Does it Worth to Reinforce With Additional Anesthesia to Improve Postoperative Course After Orthognathic Surgery?
Phase: PHASE2
Conditions: Dentofacial Deformities
Sponsor: Servei Central d'Anestesiologia

COVER PAGE STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN:
OFFICIAL TITLE:
Does it worth to reinforce with additional anesthesia to improve postoperative course after
orthognatic surgery?
DATE OF THE DOCUMENT:
11th of May, 2019

TITLE
Does it worth to reinforce with additional anesthesia to improve postoperative 
course after orthognatic surgery?
SUMMARY
Bimaxillary  osteotomy  is  a  surgery  procedure  of  the  orthognathic  surgery  field  for
correction of dental and facial abnormalities, for both functional and aesthetic cases. The incidence
of  this  abnormality  is  5-10%  of  the  population,  and  the  etiology  is  unknown,  with  genetic,
environmental  and  embryonic  factors  related.  The  surgery  technic  is  complex,  and  requires
osteotomy of the maxilla 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 anesthesia is mandatory. The investigators
propose the infiltration of local anesthesia in two different times, first pre-incision and second
before awaking the patient, for a proper control of postoperative pain. 
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 foreseeable 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 and
mandibular nerve intranasally and intraorally. 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 LA 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, has vasoconstrictor effect by itself and is less cardiotoxic than other equipotent LA
such as bupivacaine and levobupivacaine.
The investigators avoid the use of a combination of LA for maxillary and mandibular 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 pre-incision by the surgeon at the local level to
improve the surgical field. The use of clonidine is ruled out because it is not supplied in the hospital
center where the researchers 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. 
Thus, the investigators propose to use firstly lidocaine and adrenaline pre-incision (antiarritmic
effect and short duration of action). And secondly,  they propose to use ropivacaine without
adyuvant before extubation (vasoconstrictor effect and longer duration of action).
The control of postoperative pain is a primary factor to achieve greater patient satisfaction, better
rehabilitation  and  shorter  hospital  stay.  The  current  clinical  guidelines  recommend  the
management of postoperative pain control in a multimodal manner; and this includes the use of
local anesthetics.
HYPOTHESIS
Hypothesis tests: 

H0:  Patients  who  receive  LA  infiltration  in  two  stages  (pre-incision  with
lidocaine+adrenaline and pre-extubation with ropivacaine) do not have less postoperative
pain. 

H1:  Patients  who  receive  AL  infiltration  in  two  stages  (preincisional  with
lidocaine+adrenaline and pre-extubation with ropivacaine) have less postoperative pain.
OBJECTIVES
The main objective of the study is the evaluation of the effect of a peripheral pre-
incisional minor nerve block with the use of a single local anesthetic (lidocaine), compared with the
same  nerve  block  in  two  times  with  different  local  anesthetics  (lidocaine-preincisional  and
ropivacaine-pre-extubation), on the postoperative pain of patients undergoing elective bimaxillary
osteotomy,  evaluated by means of the visual analogue scale (VAS) of pain in the immediate
postoperative period (2 hours postoperatively). The secondary objectives of the study are: the
comparison of pain at 4, 8 and up to 18 hours after surgery, the comparison of the opioid use of
rescue (intravenous methadone milligrams) in the postoperative period of bimaxillary osteotomy
in the two groups of patients in the immediate postoperative period in resuscitation (2 hours
postoperatively)  and  in  the  hospitalization  floor  (18  hours  postoperatively),  comparing  the
incidence of postoperative nausea and vomiting (PONV) in the immediate postoperative period in
resuscitation (2 hours postoperatively)  and up to 18 hours after the surgery in the two groups of
patients, and the registry of complications derived from the two infiltrations.
MATERIAL AND METHODS
Study design
The investigators 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 52 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, 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  who  receive  two
infiltrations (firstly pre-incision with lidocaine and adrenaline,  secondly pre-extubation
with ropivacaine).
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, American Society of Anesthesiology Physical Status Examination System
(ASA) >3.
Procedure/Intervention
Patients will be received in the surgical area and a venous access line will be placed where
premedication (Midazolam 2mg/intravenous) and antibiotic prophylaxis (amoxicillin-clavulamic
2g/intravenous or Clindamycin 600mg/intravenous in case of patients allergic to beta-lactams) will
be  administered.  They  will  be  monitored  in  the  operating  room  (plasma  oxygen  saturation,
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/intravenous,  propofol  2mg/kg/intravenous,  rocuronium
0.6mg/kg/intravenous; and anesthetic maintenance: sevoflurane Minimum Alveolar Concentration
(MAC) 1.2 and remifentanil (RMF) Target Controlled Infusion  (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 and jaw to block
the terminal branches of the maxillary and mandibular nerve.
o
Study Group: the surgeon will proceed firstly with pre-incisional infiltration with lidocaine
and  adrenaline  and  secondly  with pre-extubation  infiltration  with ropivacaine  at  the
intraoral and intranasal submucosal level in the maxilla and jaw to block the terminal
branches of the maxillary and mandibular nerve.
PHARMACOLOGICAL TREATMENTS
o
Control  group:  Infiltration  performed  by  the  surgeon  at  the  intraoral  and  intranasal
submucosal level in the maxilla and jaw (blockage of terminal branches of the maxillary
and mandibular nerve) after intubation and previos to surgical incision.
A total of 50ml of the following preincisional mixture is infiltrated: ½blister 1mg/ml  
Adrenaline + 1blister 10ml Lidocaine 2% in physiological saline 100ml.
o
Study  group:  Two  infiltrations.  Firstly,  infiltration  performed  by  the  surgeon  at  the
intraoral and intranasal submucosal level in the maxilla and jaw (blockage of terminal
branches of the maxillary and mandibular nerve) after intubation and previos to surgical
incision. A total of 50 ml of the following preincisional mixture is infiltrated: ½ blister 1
mg/ml Adrenaline + 1blister 10ml Lidocaine 2% in physiological saline 100ml.
Secondly, infiltration performed by the surgeon at the intraoral and intranasal submucosal 
level  in  the  maxilla  and  jaw  (blockade  of  terminal  branches  of  the  maxillary  and  
mandibular nerve) before extubation. A total of 20 ml of ropivacaine 0,37%.
Previous to the surgical incision, fentanyl 0.5mcg/kg/ev will be administered again to all
patients and infusion of TCI of RMF at 2 ng/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/intravenous),  antifibrinolytic

agent (tranexamic acid 15mg/kg/intravenous), gastric protection (ranitidine 50mg/intravenous) ,
antiemetic agent (ondansetron 4mg/intravenous) and analgesics (paracetamol 1g/intravenous,
dexketoprofen 50mg/intravenous, diclofenac 75mg/intramuscular) and ketamine in subanesthetic
doses  (ketamine  20mg/intravenous  in  the  induction  and  ketamine  40mg/intravenous  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 0.2ng/ml. If NIBP increases last longer than 5 minutes, administration of
remifentanil bolus 2mcg/intravenous 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, a VAS value greater than 3 will be considered as
insufficient  pain  control  and  rescue  analgesia  will  be  administered  (first  anti-inflammatory
metamizole  2g/intravenous,  and  second  opioid  methadone  2mg/15minutes/intravenous  in
resuscitation, up to a total of 10mg/intravenous in the 2hours stay in resuscitation, and methadone
5mg/6hours/subcutaneous in hospital ward 2-18hours post-operative).
Definition of the variables
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 (American Society of Anesthesiologists) physical status classification system: 1-3
o
Temporary structure of evaluations:

Post-operative pain measured with the Visual Analogue Scale (VAS 0-10): at 2,
4, 8 and 18hours postoperatively.

Total intraoperative opioid dose (TCI-RMF effect concentration).

Total intravenous dose of opioids-methadone in the postoperative period (mg)
in  resuscitation  (2hours  postoperative)  and  subcutaneous  methadone  in
hospitalization (2-18hours postoperative).

Presence of PONV at 2, 4, 8 and up to 18hours postoperatively.

Complications derived from infiltration with lidocaine and adrenaline

Complications derived from infiltration with ropivacaine
CALCULATION OF THE SAMPLE AND STATISTICAL ANALYSIS
The sample selection method foresees the consecutive allocation of patients to two
groups:  
1. Control Group: a single pre-incision infiltration of LA lidocaine+adrenaline 
2.  Study  Group:  two  infiltrations  with  pre-incision  lidocaine+adrenaline  and  pre-
extubation with ropivacaine.  
The degree of pain is assessed using a visual analog scale (VAS) at different times after
surgery: 2, 4, 8 and 18hours. For the necessary sample size estimations, the pain measurement in
2hours postoperative will be considered as the primary response. The sample size will directly
depend on the clinically relevant minimum difference between the 2hours average pain level of
both groups. The following table provides sample sizes for different minimum difference values:  
Table 1.- Total sample size necessary to differentiate the mean degree of pain and statistical power,
assuming a standard deviation ± 1.25 for a confidence level of 95% and a t test for independent
samples.

Minimum  difference
to be detected in VAS
Effect size (d)
Power reached
70%
80%
90%
0,5
0,4 (medium)
158
200
266
1
0,8 (large)
42
52
68
1,5
1,2 (very large)
20
24
32
For example, assume a mean VAS pain level at 2hours equal to 5 and in the other group
6. That difference, assuming a deviation ± 1.25, equals a size of  effect d = 0.8, which is considered a
large magnitude. If for the researchers 1 point of difference in pain is already relevant, a total of 52
patients (26 per group) are needed to detect the difference as significant with a power of 80%. 
In  some  articles  (Annand,  Göçmen) standard  deviations  between  0.84  and  1.6 are
reported in different groups of local anesthetics and in the measurement times closer to 2hours.
For this reason, this level of variability has been assumed (± 1.25).  For a minimum difference of the
largest clinically relevant pain score, for example, 1.5 points (5 vs. 6.5 in the groups), a total size of
only 24 cases (12 per group) would be sufficient under the same conditions above. However, such
low sizes should be avoided due to possible problems in ensuring the normal distribution of the
data and being able to apply parametric tests, such as the t-test.
LIMITATIONS
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, the researchers propose the infiltration of prolonged LA after the
surgical procedure is completed before extubation of the patient. In this way, the investigators
benefit both from the effects of the first pre-incisional infiltration with lidocaine and from the
effects of the second pre-extubation infiltration with Ropivacaine. Pre-incisional lidocaine will
allow us to control intraoperative pain quickly and maintain up to 2hours, which is longer than
what the bimaxillary osteotomy lasts with the team of surgeons the investigators work with, a good
surgical field with the addition of adrenaline, and the antiarrhythmic effects in a surgery with high
incidence of intraoperative arrhythmias. With the pre-extubation infiltration with ropivacaine the
researchers will obtain a dense sensory block of up to 6-12 hours 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 tolerance orally progressively
faster and discharge earlier in hospital, with lower costs and greater effectiveness for the hospital
entity as a whole. 
On the other hand, the use of catheters for continuous infusion of LA to prolong the analgesic effect
in postoperative patients with bimaxillary osteotomy is ruled out. In bimaxillary surgery more than
one catheter should be used with the risk of infection and loss that this implies. It has also been
considered  that  for  the  control  of  mild-moderate  pain  beyond  12hours  after  surgery  it  is
satisfactory with the administration of oral analgesic drugs.
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 Good Clinical Practices International - Conference Harmonisation  Guidelines (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 (European Union) 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
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 LAs 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 this study the investigators propose the infiltration of prolonged LA after the
surgical procedure is completed before extubation of the patient. In this way the patient benefit
both from the effects of the first pre-incisional infiltration with lidocaine and from the effects of the
second  pre-extubation  infiltration  with  Ropivacaine.  Pre-incidental  lidocaine  will  allow  the
investigators to control intraoperative pain quickly and maintain up to 2hours, which is longer than
what the bimaxillary osteotomy lasts with the team of surgeons the researchers work with, a good
field of surgical work with the addition of adrenaline, and the antiarrhythmic effects in a surgery
with high incidence of intraoperative arrhythmias. With the pre-extubation ropivacaine we will
obtain a dense sensory block of up to 6-12hours 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 tolerance orally progressively faster and discharge
earlier in hospital, with lower costs and greater effectiveness for the hospital entity as a whole.
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