Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402

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Journal of Cranio-Maxillo-Facial Surgery

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The trigeminocardiac reflex: Does the activation pathway of its

efferent arc affect the intensity of the hemodynamic drop during the
management of maxillofacial fractures?
Ghada Amin Khalifa a, d, *, Manal Foad Abd-Elmoniem b, Fatma Ibrahim Mohamed c, d
a
Maxillofacial Surgery and Diagnostic Science, College of Dentistry, Qassim University, Saudi Arabia
b
Anaesthesia, Intensive Care, and Pain, Faculty of Medicine for Girls, Al Azhar University, 11727, Nasr City, Cairo, Egypt
c
Oral and Maxillofacial Surgery, Faculty of Dentistry, Deraya University, Minya, Egypt
d
Dental Medicine for Girls, Al Azhar University, 11727, Nasr City, Cairo, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: The study aimed to correlate between the stimulated nerve, intensity of trigeminovagal reflex (TVR), and
Paper received 26 March 2020 neuropathophysiological pathway by which the efferent arc is activated. Material and methods: A
Accepted 7 February 2021 retrospective study included patients who developed TVR during the surgical management of
Available online 12 February 2021
mandibular, midface, and orbital fractures. The reflex was divided into type I, II, III, and IV-TVR according
to the following nerves: ophthalmic, maxillary, mandibular, and non-trigeminal nerves, respectively. The
Keywords:
magnitude of hemodynamic drops was identified at the intraoperative baseline, during reflex, and
Trigeminovagal reflex
postoperatively. The needed time to elicit the reflex, frequency and duration, need for medical inter-
Oculocardiac Reflex
Afferent and efferent arc
vention, and sequence of the drop were also recorded. P - values < 0.05 was considered significant.
Hemodynamic drop Out of 260 patients’ files were reviewed, the TVR was observed in only 30 (11.55 %) patients. The
Mandibular fractures ophthalmic nerve activation significantly caused the greatest intensity and magnitude of hemodynamic
Orbital fractures drop, followed by maxillary nerve, then mandibular division, and the lowest one was non-trigeminal
Midface fractures nerves. The highest mean of drops in the mean arterial blood pressure (MABP) was 62.92 ± 2.39 with
the type ITVR, whereas those of the type II, III, and IV were 75.5 ±3.98, 81.02±1.31, and 82.22±1.85,
respectively. Also, the type I-TVR led to the greatest decrease in the heart rate (HR) with the mean
equaled to 52.31± 3.91. The drop percentage in the MABP was -30.5, -17.5, -12, -10.08 for type I, II, III, and
IV, whereas those of the HR were - 33.9, -27.13, -26.6, and -25 with type I, II, III, and IV, respectively. All
results showed highly significant differences with p-values less than 0.001 when comparing between the
baseline and intraoperative values of each TVR type.
There is a positive correlation between the activated pathway of the TVR and the intensity of its
efferent arc response due to the neural pathway of each division in the brainstem circuitry. Under-
standing of the pathophysiology and mechanism of the TVR, together with the rapid recognition and
treatment could prevent serious negative outcomes, especially when the ophthalmic nerve is stimulated.
1Introduction
© 2021 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights
reserved.

The incidence of maxillofacial injuries is continuously
increasing all over the world, and sometimes they are concomitant
with serious complications (Brucoli et al., 2019; Mourouzis et al.,
2018). In the field of maxillofacial surgery, the trigeminovagal re-
flex (TVR) is a physiologic response of the body to pressure effects
in the regions which are innervated by the trigeminal nerve (TN),
but it could also occur with non-trigeminal activation, such as
intracranial, pelvic, and thoracic surgeries, etc (Elsayed et al., 2019;
Schaller et al., 2009). Despite the uncommon development of the
TVR, it is one of the inherent intraoperative complications which

* Corresponding author. Maxillofacial Surgery and Diagnostic Science, College of Dentistry, Qassim University, Saudi Arabia.
E-mail addresses: ghadaamin@ymail.com, G.Khalifa@qu.edu.sa (G.A. Khalifa), d_taha66@yahoo.com (M.F. Abd-Elmoniem), fatma_ibrahim36@yahoo.com (F.I. Mohamed).

https://doi.org/10.1016/j.jcms.2021.02.004
1010-5182/© 2021 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed
could be a life-threatening condition. This is because it may lead to
asystole and even cardiac arrest during surgeries (Huang et al.,
2017; Kiani et al., 2016). Higher incidence was reported in chil-
dren, but it may be also observed at any age, even without the
presence of any preexisting cardiac problems (Guedes et al., 2019;
Kim et al., 2012; Lübbers et al., 2010).
The TVR is classified into two categories: the proximal TVR (the
sensory impulses travel from trigeminal ganglion to trigeminal
sensory nuclei in the brain stem as in intracranial surgeries) and
distal TVR (the stimulation starts from peripheral divisions to tri-
geminal ganglion and then to trigeminal sensory nuclei). The distal
TVR is further subdivided into four classes according to the stim-
ulated division. The stimulation of the ophthalmic, maxillary, and
mandibular division leads to the development of the type I, II, and
III-TVR, respectively. The type IV-TVR is categorized if the signs are
manifested in the manipulation of tissues that have non-trigeminal
innervation (Başag
aog
lu et al., 2018). Although the distal TVR is
widely observed, the correlation between its activated afferent arc,
the surgical step, the needed period of stimulation to elect the re-
flex, and its intensity is still not documented. Also, to our knowl-
edge, there is no study that explains why the TVR is mostly
encountered with the activation of the ophthalmic nerve. So, our
study aimed to link the neural pathophysiology of the TVR and
intensity of the hemodynamic drop during the management of
maxillofacial fractures in order to review and explain its
mechanism.
2. Patients and methods
2.1. Study Design
To answer the study question, a retrospective observational
cohort study was implemented between May 2015 and November
2019 at the Oral and Maxillofacial Surgery Department, Al Zahraa
Educational Hospital, Al Azhar University and Benisuef Govern-
mental General Hospital. The hospitals' database was accessed to
select the patients' files who met the following inclusion criteria: 1)
adult patients with orbital, midface, or mandibular fractures which
were managed by open reduction and rigid fixation, 2) TVR was
reported intraoperatively for at least one time, 3) all patients’ de-
mographic data were available, 4) all records of hemodynamic
changes were reported, 5) a standard anesthetic protocol was fol-
lowed, and 6) patients were without any systemic or neurological
disorders (American Society of Anesthesiologists status type I). The
files were excluded if one of these criteria was present: 1) any
preoperative systemic diseases, such as cardiac pacemaker, cardiac
arrhythmia, hypertension, myocardial infarction, diabetes, or ce-
rebral stroke, 2) any medications, for at least one month prior to the
study that might affect autonomic nervous system function, such as
sleeping pills, tranquilizers, or antidepressants, and 3) any change
in the anesthetic protocol. Written informed consent was obtained
from all patients before surgeries, and the local ethics review
committee of the Faculty of Dental Medicine for Girls at Al Azhar
University approved access to the patients' files.
2.2. Study variables
The patients’ files which met the inclusion criteria were classi-
fied into four types. Type I-TVR was triggered by stimulation of
ophthalmic division, type II-TVR was considered if the activation of
the maxillary branch occurred, whereas type III-TVR was elicited
with mandibular nerve stimulation. Finally, type IV-TVR was
documented when the reflex occurred with the manipulation of
non-trigeminal structures at the maxillofacial region (areas sup-
plied by the cervical plexus). The predictable variables of the study
395
Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402
were the stimulated nerve and the surgical step of the fracture
management at which the TVR occurred. The primary outcome
variable was the magnitude of the hemodynamic drop from the
baseline records to the intraoperative records during the occur-
rence of TVR. The percentage of decrease was also recorded as a
secondary outcome variable.
2.3. Surgical and Anesthetic Protocol
All surgical procedures were performed under a unique hypo-
tensive anesthetic protocol. All the patients fasted for 6 h before
surgeries. In the preanesthetic phase, 8 mg and 2 mg of dexa-
methasone and midazolam, respectively, were intravenously
injected as premedication drugs in all patients. In the operating
room, standard monitoring methods were applied, and they
included the use of ECG, pulse oximetry, oscillometer noninvasive
automated ambulatory blood pressure measurement, and cap-
nography. All the measurements were digitally recorded from the
monitor of the anesthetic machine (Vista 120 S, Drager-Primus
anesthetic machine, medical GmbH, Germany). The anesthetic
protocol was performed as follows: 1) the induction phase was
achieved via the intravenous injection of 1 mcg/kg fentanyl, 2 mg/
kg propofol, and 0.5 mg/kg atracurium, 2) the endotracheal tube of
suitable size was inserted and connected to the ventilator of the
anesthetic machine, 3) the respiratory rate and tidal volume were
adjusted to maintain the end tidal carbon dioxide within 10 %
variation from the patient's baseline value, 4) the intravenous fluid
therapy was performed according to the usual standards, and 5) the
maintenance of anesthesia was performed through administration
of 50 % oxygen with isoflurane 1e2 % and 0.1 mg/kg atracurium.
During the surgery, the hemodynamic variables, 20% variation from
the baseline values, were maintained by administration of intra-
venous sodium nitroglycerin 5 mcg/min via continuous infusion to
maintain the systolic blood pressure (SBP) at 85e90 mmHg and the
main arterial blood pressure (MABP) at 60e65 mmHg. At the end of
the surgery, the decision for extubation was made if the following
vital criteria were recorded: 1) normal pulse oximeter readings
(95e100 % arterial oxygen level), 2) adequate ventilation (tidal
volume higher than 5 mL/kg, end-tidal carbon dioxide below
50 mmHg), 3) hemodynamics stability, and 3) signs of a full reversal
in anesthesia (obeying the verbal commands and intact cough re-
flex). Neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg) were
intravenously administrated to reverse the neuromuscular block.
The endotracheal tube was not extubated if there was a possibility
of airway edema or electrolyte imbalance.
The following surgical steps were performed for all the patients
to manage their fractures: 1) extraoral or intraoral approaches that
were selected according to the site of fracture (Table 1), 2) open
reduction, 3) internal rigid fixation via miniplate osteosynthesis,
and 4) suturing. All operations were done by the same surgical
team and anesthesiologist.
2.4. Data collection
For each group, the changes in the heart rate (HR), SBP, diastolic
blood pressure (DBP), MABP, and oxygen saturation (SpO2) were
recorded to determine the hemodynamics and respiratory alter-
ations. The surgical step, at which the reflex occurred, was also
documented. The MABP was calculated by using the following
formula: DBP
2 þ SBP÷3. The drop percentage of the decrease
from the baseline parameters to the intraoperative records during
the occurrence of the TVR was also calculated to determine the
intensity of the TVR. The change from baseline values (V baseline) to
new values (V new) was calculated via the following equation:
V ðnewÞ  V ðbaselineÞ÷V ðbaselineÞ
100:Furthermore, the
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402

frequency of the TVR during the surgery and its class, either class A
(the alterations in the HR occurs before that of the MABP) or class B
(the changes in the MRBP occurs first), were documented. More-
over, the need for medical intervention and postoperative occur-
rence of the TVR were also reported.
2.5. Statistical Analysis
Statistical package of social sciences software (version 25.0)
(SPSS, Inc., Chicago, IL, USA) was used for statistical analysis. A
paired sample t-test was used to determine the statistical differ-
ences between the effects of the trigeminal divisions on the in-
tensity and frequency of the TVR. Means and standard deviations
(SD) were calculated, and the correlation test was used to correlate
between different variables. P-values less than 0.05 were deemed
to indicate statistical significance.
3. Results
Out of 260 patients' files reviewed, the TVR was observed in only
30 (11.55 %) patients during the surgical management of their
fractures. The patients’ demographic data are shown in Table 2. The
data present in Tables 3e6, showed that the TVR significantly
occurred when the ophthalmic division (type I-TVR; 43.33 % of 30
cases) was stimulated, followed by the stimulation of the maxillary
nerve (type II-TVR; 30 % of 30 cases). The results also showed that
the stimulation of the mandibular nerve (type III-TVR; 16.67 % of 30
cases) exhibited the least incidence for the TVR occurrence, when it
is compared to its incidence during the stimulation of the
ophthalmic and maxillary nerves. Also, the incidence of the type IV-
TVR constituted 10 % of the TVR cases. The type I-TVR also had the
higher prevalence of the occurrence when each type was compared
to its total number of the cases. The percent of the reflex occurrence
in regard to the total number of the reviewed files in each type was
as follows: 1) thirteen cases (26 %) out of 50 areas which are sup-
plied by the ophthalmic nerve developed the reflex, 2) the type II-
TVR was reported in 12.86 % (9 cases out of 70 subjects who had
operations in the area of the maxillary nerve), 3) the type III-TVR
occurred in 6.25 % (5 cases out of 80 patients who their mandib-
ular nerve was stimulated), and 4) Five percent of the cases
developed type IV-TVR (only 3 subjects out of 60 areas that are
innervated with the great auricular branch of the cervical plexus,
cervical spinal 2 and 3).
Regarding the frequency of the TVR during the surgery, it
occurred more than once in 53.85 % of the cases that had type I-
TVR. In type II-TVR, the reflex frequently occurred in 44.44 % of the
patients, whereas only 20 % of the subjects who had type III-TVR
reported frequent episodes of the reflex during the surgery. A sin-
gle episode of the TVR was recorded in the patients who had type
IV-TVR. The cessation of the procedure was enough to stop TVR in
the majority of the cases. Only five patients (16.67 %) needed the
intravenous injection of atropine (0.6 mg/kg) to control the TVR.
Three of them had type I-TVR and the others had type II-TVR.
The results also demonstrated a positive correlation between
the occurrence of the TVR and the surgical step. In type I-TVR, the
stage of eyeball retraction was the most common cause for the
occurrence of TVR (eight out of 13 patients, 61.54%), followed by the
release of the inferior rectus muscle entrapment (three patients,
23.07 %), and then the plate fixation and reflection of orbital floor
mucoperiosteum that constituted 7.69 % for each. However, with
type II-TVR, the reduction of fractures was the predominant cause
(four out of nine patients, 44.44 %). The subciliary incision precip-
itated type II-TVR in 33.33 % of the patients (three patients); the
maxillary vestibular incision and plate fixation were the main cause
(11.11 % for each) in type II-TVR. The type III-TVR mainly occurred
during the stage of the fracture reduction (80 % of cases), and the

Table 1
Surgical approaches to fractures and type of TVR.

Surgical approach Site of fracture Innervation Type of TVR

a
Subperiosteal dissection of orbit Orbital floor Ophthalmic division Type I
Lower eyebrow approach/lateral eye brow approach Zygomaticofrontal suture Ophthalmic division Type I
Subciliary lower-eyelid approachb Zygomaticomaxillary Maxillary division Type II
Maxillary vestibular approach Zygomatic butters Maxillary division Type II
Mandibular vestibular approach Angle fracture Mandibular division Type III
Submandibular approach Angle fracture Non-trigeminal innervation Type IV
a
The last layer of the subciliary incision after dissection of skin and orbicularis oculi muscle.
b
TRC that occurred during skin and orbicularis oculi muscle incision was included in type II, whereas that occurred during subperiosteal dissection of orbital floor was
implicated to type I.

Table 2
Patients’ demographic data.

Parameters Type I Type II Type III Type IV

Ophthalmic nerve Maxillary nerve Mandibular nerve Non-trigeminal innervation

Site of fracture Orbital floor Zygomatic complex Mandibular Angle! Mandibular Angleb
Zygomaticofrontal
Patients number (total number: 30 patients)a 13 9 5 3
Sex: 9 7 2 1
Male 4 2 3 2
Female
Age in year (mean ± SD) 33.54 ± 1.23 38.23 ± 0.873 29.13 ± 0.421 28.13 ± 0.192
Preoperative hemodynamic parameters (mean ± SD): 80.78 ± 1.23 82.08 ± 0.23 81.48 ± 1.23 81.28 ± 1.53
HR (beats/min) 119.32 ± 1.45 120.32 ± 1.85 119.92 ± 1.38 117.32 ± 0.45
SBP (mmHg) 82.68 ± 0.25 81.68 ± 1.25 81.47 ± 0.39 80.48 ± 0.95
DBP (mmHg) 95.94 ± 1.78 94.04 ± 0.78 95.74 ± 1.78 93.94 ± 1.08
MABP (mmHg) 98.21 ± 1.05 97.21 ± 1.85 99.21 ± 1.75 99.01 ± 1.29
Spo2 (%)
a
Total number of TVR among patients with maxillofacial fractures!: Mandibular fractures approached via intraoral incisions.
b
Mandibular fractures approached through extraoral incisions.

396
 G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed
Table 3
The hemodynamic records of type I-TVR.

Number (13 out of 50 Type of fracture Surgical procedure HR SBP (mmHg) DBP MAPR SpO2 (%) Number of Need for Time (sec) Class of
cases) (beats/min) (mmHg) (mmHg) times treatment TVR

C D C D C D C D C D

1 Orbital floor Reflection of mucoperiosteum 80 54 119 90 79 50 92.33 63.33 98 89 1 Stop 8 A

manipulation
2 Orbital floor Release of inferior rectus muscle 79 55 120 91 80 52 93.33 65 99 88 2 Stop 9 B
entrapment manipulation
3 Orbital floor Eye ball retraction 78 50 110 88 78 55 88.67 66 98 87 2 Stop 8 A
manipulation
4 Orbital floor Eye ball retraction 80 51 115 80 77 51 89.67 60.67 97 90 1 Stop 10 A
manipulation
5 Orbital floor Eye ball retraction 80 55 118 81 79 60 92 67 96 89 1 Stop 10 A
manipulation
6 Orbital floor Eye ball retraction 80 52 119 83 80 53 93 63 98 88 2 Stop 9 B
397

manipulation
7 Orbital floor Eye ball retraction 79 50 120 88 80 49 93.33 62 100 89 1 Stop 8 B
manipulation
8 Orbital floor Eye ball retraction 78 51 114 80 76 53 88.67 62 97 88 3 Atropine 8 A
9 Orbital floor Eye ball retraction 83 52 114 87 77 51 89.33 63 97 86 2 Atropine 8 A
10 Orbital floor Eye ball retraction 84 50 119 79 79 49 92.33 59 96 89 4 Atropine 8 A
11 Orbital floor Release of inferior rectus muscle 78 52 118 88 78 55 91.33 66 98 89 2 Stop 9 A
entrapment manipulation
12 Orbital floor Release of inferior rectus muscle 70 52 110 80 79 51 89.33 60.67 99 87 1 Stop 8 B
entrapment manipulation
13 Zygomaticofrontal Plate fixation 80 56 120 81 80 50 93.33 60.33 99 89 1 Stop 10 A

Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402

suture manipulation
Mean —————— —————— 79.15 52.31 116.61 84.31 78.61 52.23 90.51 62.92 97.84 88.30 ————— —————— 8.69 ± 0.67 —————
± SD ±3.15 ±3.91 ±3.49 ±4.23 ±1.27 ±2.94 ±2.68 ±2.39 ±1.16 ±1.06
Margin of Error: —————— —————— 0.87 0.54 0.97 1.17 0.35 0.82 0.74 0.66 0.32 0.29 ————— —————— 0.23 —————
ESM 1.71 1.07 1.90 2.30 0.69 1.60 1.45 1.28 0.63 0.57 0.45
CI
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402

Table 4
The hemodynamic records of type II-TVR.

Number (9 out Type of fracture Surgical HR SBP (mmHg) DBP MAPR SpO2 (%) Number Need for Time (Sec) Class of
of 70 cases) procedure (beats/min) (mmHg) (mmHg) of times treatment TVR

C D C D C D C D C D

1 Zygomatic Subciliary 79 58 116 99 79 67 91.33 77.67 99 92 2 Stop 15 A

complex fracture incision manipulation
2 Zygomatic Maxillary 80 53 122 104 80 68 94 80 99 91 1 Stop 16 A
complex fracture vestibular manipulation
incision
3 Zygomatic Fracture 78 58 110 93 78 66 88.67 75 98 89 2 Stop 15 A
complex fracture reduction manipulation
4 Zygomatic Plate fixation 81 54 120 102 77 65 91.33 77.33 100 90 1 Stop 16 A
complex fracture manipulation
5 Zygomatic Fracture 80 55 119 101 79 67 92.33 78.33 96 89 2 Stop 17 A
complex fracture reduction manipulation
6 Zygomatic Fracture 78 59 119 101 80 66 93 77.67 98 91 3 Stop 18 A
complex fracture reduction manipulation
7 Zygomatic Fracture 79 58 117 99 80 68 92.33 78.33 100 93 1 Stop 19 B
complex fracture reduction manipulation
8 Zygomatic Subciliary 78 59 116 98 76 64 89.33 75.33 99 89 1 Atropine 20 A
complex fracture incision
9 Zygomatic Subciliary 71 59 119 101 77 65 91 77 98 89 1 Atropine 20 A
complex fracture incision
Mean —————— —————— 78.22 57 117.56 99.78 78.44 65.78 91.48 75.5 98.56 90.33 ————— —————— 17.33 ± 3.56 ————
± SD ±2.73 ±2.21 ±3.24 ±2.94 ±1.42 ±092 ±1.59 ±3.98 ±1.36 ±1.45
Margin of Error: —————— —————— 0.91 0.74 1.08 0.97 0.47 0.30 0.53 1.33 0.39 0.47 ————— —————— 0.63 ————
ESM 1.79 1.45 2.11 1.91 0.93 0.60 1.04 2.61 0.76 0.92 1.23
CI

Table 5
The hemodynamic records of type III-TVR.

Number (5 out of Type of fracture Surgical HR (beats/ SBP DBP MAPR SpO2 (%) Number of Need for Time Class of
80 cases) procedure min) (mmHg) (mmHg) (mmHg) times treatment (sec) TVR

C D C D C D C D C D

1 Mandibular angle Fracture 80 59 120 105 80 70 93.33 81.67 100 92 1 Stop 20 A

fracture reduction manipulation
2 Mandibular angle Fracture 79 59 119 102 78 70 91.67 80.67 99 91 1 Stop 20 B
fracture reduction manipulation
3 Mandibular angle Plate fixation 78 58 118 104 79 69 92 80.67 98 90 2 Stop 20 A
fracture manipulation
4 Mandibular angle Fracture 77 57 115 103 77 67 89.67 79 97 90 1 Stop 20 A
fracture reduction manipulation
5 Mandibular angle Fracture 79 55 123 109 79 70 93.67 83 96 89 1 Stop 20 A
fracture reduction manipulation
Mean —————— —————— 78.6 57.6 119 104.6 78.6 69.2 92.07 81.02 98 90.4 ————— —————— 5 ± 0.00 ———
± SD ±1.02 ±1.50 ±2.61 ±2.41 ±1.02 ±1.16 ±1.42 ±1.31 ±1.41 ±1.02
Margin of Error: —————— —————— 0.46 0.67 1.17 1.08 0.46 0.52 0.64 0.58 0.63 0.46 ————— —————— 0.00 ———
ESM 0.89 1.31 2.29 2.11 0.89 1.02 1.25 1.15 1.24 0.89 0.00
CI

Table 6
The hemodynamic records of type IV-TVR.

Number (3 out of Type of fracture Surgical HR (beats/ SBP (mmHg) DBP MAPR SpO2 (%) Number of Need for Time Class of
60 cases) procedure min) (mmHg) (mmHg) times treatment (sec) TVR

C D C D C D C D C D

1 Mandibular Submandibular 80 59 119 107 79 71 92.33 83 98 89 1 Stop 30 A

angle fracture incision manipulation
2 Mandibular Submandibular 79 59 120 108 80 72 93.33 84 99 88 1 Stop 30 A
angle fracture incision manipulation
3 Mandibular Submandibular 77 59 110 99 78 70 88.67 79.67 98 87 1 Stop 30 A
angle fracture incision manipulation
Mean —————— —————— 78.67 59 116.33 104.67 78.61 71 91.44 82.22 93.33 88 ————— —————— 10 ± 0.00 ———
± SD ±1.24 ±0.00 ±4.49 ±0.72 ±4.03 ±0.82 ±2.68 ±1.85 ±0.22 ±0.67
Margin of Error: —————— —————— 0.72 0.00 2.60 0.20 2.33 0.47 2.00 1.07 0.27 0.47 ————— —————— 0.00 ———
ESM 1.41 0.00 5.09 0.39 4.56 0.92 1.16 2.10 0.53 0.92 0.00
CI

398
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402

Table 7
The percent of changes in hemodynamic changes.

Baseline vs operation MABP (mmHg) Baseline vs operation HR (Beat/min) Baseline vs operation SpO2 (%) Class of TCR n
TCR (%)

Mean ± SD Mean ± SD Percent of P-value Mean ± SD Mean ± SD Percent of P-value Mean ± SD Mean ± SD Percent of P-value Class Class
change change change A B

Type 90.51 62.92 30.5 0.00001 79.15 52.31 33.9 0.00001 97.84 88.30 9.8 0.00001 9 4
(n ¼ 13) ±2.68 ±2.39 ±3.15 ±3.91 ±1.16 ±1.06 (69.23) (30.77)
Type II 91.48 75.5 17.5 0.00001 78.22 57 27.13 0.00001 98.56 90.33 8.35 0.00001 8 1
(n ¼ 9) ±1.59 ±3.98 ±2.73 ±2.21 ±1.36 ±1.45 (88.9) (11.1)
Type III 92.07 81.02 12 0.000011 78.6 57.6 26.7 0.00001 98 90.4 7.75 0.000023 4 (80) 1 (20)
(n ¼ 5) ±1.42 ±1.31 ±1.02 ±1.50 ±1.41 ±1.02
Type IV 91.44 82.22 10.08 0.0087 78.67 59 25 0.000024 93.33 88 5.7 0.0001 3 (100) 0
(n ¼ 3) ±2.68 ±1.85 ±1.24 ±0.00 ±0.22 ±0.67

Baseline: records after intubation.

patients but six developed class A TVR. Those six patients devel-
oped class B TVR. Four of them had type I-TVR, one case showed
type II-TVR, whereas the last one developed type III-TVR. None of
the patients developed TVR postoperatively.

4. Discussion

To the best of our knowledge, none of the TVR clinical assess-

Fig. 1. A drawing showing the parasympathetic limb of the trigeminal nerve (blue
lines) to cerebral blood vessels through the ophthalmic nerve (V1). The maxillary
nerve also provides parasympathetic fibers to cerebral blood vessels through the
connection between the trigeminal and pterygopalatine ganglia.
submandibular incision was the only cause for the development of
type IV-TVR.
All the study's cases showed the classic signs of the reflex, and
the total event lasted for a mean period of 3.17 ± 0.903 min. The
Type I- TVR had the longest time, whereas the signs lasted for a
period that ranged from 2.11 to 2.30 min. In other types, all he-
modynamic records returned to their normal values within a period
that ranged between 30 and 120 s. Also, the type I-TVR required the
shortest time period of the tissue manipulation (8e10 s) to elect the
reflex, and the type IV-TVR needed the longest period of time
(25e30 s). The maxillary nerve stimulation elicited the reflex after
10e15 s, whereas the manipulation of the areas supplied by the
mandibular nerve led to development of the reflex after 20 s.
The baseline and drop values in the HR, SBP, DPS, MABP, and
SpO2 are summarized in Table 7. A highly positive correlation factor
was documented between the type of the TVR, surgical step, and
intensity of the reflex. The drop percentage of the hemodynamics
drop revealed that the type I-TVR has the greatest intensity and
magnitude of hemodynamics instability. The drop percentage of
decrease in the MABP was 30.5, - 17.5, - 12, and - 10.08 for type I,
II, III, and IV-TVR, respectively. Additionally, the type I-TVR signif-
icantly reported the maximum intensity of the decrease in the HR
and SpO2 records (Table 7). Regarding the class of TVR, all the
399
ments have not yet been linked between the anatomy of the TVR
arcs and its neural pathway. Also, they did not explain why the
stimulation of the ophthalmic nerve is considered the greatest
contributing factor. So, our study aimed to correlate the type of the
TVR and its neural pathway. The study's results did not demon-
strate any variations from other reports which proved that the
greatest magnitude of the hemodynamic drop occurs with the
stimulation of the ophthalmic nerve, followed by the maxillary
nerve, and then the mandibular and non-trigeminal innervations
(Woernley et al., 2017; Kiani et al., 2016; Kosaka et al., 2000). We
believe that the anatomical location of each nerve in the brainstem
and the mechanism by which it stimulates the parasympathetic
cranial outflow to the cardiovascular system and other structures
have an impact on the occurrence and intensity of the TVR. The
ophthalmic and maxillary nerves are able to stimulate the para-
sympathetic outflow of the vagus nerve through two pathways. The
first one is the stimulation of the trigeminovascular system (TVS).
The other pathway is the somatotopic arrangement in the spinal
trigeminal nucleus (STN), so they have a dual effect, whereas the
mandibular and non-trigeminal innervations elicit the TVR only
through the somatotopic arrangement in the STN.
The stimulation of the TVS results in vasodilatation of cerebral
arteries (Fig. 1) that triggers protective reflexes which are associ-
ated with a bradycardia to preserve oxygen consumption by
minimizing the HR (Lemaitre et al., 2015). The ophthalmic nerve
has the largest contribution to the TVS via the Gasserian ganglion.
Therefore, its stimulation activates more parasympathetic fibers as
reported by many authors (Ruthirago et al., 2017; Shiflett et al.,
2015; Bleys et al., 2001). The maxillary nerve has the second
largest contribution via the pterygopalatine ganglion (Bohluli et al,
2009a, 2010b). So, its stimulation also stimulates the TVS but with a
lesser incidence and intensity than the ophthalmic nerve. The
maxillary contribution occurs either directly via the adipose tissues
of the pterygopalatine fossa which extends into the cavernous sinus
to share in the formation of the lateral cavernous nerve plexus that
constitutes a part of the TVS (Bleys et al., 2001) or indirectly
through the ophthalmic nerve. The ophthalmic nerve receives the
parasympathetic fibers of the maxillary nerve via a communicating
nerve between its zygomatic branch and the ophthalmic division
(Bohluli et al., 2009) or through the direct connection between the
Gasserian and pterygopalatine ganglia (Edvinsson et al., 2018).
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed
Fig. 2. An illustration demonstrating the distribution of the trigeminal division through parts of the spinal sensory nucleus in the medulla oblongata: The V1 is the ophthalmic
nerve that terminates in the pars caudalis (C), the V2 is the maxillary division that ends in the pars interporalis (I), and the mandibular branch (V3) ends in the pars oralis (O).
Fig. 3. A diagram showing the relation between parts of the spinal trigeminal ganglion
(O, I, and C) and the parasympathetic nuclei of the cardiovascular system on the
sagittal view of the brainstem at the level of medulla oblongata. The brown nucleus
denotes the nucleus ambiguous of the vagus nerve (
) which mainly carries the
preganglionic parasympathetic fibers to the heart; The yellow one represents the
motor dorsal nucleus that carries the preganglionic parasympathetic fibers mostly to
walls of blood vessels. Both nuclei are in close relation to pars caudalis (C) and pars
interporalis (I). Pars oralis (O) has the farthest location in the relation to both para-
sympathetic nuclei of the vagus nerve.
400
Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402
Therefore, many authors announced that the ophthalmic division
constitutes the afferent limb of the TVR when the maxillary nerve is
stimulated (Bohluli et al., 2009). This explains the higher incidence
and magnitude of hemodynamic changes that occur with the type
II-TVR as compared to type III and IV-TVR.
There is a wide controversy in the literature regarding the
mandibular nerve contribution to the TVS. Many authors proved
that it has no contribution () (Bohluli et al., 2011), and even those
who suggested its contribution via otic ganglion mentioned that it
is nil (Bleys et al., 2001). Thus, both type III and type IV-TVR are
developed via only one pathway, which is the somatotopic
arrangement in the brainstem. On the other hand, others reported
that the TVS activation develops a diving reflex which is manifested
by either maintained or increased MABP that is opposite to the
decreased MABP during the TVR. So, they omitted the role of the
TVS in stimulating the occurrence of the TVR (Kiviniemi et al.,
2012). Nevertheless, there are many authors who considered that
the diving reflex is a subtype of the TVR which is mainly elicited by
the stimulation of the ophthalmic nerve (Lemaitre et al., 2015;
Yorgancilar et al., 2012).
The somatotopic arrangement in the STN determines the rela-
tion between each nerve and the parasympathetic nuclei of the
vagus nerve (Fig. 2). The ophthalmic division synapses in the pars
caudalis (the most inferior part of the STN), the maxillary division
terminates in the pars interporalis (the middle part of the nucleus),
and the mandibular division ends in the pars oralis (its superior
part) (Cramer GD, Darby, 2014). The dorsal motor nuclei of the
vagus nerve (DMNV) provide the main parasympathetic supply to
the gastrointestinal tract and blood vessels, whereas the para-
sympathetic output to the heart and lungs comes mainly from the
nucleus ambiguous (NA) and to a lesser extent from the DMNV. The
parasympathetic control in the NA is located at its caudal part
(Vasudev et al., 2015). Both pars caudalis and vagal nuclei are
located at the base of the fourth ventricle in the medulla oblongata
(Figs. 3 and 4). Therefore, the ophthalmic nerve has the closest
position to the vagal nuclei, followed by the maxillary division. The
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed
mandibular nerve has the farthest position because the pars oralis
is located in the caudal part of the pons (Dampney, 2016; Wehrwein
and Joyner, 2013). We believe that the greatest intensity of the type
I- TVR is owed to the close approximation between the ophthalmic
nerve and vagal nuclei, where it is well proved that the intensity
and velocity of the nerve signals depend on some neural parame-
ters like radius and length (El Hady and Machta, 2015). However,
there is another school of thought that omits our belief. This school
suggested that each trigeminal division is distributed throughout
the whole length of the STN. The pars oralis and pars interporalis
receive fibers that carry impulses of the discriminative tactile
sensation, whereas the pars caudalis receives impulses of the pain
and temperature (Lipari et al., 2017).
Despite that, this could explain why painful stimuli are able to
develop the TVR with an intensity more than other types of stimuli.
This is also due to the close relation between the pars caudalis and
vagal nuclei. Thus, among all surgical procedures, eyeball retraction
is able to produce the highest intensity of hemodynamic drop.
Eyeballs are very rich in mechano-nociceptors per square inch,
more than anywhere else in the body, and the mechanical stretch is
the most painful stimuli of those that provoke pain (Shakil et al.,
2019). The same is also reported about the manipulation of the
fractured segments, which leads to mechanical stretch painful
stimuli with a high strength (Kosaka et al., 2001; Lübbers et al.,
2010)). Also, the nature of the stimuli is the largest potential risk
Fig. 4. A drawing showing the medial to lateral positions of brainstem nuclei of the
trigeminal and vagus nerves. The nucleus ambiguous (NA) (the main parasympathetic
supply to the cardiac muscles) is closer to pars interporalis (I, V2) and pars caudalis (C,
V1) than the motor dorsal vagal nucleus (DMNV) (the main parasympathetic supply to
the smooth muscles of the blood vessels).
401
Journal of Cranio-Maxillo-Facial Surgery 49 (2021) 394e402
factor that evokes the TVR, where the sustained and abrupt traction
is able to elicit the TVR more than gentle and smooth traction as
reported by Cha et al. (2002).
The ophthalmic nerve is also indirectly stimulated during the
release of the entrapped inferior rectus muscle through the
manipulation of the ciliary ganglion via long and short ciliary
nerves. This indicates that there are multiple ways by which the
ophthalmic nerve is stimulated at the same time during surgeries,
which increases the strength of the stimuli with a subsequent in-
crease in intensity of the parasympathetic vagal stimulation, as
suggested by others (Woernley et al., 2017). The sequence of the
hemodynamic changes was also investigated in our study. The re-
sults demonstrated the predominance of class A over class B. This
also could be due to the closer position of the NA (main para-
sympathetic supply to the heart) to the STN (Fig. 4) than that of the
DMNV (main parasympathetic supply to blood vessels) (Noseda
and Burstein, 2013). So, the activation of the parasympathetic
supply to the heart occurs earlier than that of the blood vessels.
The small sample size is the main limitation of this study.
Nevertheless, it has clinical importance where it anatomically ex-
plains why the ophthalmic nerve develops TVR with the greatest
intensity of the hemodynamic drop. Understanding the anatomical
relations enables us to more greatly emphasize the importance of
the interaction between the anesthesiologist and surgeon, together
with the careful monitoring of the HR and PB, during every surgical
step of the midface and orbital fractures management to avoid
serious negative outcomes.
5. Conclusion
It can be concluded that the ophthalmic nerve elicits the TVR via
its largest contribution to the TVS and its closest anatomical rela-
tion with the vagal nuclei in the brainstem circuitry. So, its stimu-
lation is able to develop TVR with the highest incidence and
intensity. The maxillary nerve also has the same mechanisms as the
ophthalmic nerve but to a lesser extent. The mandibular nerve and
other non-trigeminal innervations have a low effect because they
have only one neural pathway to elicit the TVR. Therefore, under-
standing of the neural pathophysiology and mechanisms of the
TVR, together with rapid recognition and treatment, could prevent
serious negative outcomes, especially during the management of
the orbital and midface fractures.
Declaration of Competing Interest
No.
SD: Standard deviation.
Class A is allocated when the TVR showing heart rate changes
before changes which occur in the mean arterial blood pressure;
class B is assigned to patients with TVR showing changes in the
mean arterial blood pressure before heart rate alterations (Leon-
Ariza et al., 2018); C: Baseline records after intubation; D: Records
during the TVR; ESM: The standard error of the mean; CI: Confi-
dence intervals 95 %.
Class A is allocated when the TVR showing heart rate changes
before changes which occur in the mean arterial blood pressure;
class B is assigned to patients with TVR showing changes in the
mean arterial blood pressure before heart rate alterations (Leon-
Ariza et al., 2018); C: Baseline records after intubation; D: Records
during the TVR; ESM: The standard error of the mean; CI: Confi-
dence intervals 95 %.
Class A is allocated when the TVR showing heart rate changes
before changes which occur in the mean arterial blood pressure;
class B is assigned to patients with TVR showing changes in the
mean arterial blood pressure before heart rate alterations (Leon-
G.A. Khalifa, M.F. Abd-Elmoniem and F.I. Mohamed
Ariza et al., 2018); C: Baseline records after intubation; D: Records
during the TVR; ESM: The standard error of the mean; CI: Confi-
dence intervals 95 %.
Class A is allocated when the TVR showing heart rate changes
before changes which occur in the mean arterial blood pressure;
class B is assigned to patients with TVR showing changes in the
mean arterial blood pressure before heart rate alterations (Leon-
Ariza et al., 2018); C: Baseline records after intubation; D: Records
during the TVR; ESM: The standard error of the mean; CI: Confi-
dence intervals 95 %.
Acknowledgment
We would like to express our thanks to Alaa Akram Elmarakby,
Medical Student, Faculty of Medicine, Helwan University for her
assistance in accomplishing our paper and drawing our illustra-
tions. Also, we are grateful for Engineer/Amor Okacha Abdelmaged
Khelly, Visual artist and Freelance illustrator, and Dr. Heba
Mohamed Azouz, Neurosurgery specialist and medical illustrator at
Cairo University Hospital for the time and effort they have spent on
the professional drawing of the illustrations via computer software.
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