Keywords intranasal dexmedetomidine - transnasal trans-sphenoidal - skull base neurosurgery
Introduction
Transnasal transsphenoidal (TNTS) approach for surgical excision of the pituitary
gland is preferred by neurosurgeons worldwide as it offers a rapid midline access
to the sella with minimal risk of brain trauma or hemorrhage, excellent exposure of
the pituitary with adequate working space, and is associated with less postoperative
pain and a shorter hospital stay with a lower incidence of postoperative complications.[1 ]
[2 ] Despite these numerous merits, the TNTS approach creates wide fluctuations in hemodynamic
parameters, particularly, hypertension and tachycardia that is attributed to the routine
application of adrenaline-soaked nasal packing and the intense noxious stimulus during
nasal speculum insertion, sphenoid, and sellar dissection.[3 ] None of the routinely used anesthetic agents are able to effectively blunt these
undesirable hemodynamic responses, thus resulting in a need for increased doses of
anesthetic or vasoactive agents.[4 ]
[5 ]
[6 ]
The main purpose of the nasal mucosa preparation and the intraoperative blood pressure
control during endoscopic TNTS surgery is to provide a relatively bloodless and dry
surgical field to improve visibility and facilitate the surgical approach. Unfortunately,
the conventional practice of packing the nose with 1% lignocaine with adrenaline (1:10,000–1:20,000)
and further infiltration of the nasal mucosa with various dilutions of lignocaine
with adrenaline (1:50,000–1:200,000) preparations often cause hemodynamic changes
that can be catastrophic in patients with secretory pituitary adenomas such as Cushing's
disease and acromegaly who have an increased sensitivity to chatecholamines.[3 ]
[6 ]
[7 ]
Dexmedetomidine (DEX), a selective α2 -receptor agonist, is used for its sedative, analgesic, and anxiolytic properties
in clinical practice.[8 ]
[9 ] It has an analgesic-sparing effect, significantly reducing opioid requirements in
both intra- and postoperative periods.[10 ] DEX also has a sympatholytic effect, which can reduce the stress response to surgery
and ensure a stable hemodynamic state.[11 ] Intranasal DEX is convenient, effective, noninvasive, and also has useful analgesic
and sedative effects in surgical procedures.[12 ]
[13 ] Cheung's research has shown that intranasal DEX 1 and 1.5 μg/kg in surgical procedures
produced significant sedation and less postoperative pain.[13 ]
[14 ]
DEX has vasoconstrictive effects on peripheral blood vessels.[15 ]
[16 ] Locally injected DEX results in peripheral vasoconstriction without a systemic cardiovascular
response via the peripheral α2A -adrenoceptor subtype.[17 ] Further studies have also shown that activation of postsynaptic α2 -adrenoceptors will cause vasoconstriction (through the activation of α2 -adrenoceptors on vascular smooth muscle cells).[18 ]
However, the clinical use of intranasal DEX for its local effect of vasoconstriction
and hence its effects on the local bleeding during raising of the mucosal flap and
on the intraoperative hemodynamics after infiltration of the mucosa with adrenaline
in patients undergoing TNTS approach for pituitary adenoma surgery has not been explored.
We performed this study to evaluate the feasibility and efficacy of DEX for preoperative
nasal passage preparation on the surgical field visualization and hemodynamic profile
of patients during TNTS surgery.
Material and Methods
We conducted a prospective pilot study on patients undergoing TNTS excision of pituitary
tumors. Since the nasal mucosal vasoconstrictor effect of DEX in preparation of nasal
mucosa in TNTS surgeries has not been evaluated before, a pilot study was warranted
to evaluate the vasoconstrictor effects of DEX on the nasal mucosa for preparation
for TNTS surgery. The study protocol was approved by the Institutional Ethics Committee
and written informed consent was obtained from all the participants. Patients who
were pregnant or lactating had decreased levels of consciousness, raised intracranial
tension, recurrence of tumor, pituitary apoplexy, cardiac pathology, previous nasal
surgery, or history of allergy to any of the study drugs were excluded from the study.
The primary outcome parameters studied were the quality of surgical field visualization
through the endoscope and the amount of bleeding that occurred while raising the nasal
mucosal flap. The secondary outcome parameters assessed were the intraoperative anesthetic
requirement and hemodynamic profile.
Preprocedure, no sedative premedication was administered. Standard preinduction monitoring
consisted of electrocardiography (ECG), oxygen saturation (SpO2 ), and noninvasive blood pressure. Standard anesthetic induction was done with injections
(Inj.) fentanyl 1 to 2 μg/kg, propofol 2 mg/kg, and vecuronium 0.1 mg/kg. After intubation,
anesthesia was maintained using a combination of oxygen: air (50% FiO2 ) and sevoflurane titrated to a bi-spectral index (BIS) of 40 to 60. The radial artery
was cannulated for invasive blood pressure monitoring. Analgesia and muscle relaxation
was provided with infusions of Inj. fentanyl at 2 μg/kg/h and Inj. atracurium at 0.3
to 0.6 mg/kg/h, respectively. The posterior pharynx was packed with moist cotton gauze
to prevent the entry of surgical bleed into the esophagus and stomach.
Our surgeries were performed by the same surgical team consisting of one otolaryngologist
and one skull base neurosurgeon. Nasal preparation was performed by the surgeon using
cotton strips soaked in DEX. Cotton strips were imbibed with the solution; the excess
was carefully removed until the cotton strip was saturated but not dripping upon compression.
In a study done by Tang et al to evaluate the effect of intranasally administered
DEX in combination with local anesthesia (LA) on the relief of stress and the inflammatory
response during functional endoscopic sinus surgery (FESS), the nasal mucosa was prepared
with 1.5 µg/kg of DEX drops.[19 ] Intranasal DEX 2 µg/kg is routinely used as a premedication/sedation in the pediatric
patient undergoing magnetic resonance imaging (MRI) so we also used the same dose
of drug to evaluate the efficacy of the drug as a vasocontrictor.[20 ]
[21 ] The entire dose 2 µg/kg of DEX is diluted in 10 mL of saline that will be adequate
to soak the six cotton strips, which is required for the study. Each strip approximately
absorbed approximately 1 to 2 mL. Each nasal cavity was packed with three packs. One
placed on the floor of the nasal cavity, the other was placed over it to encroach
into the middle meatus and the last one was placed over the second one to anaesthetize
the frontal recess area. The nasal packs were left in situ for 10 minutes.
Prior to surgical incision, nasal septal mucosa was infiltrated with 1% lignocaine
with adrenaline solution (1:100,000). Hemodynamic parameters that included the heart
rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean
blood pressure (MAP) were measured at seven time points (T0, baseline; T1, 5 minutes
after nasal packing; T2, 15 minutes after nasal packing; T3, after local infiltration;
T4, at the beginning of surgery; T5, 30 minutes into surgery; T6, at the end of surgery;
T7, on arrival to the surgical intensive care unit [ICU]). Quality of intraoperative
surgical field during endoscopic surgery was evaluated by the surgeons using the Formmer's
scores for assessing surgical field quality (1, mild bleeding without any surgical
nuisance; 2, moderate bleeding, without any interference to surgery; 3, moderate bleeding
that moderately compromised surgical field; 4, bleeding, heavy but controllable, that
significantly interfered the surgery; 5, massive uncontrollable bleeding).[22 ] The end-tidal sevoflurane and minimum alveolar concentration (MAC) required for
sevoflurane to achieve a BIS of 40 to 60 was noted. If the blood pressure and HR remained
greater > 20% of the baseline, additional bolus doses of 5 mg of Inj. labetalol were
administered until the hemodynamic parameters return to baseline. Total of the additional
Inj. labetalol boluses were recorded for each patient. At the end of the procedure,
after reversal of neuromuscular blockade, when the patients were able to obey simple
commands, they were extubated and shifted to the surgical ICU for postoperative care.
Statistical Analysis
Data from the study were summarized as mean and standard deviation (SD). Associations
were tested using chi-square test for nonparametric data and for continuous variables
ANOVA (analysis of variance) for repeated measures. A p < 0.05 was considered as statistically significant and < 0.01 as highly significant.
SPSS 17.0 (SPSS Inc., Chicago, Illinois, United States) was used for analysis.
Results
Twenty patients were enrolled in our study. The mean age of the population was 44.2 ± 9.6
years having an average weight of 65.3 ± 10.2 kg with a male-to-female ratio of 2:3.
The mean surgical duration was 245 ± 28.8 minutes. Eight of the patients had a secretory
pituitary adenoma of whom four had cortisol-secreting, three had growth hormone–secreting,
and one had prolactin-secreting tumors. Three patients were hypertensives under control.
Seventeen (85%) patients had grade 1 Formmer's score that was an excellent surgical
field quality, characterized by a mild ooze not creating any surgical interference.
Two (10%) patients had a Formmer's score of 2, which was characterized by moderate
bleeding without surgical interference and one (5%) had a Formmer's score of 3, where
the surgeons encountered moderate bleeding that moderately compromised the surgical
field ([Table 1 ]).
Table 1
Surgical field quality as graded by the Formmer's score
Surgical field quality by
Formmer's score
No. of patients (n = 20)
1
17
2
2
3
1
4
0
5
0
Note: 1, mild bleeding without any surgical nuisance; 2, moderate bleeding, without
any interference to surgery; 3, moderate bleeding that moderately compromised surgical
field; 4, bleeding, heavy but controllable, that significantly interfered the surgery;
5, massive uncontrollable bleeding.
The hemodynamic changes in our population have been summarized in [Table 2 ]. We noted a reduction in HR at 5 minutes postnasal pack from the prepacking basal
HR that further continued on a downward trend even after submucosal injection with
adrenaline. Moreover, we noted that the HR plateaued through the surgical dissection
phase returning back to near baseline values at the time of extubation. The notable
fact was that there were minimal fluctuations in the HR following submucosal injections
of local anesthetic with adrenaline. A similar pattern was registered in the values
of SBP, DBP, and the MAP as well. A decrease in SBP, DBP, and MAP was noted in the
first 5 minutes postpacking with a transient minimal increase during the submucosal
infiltration followed by a gradual decreasing trend during the dissection phase ([Fig. 1 ]). These fluctuations in the measurements were found to be statistically insignificant
(p > 0.05). None of the patients had cardiac arrhythmias during the procedure. The hemodynamic
response did not differ between the patients with secretory and nonsecretory tumors
and those who were hypertensives and nonhypertensives.
Fig. 1 Trends in BP. T0, baseline; T1, 5 min after nasal packing; T2, 15 minutes after nasal
packing; T3, after local infiltration; T4, at the beginning of surgery; T5, 30 minutes
into surgery; T6, at the end of surgery; T7, in the surgical ICU (error bars = ± 1.96
SE). BP, blood pressure; ICU, intensive care unit; SE, standard error.
Table 2
Summary of the hemodynamic changes in our patient population
Stage of surgery
HR (beats/min)
(Mean ± SD)
SBP
(mm Hg)
(Mean ± SD)
DBP
(mm Hg)
(Mean ± SD)
MAP
(mm Hg)
(Mean ± SD)
Et Sevo (%)
(Mean ± SD)
MAC
(Mean ± SD)
BIS
(Mean ± SD)
T0
80.2 ± 10.1
124 ± 10.1
72.0 ± 7.3
89.3 ± 7.2
1.8 ± 0.2
0.8 ± 0.1
49.2 ± 5.9
T1
72.4 ± 9.6
115.2 ± 7.3
69.5 ± 9.2
84.5 ± 9.9
1.6 ± 0.1
0.7 ± 0.1
43.3 ± 4.9
T2
71.2 ± 10.1
111.1 ± 6.8
65.7 ± 7.1
80.7 ± 8.0
1.0 ± 0.1
0.5 ± 0.2
40.2 ± 6.6
T3
68.5 ± 8.7
114.7 ± 5.1
73.4 ± 4.9
86.9 ± 10.9
1.1 ± 0.1
0.5 ± 0.1
41.5 ± 4.8
T4
66.7 ± 9.3
111.2 ± 2.5
64.0 ± 5.7
79.7 ± 8.6
1.3 ± 0.2
0.6 ± 0.1
41.8 ± 7.9
T5
69.9 ± 11.3
111.1 ± 3.3
62.5 ± 6.3
78.3 ± 9.9
1.3 ± 0.1
0.6 ± 0.1
47.9 ± 5.8
T6
77.3 ± 9.7
115.1 ± 4.3
69.5 ± 5.1
84.3 ± 10.8
0.3 ± 02
0.1 ± 0.1
94.2 ± 9.3
T7
74.1 ± 6.3
112.0 ± 2.7
69.0 ± 3.4
83.3 ± 7.2
NA
NA
NA
Abbreviations: BIS, bi-spectral index; DBP, diastolic blood pressure; Et, end tidal;
HR, heart rate; MAC, minimum alveolar concentration; MAP, mean arterial pressure;
NA, not available; SBP, systolic blood pressure; SD, standard deviation; Sevo, sevoflurane.
The end-tidal concentration of the anesthetic agent sevoflurane reduced by 44% after
the DEX nasal pack compared with the postinduction baseline, to maintain a BIS of
40 to 60 reaching the lowest requirement during the surgical dissection phase ([Table 2 ]). Toward the end of the sellar dissection, there was a gradual increase in the requirement
of the anesthetic agent even though it remained significantly below the baseline (p < 0.05). This drop was concurrently reflected by a drop in the MAC requirements to
maintain a BIS between 40 and 60. The MAC requirements of sevoflurane was reduced
by a mean of 30% from the baseline following the nasal packing with DEX with the lowest
requirement being during the sinus dissection phase and minimally increasing later
on to plateau at 0.6 ± 0.1 MAC to maintain the same BIS. The total fentanyl requirement
of the patients was 5.1 ± 0.6 µg/kg. None of the patients required rescue antihypertensive
therapy with Inj. labetalol boluses. Two patients (10%) had postoperative nausea and
vomiting (PONV).
Discussion
The major challenges for endoscopic pituitary surgery are the rich vascularity and
complex anatomy of the nose.[3 ] Vasoconstriction of this highly vascular field is achieved conventionally through
a combination of 1% lignocaine with adrenaline (1:20,000–1:40,000) as soaked cotton
pledgets and injecting the nasal mucosa with various concentrations of lignocaine
with adrenaline (1:50,000–1:200,000) during nasal dissections at the anterior aspect
of the middle turbinate, sphenopalatine, and greater palatine foramen regions.[6 ]
[7 ] The tachycardia, hypertension, and arrhythmias secondary to the systemic absorption
of adrenaline from the highly vascular nasal mucosa can be catastrophic in patients
presenting with Cushing's disease and acromegaly who have an increased sensitivity
to adrenaline as well as associated cardiac abnormalities secondary to the excessive
levels of hormones such as cortisol, growth hormone, and insulin-like growth factor.[3 ]
[6 ]
[7 ] Several alternatives such as cocaine and xylometazoline have been previously considered
but abandoned due to their ineffectiveness or the incidence of adverse effects.[1 ]
[5 ] None of the routinely used anesthetic agents, in standard doses, effectively blunt
the undesirable hemodynamic responses. Consequently, increased doses of anesthetic
agents are required, resulting in the increased occurrence of adverse effects of the
anesthetics.[4 ]
[5 ] Iirola studied the bioavailability of DEX after intranasal administration. Plasma
DEX concentrations were measured for 10 hours, and pharmacokinetic variables were
calculated with standard noncompartmental methods. HR, blood pressure, concentrations
of adrenaline and noradrenaline in plasma, and central nervous system drug effects
(with the Maddox wing, BIS, and three visual analog scales) were monitored to assess
the pharmacologic effects of DEX. Following intranasal administration, peak plasma
concentrations of DEX were reached in 38 (15–60) minutes and its absolute bioavailability
was 65% (35–93%) (medians and ranges). Pharmacologic effects were similar to those
of intravenous administration.[23 ] Intranasal DEX, with bioavailability and pharmacological effects comparable with
intravenous administration, has been demonstrated to be beneficial in providing improved
surgical conditions for endoscopic sinus procedures of otolaryngologists.[14 ]
Our findings that 85% of the patients had grade 1 Formmer's scale suggests that intranasal
DEX provides adequate surgical field conditions. The initial step of the surgery involves
nasal mucosal dissection that requires that the nasal mucosa be prepared and bloodless.
As our title implies, we only assessed the efficacy of DEX as an agent for nasal passage
preparation prior to the surgery and its advantages. The surgical field quality assessed
was the state of the nasal mucosa till the point when the surgeon raised the nasal
flap for sinus dissection. In conventional practice initial nasal packing is done
with adrenaline (1:20,000–1:40,000) soaked strips followed by injection of adrenaline
(1:200,000) before raising the mucosal flap. This involves adverse hemodynamic response
that is detrimental to the patient's cardiovascular system. In our study we have substituted
this step of dual adrenaline insult with DEX nasal packs followed by adrenaline injection,
wherein the advantage is that the α-blockade provided by the DEX will negate the adverse
effect of the adrenaline injection that results in a better hemodynamic profile. Hypertensive
surges caused by the adrenaline injections result in bleeding spurts whereby the blood-less
field achieved by the vasoconstrictive effect of adrenaline is eventually lost. The
surgical field quality is assessed by the surgeons till the stage of raising the nasal
flap that is offered solely by the DEX nasal pack. Since this was a pilot study to
evaluate whether mucosal preparation with DEX is a feasible option instead of high
doses of adrenalin-soaked cotton strips, we did not include a control group in our
study.
Between 50 and 90% of patients undergoing pituitary surgery require either the use
of antihypertensive or vasoactive drugs to achieve intraoperative hemodynamic stability.
The absence of significant tachycardia and hypertension after infiltrating the nasal
submucosa with adrenaline in our study was remarkable. None of the patients had cardiac
arrhythmias during the procedure nor did they require rescue antihypertensive therapy
suggesting an added benefit of stable intraprocedural hemodynamic profile. Intranasal
DEX is known to decrease plasma epinephrine and norepinephrine level perioperatively
and attenuates hypertensive responses associated with surgical stimulation.[19 ]
The 44% reduction in end-tidal concentration of sevoflurane from postinduction baseline,
despite a gradual increase in the requirement of the anesthetic agent toward the end
of sellar dissection, remained significantly below the baseline (p < 0.05). The opioid requirement of 5.1 μg/kg was low as compared with routine pituitary
adenoma surgery of similar duration with requirements in the range of 7.7 μg/kg.[24 ]
This decreased anesthetic and analgesic requirement as a consequence of intranasal
DEX permits an early and predictable recovery of consciousness which is particularly
important in preventing airway obstruction in patients with secretary pituitary tumors
such as acromegaly and Cushing's disease that are associated with a high incidence
of obstructive sleep apnoea.[5 ]
[6 ] The use of postoperative nasal packs that makes these patients obligate mouth breathers
increases the risk of airway obstruction. Preventing aspiration of hemorrhagic secretions
from the nasopharynx requires an awake patient with intact airway reflexes. DEX reduces
the intraoperative opioid requirements and modifies the stress and inflammatory response
to surgical trauma, thereby attenuating the perioperative pain and improving the postoperative
outcome.[24 ] Another advantage of DEX is the absence of the risk of respiratory depression and
its associated complications.[25 ] Transnasal pituitary surgeries have an incidence of PONV as high as 50%. In our
study DEX appears to be effective in reducing the incidence of PONV (10%), which may
be attributed to the reduced requirement of intraoperative opioids.[6 ]
The limitations of this pilot study is the limited sample size as this was a study
to assess the feasibility of DEX as an agent for nasal passage preparation that was
never attempted before. The efficacy of DEX in patients with cardiac pathologies and
recurrent transnasal pituitary tumor surgeries requires further research.
Conclusion
To conclude, intranasal DEX appears to be a feasible agent for nasal passage preparation
in patients undergoing TNTS approach in skull base neurosurgery by providing good
endoscopic visualization with minimal nasal mucosal bleeding with a stable hemodynamic
profile.
