Effects of Ultrasound-guided Bilateral Suprazygomatic Maxillary Nerve Block on Postoperative Pain After Elective Bimaxillary Osteotomy in Adult Patients
Phase: NA
Conditions: Dentofacial Deformities, Regional Anesthesia Morbidity
Sponsor: Servei Central d'Anestesiologia

COVER PAGE STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN:
OFFICIAL TITLE:
Effects of ultrasound-guided bilateral suprazygomatic maxillary nerve block
on postoperative pain after elective bimaxillary osteotomy in adult patients.
DATE OF THE DOCUMENT:
13th of March, 2019

TITLE
Effects of ultrasound-guided bilateral suprazygomatic maxillary nerve block
on postoperative pain after elective bimaxillary osteotomy in adult patients.
SUMMARY
Bimaxillary osteotomy is a surgery procedure of the orthognathic surgery field with the
aim to correct dental and facial abnormalities, for both functional and aesthetic cases. The incidence
of  this  abnormality  is  5-10%  of  the  population,  and  its  etiology  is  unknown,  with  genetic,
environmental and embryonic factors related. The surgical technique is complex, and requires
osteotomy of the maxillary and jaw, which allows toward, forward, impact and rotation of these
bones to fix the edges of the face. The anesthetic management of these patients is a challenge
because  of  the  difficult  airway  management  and  the  perioperative  pain  control.  Multimodal
approach for pain control is a fact, and the use of local and regional anesthesia is mandatory. We
propose bilateral suprazigomatic maxillary nerve block for a proper control of postoperative pain
after bimaxillary osteotomy.
INTRODUCTION
Bimaxillary osteotomy is a surgical procedure in the field of orthognathic surgery (from 
Latin, "orthos" straight and "gnathos" jaw) for the correction of dentofacial deformities, both for 
functional and aesthetic reasons. The incidence of this deformity is estimated to be arround the 5-
10% of the population. Genetic, environmental and embryonic factors are postulated to be the 
origin of such deformity, though its origin is still unknown. The surgical technique is complex, with 
the performance of mandibular and upper jaw osteotomies that allow to advance, retrude, impact 
and rotate these bones, to align the facial axes. For all these reasons, the anesthetic management of 
these patients is a challenge. First, the foreseable difficulty of managing the patient's airway; and 
second, the control of the patient's pain in the perioperative period.
Therefore, bimaxillary osteotomy is a frequent surgery and potentially painful in adults. Bimaxillary
surgery under general anesthesia is the common practice. And peripheral non-ultrasound-guided
peripheral nerve blocks are widely used by surgeons. These minor blockades are used to avoid the
undesired effects of anesthetics and analgesics; mainly the adverse respiratory effects of opioids.
The practice of loco-regional anesthesia provides a control of perioperative pain in a multimodal
way showing effective postoperative analgesia and minimizing the respiratory depression caused
by the excess use of opioids. 
In general, during bimaxillary surgery the surgeon performs the infiltrations with local
anesthetic (LA) in a pre-incisional manner for the  blockade  of the  terminal branches of the
maxillary nerve intraorally and intranasally. The choice of LA is influenced by considerations such
as the start of action, duration and toxicity. A wide range of LA has been used in maxillofacial
surgery, such as lidocaine and ropivacaine among others. Both LA produce a reversible blockade of
the sodium channel of the neuronal membrane, and are synthetic derivatives of cocaine. Both
possess three essential functional units (hydrophilic tertiary amide chain, linked by an intermediate
amide chain, to another lipophilic aromatic ring-portion). This means, both LA are amide type; but
even if they belong to the same group of LAs there is still great differences in the beginning of
action, duration of action and toxicity. Lidocaine has a faster start of action (short latency) than
ropivacaine, and has an antiarrhythmic effect. Ropivacaine is more potent, the action last longer
than  lidocaine,  and  is  less  cardiotoxic  than  other  equipotent  LA  such  as  bupivacaine  and
levobupivacaine. 
Subsequently, the introduction of loco-regional nerve blocks has meant for the anesthesiologist, in
the last three decades, a revolution in the management and control of perioperative pain. The
expansion of the practice of loco-regional nerve blocks has been seen in both upper and lower
limbs, as well as in trunk and abdomen. On the contrary, the facial blockages (both superficial and
deep) have not experienced the same; laying its practice to the surgeon, or to anesthesiologists
working on the chronic pain domain. The subsequent introduction of ultrasonography (USG) in the

1990s in the perioperative period also represented an important advance for anesthesiologist both
in terms of safety and in terms of ease of management of venous and arterial catheterizations, and
practice of loco-regional blockages. Consequently, USG experienced anesthesiologists have recently
published in regards to the use of ultrasounds (US) for the blockage of facial nerves in children and
adults undergoing maxillofacial surgery. USG devices are increasingly accessible, more portable,
cheaper and safer; and therefore, its introduction in the field of perioperative pain management of
maxillofacial surgery has still a long way to go.
The maxillary nerve, just like the ophthalmic, is only sensitive. It is detached from the
anterolateral border of the trigeminal ganglion, laterally to the ophthalmic. From its origin, it goes
above, crosses the round hole and penetrates into the background of the infratemporal fossa until it
enters the pterygopalatine fossa (except the middle meningeal nerve, all its branches reach the
pterygopalatine fossa before reaching the facies). In the pterygopalatine fossa the maxillary nerve is
located  in  the  upper  part  of  the  cavity  and  passes  superiorly  to  the  maxillary  artery  and
superolaterally to the pterygopalatine ganglion. The maxillary nerve receives and conducts the
sensitivity of the skin of the cheek, the lower eyelid, the wing of the nose and the upper lip. Its deep
branches drive the sensitivity of the mucosa of the lower part of the nasal cavities or respiratory
area, and of the dental roots and the gums of the maxilla.
Therefore, in order to produce an effective anesthesia of the maxillary area, the needle can be
introduced through the pterygomaxillary fissure to the pterygopalatine fossa, with risk of vascular
and nerve puncture. However, with real-time vision of the ultrasound-guided block, these risks will
be limited, allowing a direct localization of the maxillary artery, position of the needle and the
distribution of LA within the pterygopalatine fossa. The pterygopalatine fossa is anatomically deep
and  surrounded  by bones.  The  most  optimal  ultrasound  window  is  the  infrazigomatic  path,
allowing  the  visualization  of  the  entire  axis  of  the  pterygopalatine  fossa  up  to  the  foramen
rotundum.
The  usual  practice  for  the  ultrasound-guided  maxillary  nerve  block  is  the  placement  of  the
ultrasound  probe  in  an  infrazigomatic  position  and  the  introduction  of  the  needle  by
suprazigomatic route for better visualization of the procedure. The approach by suprazigomatic
route from the frontozigomatic angle is one of the safest and recommended routes to reach the
foramen rotundum. This trajectory limits the insertion of the needle in the anterior portion of the
foramen rotundum, avoiding, this way, the inadvertent puncture of the intraorbital content through
the infraorbital fissure. 
Experienced anesthesiologists in anesthesia for maxillofacial surgery, perform bilateral ultrasound-
guided blockade of the maxillary nerve by suprazigomatic route with ropivacaine for greater
control of perioperative pain. They avoid the use of a combination of LA for maxillary nerve block.
The  combination  of several  local anesthetics  in  the  same  nerve  block is  sometimes  used in
perioperative anesthesia with the intention of compensating the short duration of action of some
agents whose start of action is fast, such as lidocaine, and the high latency of the agents that present
a more lasting action, such as ropivacaine. The combination of lidocaine and ropivacaine offers
clinical advantages (rapid onset, long duration). However, to date, indications for combining LA are
scarce because of the use of catheters in many forms of regional anesthesia that allow to prolong
the duration of the block. This is nevertheless not an extended practice among anesthesiologists in
maxillofacial surgery. On the other hand, it is important to also remember avoiding the use of
maximum doses of two LA combined, which is based on the erroneous belief that their toxicities are
independent; on the contrary, the toxicities have an additive character.
Multiple drugs have been used to increase the time of action of LA, such as adrenaline, clonidine,
dexamethasone, ketamine and dexmedetomidine, among others. In our patients, adrenaline is
always administered along with physiological serum by the surgeon at the local level to improve
the surgical field, both in patients who undergo pre-incision infiltration and bilateral blockade of
the maxillary nerve. The use of Clonidine is ruled out because it is not supplied in the hospital
center where we will carry out the study. The use of dexamethasone and ketamine is ruled out,
because they will be administered intravenously in the patient's perioperative period as anti-
inflammatory agents and anesthetic adjuvant, respectively. And the use of Dexmedetomidine is also
ruled out in order to prolong the effect of the nerve blockade as this indication is not in the
technical file.
HYPOTHESIS

Hypothesis tests:
•  H0:  Patients  who  receive  bilateral  ultrasound-guided  blockade  of  the  maxillary  nerve  by
suprazigomatic  route  with  ropivacaine  and  dexmedetomidine  don’t  have  less  immediate
postoperative pain and don’t require fewer opioids in the immediate postoperative period than
patients who receive a pre-incisional infiltration with lidocaine
•  H1:  Patients  who  receive  bilateral  ultrasound-guided  blockade  of  the  maxillary  nerve  by
suprazigomatic route with ropivacaine and dexmedetomidine have less immediate postoperative
pain and require fewer opioids in the immediate postoperative period than patients who receive a
pre-incisional infiltration with lidocaine
OBJECTIVES
Main objective of the study is the evaluation of the effectiveness of the bilateral ultrasound-
guided  ultrasound  blockade  with  ropivacaine  suprazigomática,  compared  to  the  peripheral
infiltration of the nerve with lidocaine and adrenaline, on the consumption of opioids for control of
perioperative pain of patients intervened of elective bimaxillary osteotomy, evaluated by means of
the analogical visual scale of pain in the immediate postoperative period (2 hours postoperatively).
The secondary objectives of the study are: comparison of the use of opioids in the intraoperative
period (Target Controlled Infusion - TCI ng / ml - intravenous remifentanil), comparison of the use
of  rescue  opioids  (milligrams  of  intravenous  methadone)  in  the  postoperative  period  in
hospitalization (2-18h postoperative), the comparison of the incidence of immediate postoperative
nausea and vomiting (PONV) in resuscitation and up to 18 hours after surgery, the comparison of
initiation of oral tolerance after the end of surgery, and the registry of complications derived from
ultrasound-guided maxillary nerve block.
MATERIAL AND METHODS
Study design
We propose a double-blinded prospective comparative experimental study (patient and
nurse). After the approval of the ethics committee of our hospital and the signed consent from each
of the patients in the study, patients will be scheduled for bimaxillary osteotomy and will be
randomly and prospectively assigned to one of the two groups with a plan to register up to 58
patients. Patients will not know the group that they have been assigned consecutively; and both the
postoperative resuscitation nurses and the hospitalization nurses who will perform VAS records,
opioid consumption, oral tolerance initiation, PONV and postoperative complications, will also be
unaware of the analgesic treatment that the patient has received in the operating room. Patients
will be assigned randomly to one group or another:
o
Control  group:  patients  undergoing  elective  bimaxillary  osteotomy  who  receive  a
preincisional infiltration of lidocaine and adrenaline.
o
Study  group:  patients  undergoing  elective  bimaxillary  osteotomy  whith  bilateral
echoguided blockade of the maxillary nerve by suprazigomatic route with ropivacaine; and
infiltration with preincisional adrenaline.
Population
The source and mechanism of subject selection is a convenience sample, with consecutive
recruitment in our clinic at the Maxillofacial Institute of Teknon Medical Center.
The criteria for the selection of subjects is the following. The inclusion criteria are patients who
undergo scheduled bimaxillary surgery. The exclusion criteria are: the refusal to participate in the
study, patients who are scheduled for bimaxillary surgery together with another complementary
surgical  procedure  (such  as  mentoplasty,  rhinoplasty,  blepharoplasty),  age  <18  years,
reinterventions, urgent surgeries, allergies to local anesthetics, allergies to anti-inflammatories
agents, allergies to opioids, ASA ≥3.
Procedure / Intervention

Patients will be received in the surgical area and a venous access line will be placed where
premedication (Midazolam 2mg / ev) and antibiotic prophylaxis (amoxicillin-clavulamic 2g / ev or
Clindamycin 600mg / ev in case of patients allergic to beta-lactams) will be administered. They will
be monitored in the operating room (SpO2, electrocardiogram, non-invasive blood pressure –
NIBP-, Bispectral index, Train of four TOF - CUFF neuromuscular monitor) and general intravenous
anesthesia will be carried out (anesthetic induction: fentanyl 2mcg / kg / ev, propofol 2mg / kg /
ev, rocuronium 0.6mg / kg / ev; and anesthetic maintenance: sevoflurane CAM 1.2 and remifentanil
TCI - Effective Concentration 2ng / ml). After the nasal intubation of the patient, the administration
of the LA will proceed by the following routes:
o
Control Group: the surgeon will proceed with pre-incisional infiltration with lidocaine and
adrenaline at the intraoral and intranasal submucosal level in the maxilla to block the
terminal branches of the maxillary nerve.
o
Study Group: the anesthesiologist will proceed to the bilateral blockade of the maxillary
nerve echoguided by suprazigomatic route with ropivacaine and dexmedetomidine; and
the surgeon will infiltrate with intraoral and intranasal submucosal adrenaline in the
maxilla.
PHARMACOLOGICAL TREATMENTS
o
Control  group:  Infiltration  performed  by  the  surgeon  at  the  intraoral  and  intranasal
submucosal level in the maxilla (blockage of terminal branches of the maxillary nerve)
after intubation and previos to surgical incision.
A total of 50ml of the following preincisional mixture is infiltrated: ½ amp Adrenaline + 1amp
Lidocaine 2% in physiological saline (SF) 100ml.
o
Study group: Bilateral ultrasound-guided maxillary nerve block by suprazigomatic route
after intubation and previous to surgical incision performed by the anesthesiologist.
A total of 5ml of Ropivacaine 0.37% infiltrated on each side.
Together with adrenaline infiltration performed by the surgeon at the intraoral and intranasal
submucosal level in the maxilla.
A total of 50ml of the following preincisional mixture is infiltrated: ½ amp Adrenaline + 110ml SF.
Previous to the surgical incision, fentanyl 0.5mcg/kg/ ev will be administered again to all
patients and infusion of target-controlled infusion (TCI) of remifentanil (RMF) at 2ng / ml effect
concentration will be initiated. It will be administered intraoperatory to all patients as adjuvant
therapy, as long as there is no contraindication, corticotherapy (methylprednisolone 15mg / kg /
ev), antifibrinolytic agent (tranexamic acid 15mg / kg / ev), gastric protection (ranitidine 50mg /
ev) , antiemetic agent (ondansetron 4mg / ev) and analgesics (paracetamol 1g / ev, dexketoprofen
50mg / ev, diclofenac 75mg / im) and ketamine in subanesthetic doses (ketamine 20mg / ev in the
induction and ketamine 40mg / ev slow intraoperative administration). The mechanical ventilation
by controlled volume (6ml / kg) will be adjusted to maintain a CO2 at the end of expiration around
32-38mmHg. In the intraoperative period, in cases of changes in basal NIBP equal to or greater than
20%, remifentanil will be increased / reduced in TCI 0.2mcg / ml. If NIBP increases last longer than
5 minutes, administration of remifentanil bolus 2mcg / ev will proceed. If abrupt drops of the NIBP
will proceed to stop the TCI RMF. Patients will be extubated in the operating room after removal of
pharyngeal tamponade, gastric aspiration and reversal of neuromuscular relaxation and recovery
of protective airway reflexes. In the postoperative period, an EVA value greater than 3 will be
considered as  insufficient  pain  control  and rescue  analgesia  will be  administered  (first  anti-
inflammatory metamizole 2g / ev, and second opioid methadone 2mg / 15 '/ ev in resuscitation, up
to a total of 10mg / ev in the 2h stay in resuscitation, and methadone 5mg / 6h / sc in hospital ward
2-18h post-operative).
Definition of the variables
o
demographic data: age (years), sex (man / woman)
o
anthropometric data: weight (kg), height (cm)
o
comorbidities: free text
o
ASA: 1-3

o
Temporary structure of evaluations:

Post-operative pain measured with the Analog Visual Scale (EVA 0-10): at 2, 4, 8 
and 18 h postoperatively.

Total intraoperative opioid dose (TCI-RMF effect concentration).

Total intravenous dose of opioids-methadone in the postoperative period (mg) in 
resuscitation (2 hours postoperatively) and subcutaneous methadone in 
hospitalization (2-18h postoperative).

Total dose of rescue analgesics in the postoperative period (mg of intravenous 
Metamizol) immediately after resuscitation (2 hours postoperatively) and in the 
hospital ward (2-18h postoperative).

Presence of PONV at 2, 4, 8 and up to 18 h postoperatively.
o
Time from the departure of the operating room to the beginning of tolerance orally
(hours)
o
Complications derived from the administration of LA
o
Complications derived from infiltration with lidocaine and adrenaline
o
Complications derived from the bilateral blockade of the maxillary nerve 
echoguided by suprazigomatic route with ropivacaine 
CALCULATION OF THE SAMPLE AND STATISTICAL ANALYSIS
The method of sample selection provides for the random assignment of patients in two groups:
1. Surgical pre-incision infiltration of LA lidocaine-adrenaline at submucosal level to block the 
terminal branches of the maxillary nerve practiced by the surgeon.
2. Surgical pre-incision bilateral maxillary nerve blockade ultrasound guided by suprazigomatic 
route practiced by the anesthesiologist.
The analgesic effectiveness of the blocks is evaluated by the consumption of methadone in the first 
2 post-operative hours. This measure will be considered the primary response from which to 
estimate the necessary sample size.
The sample size will directly depend on the clinically relevant minimum difference between the 
average level of methadone consumption at 2h of both groups.
The article by Moro concludes a similar effect of morphine and methadone in the control of post-
operative pain, so that the data reported in studies using morphine will be extrapolated to the use of 
methadone. At least, the data for morphine will be considered a lower level, given the great 
interpersonal variability of the drugs.
The author Kitlik reports postoperative consumptions of bolus morphine of 7.5 ± 4.0 in a group of 
patients with Transabdominal Plane-TAP block in abdominal surgery (figure 2, page 106). This 
deviation will be the one used in the sample size calculations. No randomized clinical trials similar to 
ours have been found in adults.
The following
table shows 
sample sizes for
different values 
of minimum
difference:
Table 1.- Total
sample size 
needed to
differentiate the 
mean level of
methadone 
consumption and
statistical 

power, assuming a standard deviation of ± 4 in the groups for a confidence level of 95% and a t test 
of independent samples.
    
 
Minimum difference 
to be detected in the 
average consumption 
(mg)
Size effect  (d)
Power reached
70%
80%
90%
1 (+10%)
0,2 (small)
398
506
676
2 (+25%)
0,5 (medium)
102
128
172
3 (+33%)
0,8 (large)
46
58
78
4 (+44%)
1,0 (extra large)
28
34
46
For example, suppose an average level of methadone consumption at 2 h is 9 and 12 mg in both 
groups, that is, a difference of 3 mg, or what is the same, 33% in relative terms. This percentage 
difference can be considered clinically relevant and is equivalent to an effect size d = 0.8 (large). If 
for the researchers these 3 mg difference in consumption is already relevant, a total of 58 patients 
(29 per group) are needed to detect the difference as significant with a power of 80%.
Depending on the minimum clinically relevant difference that you wish to detect, the sample size 
may vary according to the figures provided in the table above.
Note also in Figure 2 of the Kitlik article that at 24h the average consumption is 40 ± 15 mg in the
TAP group. Therefore, a difference of + 25% with another group (average 50 mg) would imply a
medium-large effect size (and not medium, as now).
That means, if the total consumption during the first 24 hours is taken as a response variable, the
necessary sample sizes will tend to be smaller.
Concerning the future statistical methodology to be used, it is also expected to use a nonparametric
Brunner-Langer model for longitudinal data (equivalent to the classic ANOVA), in order to compare
the groups in terms of the general evolution pattern. This model contrasts the hypothesis of
homogeneity of the evolution of the degree of pain, and not only the comparison in a specific time-
point.
LIMITATIONS
The use of AL with vasoconstrictor (Adrenaline) in the pre-incisional infiltrations practiced
by the surgeon provides the following advantages: it prolongs the duration of anesthesia, decreases
the systemic toxicity by decreasing the proportion of AL that is absorbed into the bloodstream, it
increases the intensity of blockade by direct alpha agonist effects in the antinociceptive neurons of
the spinal cord, provides local vasoconstriction and decreases bleeding in the surgical field and
assists us in the detection of accidental intravascular injection. Therefore, we propose in the study
group to continue asking the surgeon to perform the adrenaline infiltrations in the same places
where he performs the peripheral blockade of the maxillary nerve to provide vasoconstriction and
dissection of the necessary surgical field.
Regarding a bimaxillary osteotomy surgery, the nerves involved are both the maxillary nerve and
the mandibular nerve. The maxillary nerve we have already mentioned as we are going to block it
in an echoguided way at the level of the pterygopalatine fossa before the exit of its terminal
branches, except for the middle meningeal nerve. In the case of the mandibular nerve or inferior
maxillary nerve; for its block, we will continue asking the surgeon to perform the pre-incisional
infiltration with AL lidocaine. The blocking of the mandibular nerve is not proposed at a more
proximal level and in an echoguided manner because with the truncal anesthesia of the mandibular
nerve with intraoral access, the results are satisfactory[xxxx].
 
Ethics 

All information is provided to the patient before making the decision to participate or not in the 
study. 
The information is based on the elements included in the guidelines of the Declaration of Helsinki 
and GCP ICH Guides. 
The investigator will describe to the patient all the measures that will be carried out for data 
protection and patient privacy according with  the Organic Law 3/2018, of December 5, on the 
Protection of Personal Data and guarantee of digital rights. "It is the adaptation to the Spanish legal 
system of Regulation (EU) 2016/679 of the European Parliament and the Council of April 27 of 
2016.
The investigator must explain to the patient the limitations and risks of the study and the 
possibility of interrupting their participation in any of the stages of the study without affecting the 
relationship with the researcher and / or health personnel.
The information sheet and informed consent will be provided to the patient along with a verbal 
explanation. The patient must accept and sign before initiating any procedure related to the study.
EXPECTED RESULTS 
Infiltration with LA in the terminal branches of the maxillary nerve is the common practice for
bimaxillary osteotomy surgery, along with the administration of intravenous opioids for the control
of perioperative pain. All this has been seen to increase nausea and vomiting, resulting in greater
dissatisfaction on the part of the patient and longer hospital stay. On the other hand, with the
bilateral ultrasound blockade at the suprazigomatic level in a safe and ultrasound-guided manner,
with  adjusted  doses  of  ropivacaine,  it  is  expected  to  decrease  the  doses  of  opioids  in  the
perioperative period; and therefore, increase patient safety and satisfaction, through greater pain
control and decreased PONV; as well as, accelerate tolerance orally in the postoperative period and
hospital discharge
The choice of LA reflects the balance between the rapidity of the onset of action and the desire for a
prolonged duration of postoperative analgesia. Since maxillofacial procedures produce significant
postoperative pain, the use of long-acting LA will be a recommendation.
The combined solutions of LA have the disadvantage of a short duration of action compared to the
isolated use of a long-acting LA. In our study we propose the administration of ropivacaine, in such
a way that we obtain a dense sensory block of up to 6-18h in the postoperative period that will
benefit the patient in global terms, with less postoperative pain and greater patient comfort. , with a
decrease in postoperative nausea and vomiting, initiation of oral tolerance progressively faster and
hospital discharge earlier, with lower costs and greater effectiveness for the hospital entity as a
whole.
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