every 6 h, and intravenous morphine, initially titrated in the postanaesthesia care
unit and then patientcontrolled. Oral analgesics were repeated up to day 3.
MAIN OUTCOME MEASURES The primary outcome was morphine consumption during the first 24
postoperative hours. In a subgroup of postoperative patients distal tissue oxygen saturation was
recorded at the lateral side of the blocked calf.
RESULTS Patients in the active group received less intraoperative sufentanil (median dose 25 vs. 41mg),
needed less morphine during the first 24 h (15 vs. 27 mg) and 72 (20 vs. 35 mg) postoperative hours,
than in the control group. They also had less pain on movement, but pain at rest, the tissue oxygen
saturation and other rehabilitation outcomes were unaffected by the treatment. Tolerance outcomes
were also similar between groups.
CONCLUSION Combining the two regional blocks improves the quality of postoperative care in this frail
population, probably by reducing the amount of peri-operative opioid.

Introduction
Occlusive peripheral arterial disease affects nearly 2 million people in France;1 about 70% of the lesions
are located in the infra-inguinal area, for which a femoropopliteal bypass is frequently required.2 The
procedure generally includes one proximal inguinal incision and one distal incision, and postoperative
morbidity is noticeably high3 due to the combination of the effects of anaesthesia and immobilisation, in
a frail population. This procedure is currently conducted under either general or regional anaesthesia,4
with protocols that aim to avoid hypotensive events, and improve postoperative analgesia and
encourage early mobilisation. Neuraxial anaesthetic techniques can block all sensory territories of the
lower limb, but they do not avoid hypotensive events and might not improve postoperative outcomes
when compared with general anaesthesia.4,5 Their use is further complicated by concomitant
anticoagulation, and the use of infusion catheters to prolong postoperative nociceptive blockade can
impair mobilisation.
Blocking nociceptive afferents during the surgical procedure might reduce the resultant postoperative
hyperalgesia and also the need for intra-operative opioids: the latter may have both hypotensive and
hyperalgesic effects. Trials in different surgical models have shown a benefit from adding regional to
general anaesthesia, provided the block is effective for the whole surgical procedure. In femoropopliteal
bypass surgery an additional benefit is that regional anaesthesia could, in theory, improve postoperative
circulation by peripheral vasodilatation given that ischaemia is one of the major postoperative issues.
Such improvement of regional tissue oxygen saturation (rSO2) as measured by nearinfrared
spectroscopy (NIRS) has been found following a variety of peripheral nerve blocks.
Combined sciatic and femoral nerve blocks with bupivacaine are a promising technique that we have
introduced into our unit, but with levobupivacaine, to which we have added the a2 agonist clonidine.
Clonidine potentiates local anaesthetic effects and is known to prolong postoperative analgesia. It is well
tolerated provided the dose does not exceed 1mg kg–1. We therefore, conducted this trial to validate
the hypothesis that this local anaesthesia protocol, when combined with general anaesthesia, provides
superior postoperative analgesia for femoropopliteal bypass surgery compared with a sham block as
control. A secondary endpoint was to show an improvement in postoperative rSO2.
Methods
Ethics
Ethical approval for this study (ref. AU 973) was provided by the research ethics committee CPP Sud-Est
VI, Clermont-Ferrand, France, on 12 July 2012. The study was also authorised by the competent French
authority (ANSM) and registered on Clinical-Trials.gov (NCT01785693) and EudraCT (2012-002123-15). It
started on 30 January 2013.
The randomised, placebo-controlled, double-blind, single-centre trial was conducted in the vascular
surgery unit of the University Hospital of Clermont-Ferrand (F). The inclusion criteria were adults, aged
18 to 80 scheduled for femoropopliteal bypass. The exclusion criteria were: grade I or IV peripheral
arterial disease, emergency surgery, pregnancy or breastfeeding, respiratory insufficiency, uncontrolled
coronary artery disease, renal insufficiency defined as a creatinine clearance less than 30 ml min1
(estimated by the Modification of Diet in Renal Disease study equation for a 1.73m2 body surface),
hepatic insufficiency, diabetes mellitus with insulin treatment or with peripheral neuropathy, chronic
pain, WHO level-III current opioid medication, drug addiction, any relevant coagulation disorder such as
platelet count less than 80 000ml1 , prothrombin time less than 50% or factor V less than 50%, allergy or
other contra-indication to the molecules used in the protocol, or any cognitive impairment that
mightinterfere with informed consent, or the collection of data. Patients received a detailed explanation
of the study during a preoperative consultation. The day before surgery, they gave their signed consent
and were shown how to report pain on an 11-point numerical rating scale (NRS) from 0 (no pain) to 10
(worst possible pain).
Patients were randomised into one of the two study groups, named ‘active block’ and ‘sham’. The drugs
were administered using a blinded procedure. Randomisation was overseen by an independent research
assistant of the Clinical Investigation Centre. The anaesthetist caring for each patient had to open the
sealed envelope giving the allocation group before surgery. On arrival at the operating theatre, standard
monitoring with noninvasive blood pressure (BP), 5-lead electrocardiography and pulse oximetry was
established, and a 16-gauge peripheral venous cannula was inserted. In the active block group, two 20-
ml syringes of a local anaesthetic mixture were prepared, one for each block. The mixture was made of
10 ml of 0.25% levobupivacaine (Chirocaı¨ne; Abbott France SA, Rungis, France) and 10 ml of 0.5%
levobupivacaine and 0.5mg kg–1 of clonidine (Catapressan; Boehringer Ingelheim France, Paris, France),
without exceeding 75mg. The total dose of levobupivacaine to be administered was 150 mg. Both sciatic
and femoral nerve blocks were ultrasound-guided following an inplane approach, with the probe
protected by a sterile sheath and held perpendicular to the course of the nerve.
The skin was anaesthetised with 1% lidocaine, and the needle was inserted 2 cm lateral to the probe and
directed towards the nerve following the ultrasound beam. The femoral nerve block was performed in
the supine position, with the ipsilateral extremity abducted 10 to 20 o and slightly externally rotated with
the lateral side of the foot resting on the table. The probe was placed at the middle of the inguinal
crease. The sciatic nerve block was then performed, according to a modification of Di Benedetto’s
subgluteal approach, with the patient lain on the contralateral side with a slight forward tilt and a 60 o
flexion of the upper hip. The landmarks were the greater trochanter of the femur, the ischial tuberosity,
and a line between the two with the midpoint marked, in which the probe was placed. For both femoral
and sciatic nerve block, a 21-gauge, 9-cm needle (Stimuquick; Arrow, Kingstonupon-Thames, UK) was
used for injection. For patients of the sham group, two 5-ml syringes of 0.9% saline were prepared. The
preparation was similar to the above with regard to position, skin preparation and anaesthesia,
ultrasound probe application and injection site. The patient was left unaware of the syringes used, and
the solutions were subcutaneously injected.
The patient was then laid supine and moved to the operating room. The monitoring set up for general
anaesthesia was complemented by neuromuscular monitoring, and capnometry. Induction of general
anaesthesia was performed with 2 to 3 mg kg–1 of propofol, 0.3 to 0.3mg kg–1 of sufentanil and 0.15
mg kg–1 of cisatracurium. After tracheal intubation, anaesthesia was maintained with sevoflurane set at
the age-adjusted minimal alveolar concentration (range 0.5 to 3%), and subsequently both anaesthesia
and analgesia were adjusted according to an algorithm based on the pressure, rate, sweating, tears
(PRST ) score. If the PRST score exceeded three, the initial intervention was an age-adapted bolus of
intravenous sufentanil (15mg under 45 years, 10mg for 45 to 75 years, and 5mg over 75 years); the
second intervention was a 1% increase in sevoflurane concentration. Myorelaxation was maintained
with boluses of 0.15 mg kg–1 of cisatracurium if necessary, according to the train-of-four response at
the orbicular muscle. Mechanical ventilation set to target a PETCO2 in the range of 3.6 to 4.3 kPa and
SpO2 more than 95%. The baseline inspiratory gas was a 50/50 mixture of oxygen and air. End-
expiratory pressure was set to 5 cmH2O. Hypothermia was prevented by forced-air skin surface
warming. Systematic fluid loading was performed with 8 ml kg–1 h–1 of lactated Ringer’s solution. If
hypotension occurred, as defined by a mean BP under 70% of the baseline value, the concentration of
sevoflurane was lowered by 1% and a treatment was administered depending on heart rate (HR) (fluid
loading if more than 90 bpm, 0.5 mg of intravenous atropine if 100 bpm, urapidil otherwise). At wound
closure, 1 g paracetamol and 20 mg nefopam were administered intravenously. No information about
the study drugs was given to the staff in charge of the patient after surgery. On the patient’s anaesthetic
file only the protocol was mentioned, and the administration of ‘either levobupivacaine + clonidine or
not’. The study outcomes were collected by the nursing staff responsible for postoperative care. This
team was independent from the staff responsible for intra-operative care. Intra-operative variables such
as duration of surgery, and total dose of sufentanil administered, were noted. Patients were transferred
to the postanaesthesia care unit (PACU) and extubated as soon as possible, once SpO2 was more than
95%. T0 was given as the time of extubation.
To prevent postoperative pain, 1 g of intravenous paracetamol was administered every 6 h over a 48 h
period. Pain was assessed on a NRS ranging from 0 (no pain) to 10 (the worst pain possible). A score of
spontaneous pain above 3/ 10 prompted intravenous administration of 1 mg ml–1 titrated morphine
chlorhydrate (Morphine Aguettant; Aguettant, Lyon, France), following a written protocol. The initial
bolus was 3 mg (or 2 mg if weight <60kg), then boluses of 2 mg were administered every 5 min until the
pain score was 3/10 or less, unless excessive sedation or any sign of overdose noted. Morphine was then
delivered via a PCA device, in which 2.5 ml of droperidol were added to the 50-ml-syringe containing 50
mg of morphine; the PCA regimen was: bolus¼ 1 ml, refractory period¼ 7 min, maximal dose per 4 h ¼
30 mg, no continuous infusion. Pain score at rest and vital signs were then recorded at T0+ 30, T0+ 60
min, T0+ 90 min, T0+ 120 min and at discharge from the PACU. In the case of nausea or vomiting, 4 mg
of intravenous ondansetron were administered.
Distal tissue oxygen saturation (rSO2) of the blocked limb was continuously recorded by NIRS through an
Equanox Model 7600 (Nonin, Plymouth, Minnesota, USA) with a skin sensor (Equanox Classic Plus model
8003CA) set at the lateral side of the calf. The rSO2 data were extracted through an electronic file
(Microsoft Excel 2010; Microsoft, Redmond, Washington, USA).
Patients were transferred from the PACU to the surgical unit under the guidance of the anaesthetist
when all the following conditions were reached: modified Aldrete score greater or equal to 8, no nausea
or vomiting, pain score under 3/10, no surgical or neurological complications. An infusion of isotonic
glucose was maintained at 1 to 1.5 ml kg–1 h–1 until first oral intake, usually the morning after surgery.
Pain scores at rest and on movement (sitting/ coughing) were recorded every 4 h during the 24 first
postoperative hours, then every 8 h during the following 48 h. After discontinuation of the PCA at T0+ 72
h, rescue analgesia was delivered by 10 mg oral morphine, with a maximal dose of 20 mg every 8 h.
Morphine consumption was recorded at T0+ 24 h, T0+ 48 h and T0+ 72 h.
Sedation was assessed every 30 min until discharge from PACU, then every 8 h until T0 þ 24 h according
to the Observer’s Assessment of Alertness/Sedation scale, which quotes alertness from 5 (normal) to 1
(none) to assess four domains – responsiveness, speech, facial expression, and aspect of the eyes. At
discharge from PACU and at H0 þ 24 h and H0 þ 48 h, nausea/vomiting, hypotension/malaise,
constipation, oxygen desaturation and urinary retention were recorded. Time to first ambulation and
the length of stay in the surgical ward were also treated as outcomes. Finally, any other adverse event
was also noted, as well as any severe adverse event until the 30th postoperative day.
The primary outcome was morphine consumption during the first 24 postoperative hours. Morphine
consumption during the first 48 and 72 postoperative hours were treated as secondary outcomes, as
well as rSO2, and the other efficacy and tolerance outcomes. The postoperative opioid consumption was
standardised as milligrams of intravenous morphine, so the doses of oral morphine were divided by
three. If oral oxycodone or tramadol was given instead of oral morphine, a calculation was based on a
conversion table. Two different treatments were conducted for pain scores; in one, the raw values were
kept and missing data were not replaced to conduct analyses with a linear mixed model (see below); in
the other, missing data were replaced by multiple imputation processes and an area under the curve
(AUC) was calculated as the sum of the values [(pain at tn þ 1þ pain at tn)/2] [time (h) between tn and tn
þ 1] for each interval between observations. AUCs could therefore, be directly compared, and give more
precise information on the size of the treatment effect.
The sample size was estimated on the basis of a preliminary report of the morphine-sparing effect of a
continuous femoral nerve block,6 with a consumption at 33 mg 24 h-1 ± 11 mg in the control group and
a between-groups difference of 29 mg 24 h-1 . However, we estimated a smaller consumption (14 mg) in
our control group due to co-analgesia, and a lower difference (14 mg) due to the single shot
administration. With type-I and type-II errors of 5%, the sample size was estimated at 17 patients per
group, which was set at 24 to compensate for attrition.
Statistical analysis
Analyses were performed using Stata 13 (StataCorp, College Station, Texas, USA). The tests were two-
sided, with type-I error at 0.05. Numerical data were expressed as mean SD for normal distribution and
otherwise as median [IQR]. The normality of the distribution was checked using a Shapiro–Wilk test.
Categorical data were expressed as number of patients/events and percentage. Comparisons between
groups for nonrepeated data were conducted using the Student’s t test or the Mann–Whitney test for
numerical variables, and the x2 or Fisher’s exact test for categorical variables. For comparison of
repeatedly measured pain scores, data were analysed using random-effects regression models (linear
mixed model) to evaluate the following fixed effects: group, time-points evaluation and their interaction,
taking into account between and within patient variability (subject as random-effect). The normality of
residuals was checked. The principal analysis was done according to protocol.
Results
The CONSORT flow chartis shown in Fig. 1. The baseline characteristics of the groups were similar (Table
1), as were the intra-operative variables uninfluenced by the allocated treatment (Table 2). Table 3
shows the effects of the studied treatments on the outcomes related to the analgesic efficacy, either
directly or indirectly.
a: current opioid medication
b: preoperative opioid and intraoperative dexamethasone, l0mg
c: thrombectomy before T0+24hrs

Table 1 Baseline characteristics

The numerical data are expressed as mean SD; the binary data are expressed as number of observations
(percentage). PAD, peripheral arterial disease.
Compared with the sham block, the active bitruncal nerve block reduced the intra-operative
consumption of sufentanil, and opioid consumption during both the first 24 postoperative hours, and
the first 72 postoperative hours. There was no significant effect between the 24th and the 72nd
postoperative hours. For pain at rest, whereas no treatment effect was shown on the AUCs (despite a
trend in less pain with active block), the linear mixed model on raw data showed both a time (P< 0.0001)
and a treatment effect (P< 0.001). Pain on movement, was reduced by the active block, either with
direct comparison of AUCs, or with the linear mixed model on raw data which showed both a time (P¼
0.004) and a treatment effect (P< 0.0001). Fig. 2 shows the time course of pain at rest and at movement
in both groups, with a trend for a greater effect in the early observations. Conversely, no effect could be
identified, either on distal oxygenation or on discharge outcomes.

Table 2 Intra-operative events

Description of the surgical and anaesthetic variables independent of randomisation, per protocol
analysis (Fig. 1 for details). The numerical data are expressed as mean ± SD or median [interquartile
range]; the nominal data are expressed as number of observations (percentage). a The other cases had a
low bypass. b The other cases had a prosthetic graft.

Table 4 shows the effects of the studied treatments on tolerance outcomes. No effect could be
identified by the per-protocol analysis.

Table 3 Efficacy outcomes (per protocol analysis)

Efficacy outcomes according to the group of randomisation. The numerical data are expressed as
median [interquartile range] or median ± SD. rSO2, regional (blocked limb) oxygen saturation. a. See
Methods’ section for details. b. Data available for eight patients only. c. Data available for 12 patients
only.
Discussion
We have shown that adding a combined femoral and sciatic nerve block with levobupivacaine and
clonidine to general anaesthesia in femoropopliteal bypass surgery improved pain control and reduced
postoperative analgesic consumption, and pain on movement. However, these benefits could not be
converted into hard health outcomes such as the time to first ambulation or the duration of stay. The
better effect observed on pain on movement, compared with pain at rest, can be explained by the
analgesic protocol, which included opioids on request, probably blunting pain at rest in both groups,
while pain on movement is usually less sensitive to opioids. We reported a similar observation in a
previous trial of regional anaesthesia to treat pain after sternotomy.
Considering general and regional anaesthesia as exclusive options tends to be challenged by the
combination of the two. First, some patients are reluctant to be operated on under regional anaesthesia
alone, and would prefer a variable level of sedation. Second, the intra-operative blockade of nociceptive
afferents might prevent postoperative pain, something found more than twenty years ago in a trial of
intra-operative inferior alveolar blockade for molar extraction, where both intervention and control
groups included general anaesthesia. Similar observations have been made, for example with intra-
operative epidural blockade in major abdominal surgery, even including late postoperative pain
outcomes. In women undergoing modified radical mastectomy, intra-operative pectoral nerve blockade
improved a number of postoperative analgesia and comfort outcomes,9 and in patients undergoing total
hip arthroplasty, intra-operative lumbosacral plexus block reduced postoperative pain.11 Another trial
compared pre to postoperative infraclavicular brachial plexus block with ropivacaine for fixation of a
fractured radius, all patients also receiving general anaesthesia with remifentanil and propofol10; an
unintended effect was that postoperative analgesia was much improved following a pre-operative block
that had a much longer action than anticipated.
Time course of pain scores at rest (top) and standardised mobilisation (bottom) during the first 72 h
after the end of surgery, measured by numerical rating scale (out of 10). The limits of the boxes
represent the interquartile range, the limits of the whiskers represent the range and the inner line
represents the median value, for each group at each time of measurement. The grey and the white
boxes represent the active and the sham block group, respectively. The statistically significant time
group interactions (P < 0.05) are indicated by an asterisk.

Table 4 Tolerance outcomes (per protocol analysis)

Tolerance outcomes according to the randomisation group. The nominal data are expressed as number
of observations (percentage). n/c, not calculated.
A prolonged analgesic effect can be explained by the properties of local anaesthetic agents such as
bupivacaine, ropivacaine orlevobupivacaine, with sensory blocks lasting up to 20 h providing analgesia
for a large part of the first postoperative day. Also, depending on the type of surgery, pain can appear
before complete resolution of the sensory block. In the study on radial fixation reported above, in the
group having the block at the end of surgery the mean time to first rescue analgesic was about 6 h after
recovery from general anaesthesia, but, in the group having the block at the initiation of surgery this
mean time was about 9 h. Therefore, a genuine pre-emptive analgesia, one not explained by
pharmacokinetics, is a strong hypothesis, although two mechanisms are possible: first, avoiding central
sensitisation by blocking the nociceptive afferents during surgical stimulation, and second, limiting the
hyperalgesic effects of intra-operative opioids. The first mechanism is supported by the study in dental
surgery reported above, as in both groups, general anaesthesia was opioid-free. However, the second
mechanism cannot be excluded, as in other trials intra-operative blockade was associated with less
intra-operative opioids, either because it was dictated by the protocol, or because the perceived clinical
need was less.
Blocking the femoral or sciatic nerve could have motor effects with negative impact on postoperative
rehabilitation. We did not observe such a trend, although time to first ambulation, the only related
outcome we measured, was poorly sensitive, compared with outcomes such as quadriceps strength. But
we did see positive effects of the block on pain on movement, a relevant indicator for postoperative
analgesia, although this was not converted into better rehabilitation. One explanation for this could be a
too passive attitude of our unit, and also because the effects on pain and opioid consumption were
mostly apparent during the first 24 postoperative hours, when rehabilitation is not yet initiated. We
could not find any advantage on any tolerance outcome, probably because of the sample size, but our
cohort, mostly male smokers, was at low risk for nausea and vomiting.
In addition to a reduction in intra-operative opioids, adding a block to general anaesthesia could also
allow a lighter narcosis, therefore, minimising the haemodynamic impact. As a consequence, there are
benefits in postoperative morbidity, both in terms of life-threatening events, and also rehabilitation. In
the study of total hip arthroplasty, patients having the intra-operative block had either light or deep
intra-operative sedation; those having deep sedation had more interventions for hypotension, and
higher postoperative cognitive disturbances. Our design, by controlling equal narcosis in both groups,
did not allow such a finding, but we must note that hypotension and sedation were similar in both
groups, despite the inclusion of clonidine in the block which was likely to favour such effects.
Our negative results on rSO2 are hard to interpret, mostly because it could be measured in only 20
patients. An increase in distal oxygenation following peripheral nerve block (of either upper or lower
limb) had been shown in a before-and-after study including 40 patients, a much greater statistical
power. This effect was not observed between postoperative interventions, and the possibility of stress-
induced vasoconstriction before anaesthesia should be taken into account.
The benefits of adding peripheral blockade to general anaesthesia can be offset by some limitations of
the technique. Although low, there is some risk of neurological complications with peripheral nerve
blocks, to which diabetic patients are particularly exposed. Epidural block, as an alternative, has an
associated risk of epidural haematoma during anticoagulant therapy. It may induce more hypotensive
events and less satisfaction when compared with a peripheral nerve block after major knee surgery, for
similar analgesia. Perhaps the chief benefit of epidural block would be its prolonged action if maintained
with the help of a catheter. Finally, insufficient training or confidence are barriers to the practice of
regional blocks, and those patients who are reluctant to submit to additional needle punctures, would
hardly accept having one in addition to general anaesthesia.
As regards the limitations of our study, we tested only one regional anaesthesia protocol, which we
designed for a maximal efficacy: a sciatic nerve block that included the posterior cutaneous nerve of the
thigh to cover incisions in popliteal fossa, and a long-lasting anaesthetic agent at the maximal dose
according to the drug label, potentiated by clonidine. Protocols using less anaesthetics and favouring
motor function should also be tested. Potentiation of the block by a corticosteroid could also be
considered, and the a2 agonist dexmedetomidine is another new alternative to clonidine; however,
none of these adjuvants could be used here according to their drug label.
In conclusion, the protocol of intra-operative regional anaesthesia appears to offer sensible
postoperative advantages in femoropopliteal bypass surgery, and could be easily implemented into
current practice to improve postoperative rehabilitation. Further studies aiming at lowering the level of
narcosis associated with the block to improve haemodynamic tolerance would be useful.