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Imidazoline use in sinonasal surgery
Medical Hypotheses 82 (2014) 706–708
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Imidazoline use in sinonasal surgery R.G. Campbell a, S. Nair b, R. Sacks c, R.G. Douglas d,⇑ a
North Shore Hospital, Waitemata District Health Board, Auckland, New Zealand Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand c Macquarie University and the University of Sydney, Australia d Department of Surgery, The University of Auckland, New Zealand b
a r t i c l e
i n f o
Article history: Received 13 November 2013 Accepted 5 March 2014
a b s t r a c t The nasal mucosa is very vascular, receiving more blood flow per cubic centimeter of tissue than does muscle, brain or liver (Drettner and Aust, 1974; [1]). This vascularity can present a major problem during sinus surgery. Surgeons routinely use topical vasoconstrictors in endoscopic sinus surgery however, the optimal regimen is not clear. Imidazoline nasal sprays are often used up to 1 hour before sinonasal surgery to aid in intraoperative vasoconstriction. After the induction of anaesthesia, epinephrine-based topical and submucosal preparations are subsequently administered to further enhance vasoconstriction. Imidazolines are non-selective, partial alpha adrenoceptor agonists with a higher affinity, yet lower potency, for alpha adrenoceptors when compared to epinephrine. It is hypothesized that imidazolines block the action of epinephrine on the alpha adrenoceptors of the nasal mucosa resulting in less vasoconstriction, and a poorer intra-operative field, when compared to the use of epinephrine alone. This paper hypothesizes that preoperative imidazoline administration may adversely affect optimal intra-operative vasoconstriction. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction The nasal mucosa is very vascular with excellent absorptive abilities. It receives more blood flow per cubic centimeter of tissue than that of muscle, brain and liver [1] and this vascularity can present a major problem during extensive sinus surgery. Bleeding in endoscopic sinus surgery (ESS) is predominantly of capillary origin, and generally responds well to locally applied vasoconstrictors [2]. Locally acting agents are more effective at reducing mucosal blood flow during ESS than systemic vasodilators acting to reduce mean arterial pressure [3]. Furthermore, the application of higher concentrations of vasoconstrictors, such as epinephrine, has been shown to result in less intra-operative blood loss compared to lower concentrations [2]. This may be due to the preferential stimulation of a- and b1-adrenoceptors at higher concentrations as opposed to the preferential stimulation of b2-adrenoceptors at lower concentrations which can result in vasodilation [4]. Vasoconstrictors can also be injected submucosally (usually in association with local anesthetics). However, the application of vasocontrictors by infiltration leads to a more rapid, and therefore potentially more dangerous, rise in plasma adrenaline levels when ⇑ Corresponding author. Address: Department of Surgery, The University of Auckland, Grafton, Auckland, New Zealand. Tel.: +64 9 6311980; fax: +64 9 6311966. E-mail address: [email protected] (R.G. Douglas). http://dx.doi.org/10.1016/j.mehy.2014.03.009 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
compared to topical preparations. Plasma adrenaline concentrations are higher following infiltration compared to topical application [5]. This limits the concentration used and the effectiveness of vasoconstriction when agents are applied via infiltration [5]. As a result, endoscopic sinus surgeons routinely use topical vasoconstrictors in conjunction with infiltration of epinephrine containing solutions. Whether imidazoline nasal sprays, such as oxymetazoline and xylometazoline, and epinephrine are potentially antagonistic in their vasoconstrictive actions have not been investigated. To date, no study has compared the effect of epinephrine used alone and epinephrine used in conjunction with imidazolines on nasal mucosal blood flow. We hypothesize that use of the combination may result in less vasoconstriction than epinephrine alone.
Pharmacology of the nasal mucosal vasculature The nasal mucosal vasculature is predominantly innervated by the sympathetic nervous system [6]. Nasal vascular smooth muscle tone is controlled by both a1- and a2-adrenoceptor post-synaptic receptor subtypes [7]. When the sympathetic nerves are stimulated, they release norepinephrine, which acts via post-synaptic a1- and a2-adrenoceptors in the vasculature to cause vasoconstriction [7]. Six different genetic subtypes of a-adrenoceptor exist: a1A, a1B, a1D, a2A, a2B and a2c [8]. The a1A, a2A and a2B subtypes are the most abundantly expressed in the human nasal mucosa [9].
R.G. Campbell et al. / Medical Hypotheses 82 (2014) 706–708
However, the a2A-adrenoceptor is a pre-synaptic receptor on sympathetic nerve endings where it inhibits norepinephrine release [9]. The role of the a2A-adrenoceptor in nasal vascular tissue is unknown, however, it is not involved in imidazoline- or epinephrineinduced vasoconstrictive actions and likely plays a putative role in nasal mucosal vasoconstriction [9]. Hence, the a1A and a2B-adrenoceptors play the most important role in vasoconstriction in human nasal mucosa. The a2-adrenoceptor predominates in the nasal mucosal vasculature [9,10] and preferentially acts on veins, reducing engorgement of venous sinusoids, thereby decreasing nasal congestion and increasing nasal airflow. The a1-adrenoreceptors preferentially act on the arteries of human nasal mucosa, resulting in vasoconstriction and a reduction in blood flow [7,11,12]. This would suggest that it is the a1A receptors that should be targeted for pre- and intra-operative vasoconstriction in sinonasal surgery.
707
Xylometazoline is also a non-selective a-adrenoceptor agonist, however, it is a full agonist only at a2B-adrenoceptors where it demonstrates high affinity [9]. In particular, xylometazoline had a threefold greater affinity for a2B-adrenoceptors compared to oxymetazoline [9]. Xylometazoline demonstrates no activity at a1A-adrenoceptors, despite its higher affinity when compared to epinephrine [9]. Xylometazoline occupies this receptor, yet fails to cause receptor activation. The onset of action of xylometazoline is within a few minutes and its duration of action lasts up to 10 hours [21]. Systemic absorption of both imidazolines is limited due to their vasoconstrictive properties [20,21]. Systemic absorption may occur in the context of excessive use or gastrointestinal absorption [20,21]. Side effects of imidazolines include hypertension, local irritation and rebound nasal congestion [20,21]. No cases of mortality have been documented associated with the use of imidazolines in nasal surgery [22].
Adrenaline/epinephrine Epinephrine is often used in pre- and intra-operative vasoconstrictive preparations. It may be combined with a local anaesthetic and injected submucosally or applied topically (sometimes combined with cocaine). Epinephrine is a non-selective adrenoceptor agonist with lower affinity for, yet higher potency at, a-adrenoceptors compared to imidazolines [9]. In fact, epinephrine is the most potent a-adrenoceptor agonist [13]. The rank order of a-adrenoceptor affinities for epinephrine is a1D > a1B = a1A P a2B P a2C > a2A [9]. The rank order of affinities for imidazolines is a1A > a2A > a2C > a1B P a1D > a2B [9]. Epinephrine has a rapid onset and short duration of action [13]. When given subcutaneously, its onset of action is 5–10 min it has a half-life of 2–3 min and a duration of action of 5–10 min [13,14]. Following intramucosal infiltration, plasma epinephrine values can rise to a peak value 44 times the basal value within 1 min [5]. This represents a systemic absorption of 67% of the total administered dose [5]. Mucosal absorption rates differ based on the concentration used and whether epinephrine is used in isolation or in a solution with other substances. These rates can vary from 3.13 pg/mL per minute for 1:2000 concentration to 0.95 pg/ mL per minute for 1:50,000 concentration [15]. When administered topically, as part of Moffett’s solution (1 mL 1:1000 epinephrine, 2 mL 10% cocaine, 2 mL 1% sodium bicarbonate made up to 20 mL with sterile water), peak plasma concentrations are reached over a 15–20 min period and only 0.14% is absorbed into the systemic circulation, resulting in a much lower peak concentration over a longer period of time [5]. Potential side effects from epinephrine include: hypertension, cerebral hemorrhage, coronary ischemia and cardiac arrhythmias [16]. The risk of cardiac complications from the use of topical epinephrine in adults undergoing ESS is 0.05% [16]. The risk in children is unknown. Oxymetazoline is a non-selective a-adrenoceptor agonist with high affinity for both a1- and a2-adrenoceptors. Oxymetazoline preferentially acts on the a1A- and a2A-adrenoceptor subtypes, yet is silent at the a2A-receptor subtype [17]. Although oxymetazoline has high affinity for the a1A-adrenoceptor, it is a partial agonist at this receptor [9,18]. In particular, oxymetazoline has a fivefold greater affinity for a1A-adrenoceptors compared to xylometazoline [9]. However, oxymetazoline’s potency is 1000-fold lower than its affinity at this receptor [9]. Oxymetazoline exhibits full agonist activity at the a2B-adrenoceptor, where it is also demonstrates potency, and is therefore, predominantly a nasal venoconstrictive agent [9,18]. Oxymetazoline enters the nasal mucosa rapidly (within 5–10 min) and is released slowly with a duration of action of up to 12 hours [19,20]. In particular, mucosal vasoconstriction persists for 5–6 hours and th en gradually declines over the ensuing 6 hours [19].
Conclusion Imidazolines demonstrate higher affinities for the a-adrenoceptors compared to epinephrine [9]. However, imidazolines have a lower potency at these receptors compared to epinephrine [9]. As a result, imidazolines may potentially antagonize the action of epinephrine, a more potent vasoconstrictor agent. Animal studies have demonstrated that imidazolines inhibit adrenalinepotentiated platelet aggregation [23]. Imidazolines appear to exhibit the greatest effect on a2B-adrenoceptors and are primarily venoconstrictive agents. Their efficacy in pre-operative vasoconstriction is probably limited. In fact, their greatest benefit may be in pre-operative decongestion, providing the surgeon with a better initial intra-operative view. However, topical epinephrine will also achieve decongestion. We postulate that use of imidazolines before epeinephrine may result in poorer intra-operative vasoconstriction and less platelet aggregation than if epinephrine is used alone. Reduced intra-operative haemostasis places the patient at risk for complications such as orbital injury, major vascular and intracranial injury or incomplete surgery. Further research is required to determine the optimal vasoconstrictor regimen for sinus surgery. In the interim we would suggest that the administration of pure a agonists is not preceded by partial agonists of this receptor. Conflict of interest statement Drs. Campbell, Nair and Douglas have no financial disclosures. Professor Sacks is a consultant to Medtronic. This paper received no funding or financial support. References [1] Drettner B, Aust R. Plethysmographic studies of the blood flow in the mucosa of the human maxillary sinus. Acta Otolaryngol 1974;78(3–4):259–63. [2] Panda N, Verna RK, Panda NK. Efficacy and safety of high-concentration adrenaline wicks during functional endoscopic sinus surgery. J Otolaryngol Head Neck Surg 2012;41(2):131–7. [3] Jacobi KE, Bohm BE, Rickauer AJ, Jacobi C, Hemmerling TM. Moderate controlled hypotension with sodium nitroprusside does not improve surgical conditions or decrease blood loss in endoscopic sinus surgery. J Clin Anesth 2000;12(3):202–7. [4] Yang JJ, Wang QP, Wang TY, Sun J, Wang ZY, Zuo D, et al. Marked hypotension induced by adrenaline contained in local anaesthetic. Laryngoscope 2005;115(2):348–52. [5] Van Hasselt CA, Low JM, Waldron J, Gibb AG, Oh TE. Plasma catecholamine levels following topical application versus infiltration of adrenaline for nasal surgery. Anaesth Intensive Care 1992;20(3):332–6. [6] Dahlstrom A, Fuxe K. The adrenergic innervation of the nasal mucosa of certain animals. Acta Otorhinolaryngol 1965;59:65–72.
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R.G. Campbell et al. / Medical Hypotheses 82 (2014) 706–708
[7] Corboz MR, Rivelli MA, Varty L, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional a-adrenoceptors in human nasal mucosa. Am J Rhinol 2005;19(5):495–502. [8] Bylund DB, Bond RA, Clarke DE, et al. Adrenoceptors. In: The IUPHAR compendium of receptor characterization and classification. London, UK: IUPHAR Media; 1998. p. 58–74. [9] Haenisch B, Walstab J, Herberhold S, Bootz F, Tschaikin M, Ramseger R, et al. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol 2010;24(6):729–39. [10] Andersson KE, Bende M. Adrenoceptors in the control of human nasal mucosal blood flow. Ann Otol Rhinol Laryngol 1984;93(2 Pt 1):179–82. [11] Corboz MR, Rivelli MA, Mingo GG, McLeod RL, Varty L, Jia Y, et al. Mechanism of decongestant activity of a2-adrenoceptor agonists. Pulm Pharmacol Ther 2008;21(3):449–54. [12] Johannssen V, Maune S, Werner JA, Rudert JA, Ziegler A. a1-Receptors at precapillary resistance vessels of the human nasal mucosa. Rhinology 1997;35(4):161–5. [13] Aspen Pharmaceuticals Adrenaline Product Information. Available from:. [14] Lee TJ, Huang CC, Chang PH, Chang CJ, Chen YW. Hemostasis during functional endoscopic sinus surgery: the effect of local infiltration with adrenaline. Otolaryngol Head Neck Surg 2009;140(2):209–14. [15] de Araujo Sarmento Jnr KMDA, Tomita S, de Avila Kos AO. Topical use of adrenaline in different concentrations for endoscopic sinus surgery. Braz J Otorhinolaryngol 2009;75(2):280–9.
[16] Orlandi RR, Warrier S, Sato S, Han JK. Concentrated topical epinephrine is safe in endoscopic sinus surgery. Am J Rhinol Allergy 2010;24(2):140–2. [17] Corboz MR, Varty LM, Rizzo CA, Mutter JC, Rivelli MA, Wan Y, et al. Pharmacological characterization of a2-adrenoceptor-mediated responses in pig nasal mucosa. Auton Autacoid Pharmacol 2004;23(4):208–19. [18] Horie K, Obika K, Foglar R, Tsuimoto G. Selectivity of the imidazoline aadrenoceptors agoniosts (oxymetazoline and cirazoline) for human cloned a1adrenoceptor subtypes. Br J Pharmacol 1995;116(1):1611–8. [19] Riegle EV, Gunter JB, Lusk RP, Muntz HR, Weiss KL. Comparison of vasoconstrictors for functional endoscopic sinus surgery in children. Laryngoscope 1992;102(7):820–3. [20] Medicines and Healthcare Products Regulatory Agency. Oxymetazoline Decongestant Nasal Spray 0.05% w/v. Available from:. [21] Medicines and Healthcare Products Regulatory Agency. Sudafed 0.1% Nasal Spray. Available from: . [22] Higgins TS, Hwang PH, Kingdom TT, Orlandi RR, Stammberger H, Han JK. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope 2010;121(2):422–32. [23] Hikasa Y, Abe M, Satoh T, Hisashi Y, Ogasawara S, Hiroshi M. Effects of imidazoline and non-imidazoline a-adrenergic agents on canine platelet aggregation. Pharmacology 1999;58:171–82.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Imidazoline use in sinonasal surgery R.G. Campbell a, S. Nair b, R. Sacks c, R.G. Douglas d,⇑ a
North Shore Hospital, Waitemata District Health Board, Auckland, New Zealand Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand c Macquarie University and the University of Sydney, Australia d Department of Surgery, The University of Auckland, New Zealand b
a r t i c l e
i n f o
Article history: Received 13 November 2013 Accepted 5 March 2014
a b s t r a c t The nasal mucosa is very vascular, receiving more blood flow per cubic centimeter of tissue than does muscle, brain or liver (Drettner and Aust, 1974; [1]). This vascularity can present a major problem during sinus surgery. Surgeons routinely use topical vasoconstrictors in endoscopic sinus surgery however, the optimal regimen is not clear. Imidazoline nasal sprays are often used up to 1 hour before sinonasal surgery to aid in intraoperative vasoconstriction. After the induction of anaesthesia, epinephrine-based topical and submucosal preparations are subsequently administered to further enhance vasoconstriction. Imidazolines are non-selective, partial alpha adrenoceptor agonists with a higher affinity, yet lower potency, for alpha adrenoceptors when compared to epinephrine. It is hypothesized that imidazolines block the action of epinephrine on the alpha adrenoceptors of the nasal mucosa resulting in less vasoconstriction, and a poorer intra-operative field, when compared to the use of epinephrine alone. This paper hypothesizes that preoperative imidazoline administration may adversely affect optimal intra-operative vasoconstriction. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction The nasal mucosa is very vascular with excellent absorptive abilities. It receives more blood flow per cubic centimeter of tissue than that of muscle, brain and liver [1] and this vascularity can present a major problem during extensive sinus surgery. Bleeding in endoscopic sinus surgery (ESS) is predominantly of capillary origin, and generally responds well to locally applied vasoconstrictors [2]. Locally acting agents are more effective at reducing mucosal blood flow during ESS than systemic vasodilators acting to reduce mean arterial pressure [3]. Furthermore, the application of higher concentrations of vasoconstrictors, such as epinephrine, has been shown to result in less intra-operative blood loss compared to lower concentrations [2]. This may be due to the preferential stimulation of a- and b1-adrenoceptors at higher concentrations as opposed to the preferential stimulation of b2-adrenoceptors at lower concentrations which can result in vasodilation [4]. Vasoconstrictors can also be injected submucosally (usually in association with local anesthetics). However, the application of vasocontrictors by infiltration leads to a more rapid, and therefore potentially more dangerous, rise in plasma adrenaline levels when ⇑ Corresponding author. Address: Department of Surgery, The University of Auckland, Grafton, Auckland, New Zealand. Tel.: +64 9 6311980; fax: +64 9 6311966. E-mail address: [email protected] (R.G. Douglas). http://dx.doi.org/10.1016/j.mehy.2014.03.009 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
compared to topical preparations. Plasma adrenaline concentrations are higher following infiltration compared to topical application [5]. This limits the concentration used and the effectiveness of vasoconstriction when agents are applied via infiltration [5]. As a result, endoscopic sinus surgeons routinely use topical vasoconstrictors in conjunction with infiltration of epinephrine containing solutions. Whether imidazoline nasal sprays, such as oxymetazoline and xylometazoline, and epinephrine are potentially antagonistic in their vasoconstrictive actions have not been investigated. To date, no study has compared the effect of epinephrine used alone and epinephrine used in conjunction with imidazolines on nasal mucosal blood flow. We hypothesize that use of the combination may result in less vasoconstriction than epinephrine alone.
Pharmacology of the nasal mucosal vasculature The nasal mucosal vasculature is predominantly innervated by the sympathetic nervous system [6]. Nasal vascular smooth muscle tone is controlled by both a1- and a2-adrenoceptor post-synaptic receptor subtypes [7]. When the sympathetic nerves are stimulated, they release norepinephrine, which acts via post-synaptic a1- and a2-adrenoceptors in the vasculature to cause vasoconstriction [7]. Six different genetic subtypes of a-adrenoceptor exist: a1A, a1B, a1D, a2A, a2B and a2c [8]. The a1A, a2A and a2B subtypes are the most abundantly expressed in the human nasal mucosa [9].
R.G. Campbell et al. / Medical Hypotheses 82 (2014) 706–708
However, the a2A-adrenoceptor is a pre-synaptic receptor on sympathetic nerve endings where it inhibits norepinephrine release [9]. The role of the a2A-adrenoceptor in nasal vascular tissue is unknown, however, it is not involved in imidazoline- or epinephrineinduced vasoconstrictive actions and likely plays a putative role in nasal mucosal vasoconstriction [9]. Hence, the a1A and a2B-adrenoceptors play the most important role in vasoconstriction in human nasal mucosa. The a2-adrenoceptor predominates in the nasal mucosal vasculature [9,10] and preferentially acts on veins, reducing engorgement of venous sinusoids, thereby decreasing nasal congestion and increasing nasal airflow. The a1-adrenoreceptors preferentially act on the arteries of human nasal mucosa, resulting in vasoconstriction and a reduction in blood flow [7,11,12]. This would suggest that it is the a1A receptors that should be targeted for pre- and intra-operative vasoconstriction in sinonasal surgery.
707
Xylometazoline is also a non-selective a-adrenoceptor agonist, however, it is a full agonist only at a2B-adrenoceptors where it demonstrates high affinity [9]. In particular, xylometazoline had a threefold greater affinity for a2B-adrenoceptors compared to oxymetazoline [9]. Xylometazoline demonstrates no activity at a1A-adrenoceptors, despite its higher affinity when compared to epinephrine [9]. Xylometazoline occupies this receptor, yet fails to cause receptor activation. The onset of action of xylometazoline is within a few minutes and its duration of action lasts up to 10 hours [21]. Systemic absorption of both imidazolines is limited due to their vasoconstrictive properties [20,21]. Systemic absorption may occur in the context of excessive use or gastrointestinal absorption [20,21]. Side effects of imidazolines include hypertension, local irritation and rebound nasal congestion [20,21]. No cases of mortality have been documented associated with the use of imidazolines in nasal surgery [22].
Adrenaline/epinephrine Epinephrine is often used in pre- and intra-operative vasoconstrictive preparations. It may be combined with a local anaesthetic and injected submucosally or applied topically (sometimes combined with cocaine). Epinephrine is a non-selective adrenoceptor agonist with lower affinity for, yet higher potency at, a-adrenoceptors compared to imidazolines [9]. In fact, epinephrine is the most potent a-adrenoceptor agonist [13]. The rank order of a-adrenoceptor affinities for epinephrine is a1D > a1B = a1A P a2B P a2C > a2A [9]. The rank order of affinities for imidazolines is a1A > a2A > a2C > a1B P a1D > a2B [9]. Epinephrine has a rapid onset and short duration of action [13]. When given subcutaneously, its onset of action is 5–10 min it has a half-life of 2–3 min and a duration of action of 5–10 min [13,14]. Following intramucosal infiltration, plasma epinephrine values can rise to a peak value 44 times the basal value within 1 min [5]. This represents a systemic absorption of 67% of the total administered dose [5]. Mucosal absorption rates differ based on the concentration used and whether epinephrine is used in isolation or in a solution with other substances. These rates can vary from 3.13 pg/mL per minute for 1:2000 concentration to 0.95 pg/ mL per minute for 1:50,000 concentration [15]. When administered topically, as part of Moffett’s solution (1 mL 1:1000 epinephrine, 2 mL 10% cocaine, 2 mL 1% sodium bicarbonate made up to 20 mL with sterile water), peak plasma concentrations are reached over a 15–20 min period and only 0.14% is absorbed into the systemic circulation, resulting in a much lower peak concentration over a longer period of time [5]. Potential side effects from epinephrine include: hypertension, cerebral hemorrhage, coronary ischemia and cardiac arrhythmias [16]. The risk of cardiac complications from the use of topical epinephrine in adults undergoing ESS is 0.05% [16]. The risk in children is unknown. Oxymetazoline is a non-selective a-adrenoceptor agonist with high affinity for both a1- and a2-adrenoceptors. Oxymetazoline preferentially acts on the a1A- and a2A-adrenoceptor subtypes, yet is silent at the a2A-receptor subtype [17]. Although oxymetazoline has high affinity for the a1A-adrenoceptor, it is a partial agonist at this receptor [9,18]. In particular, oxymetazoline has a fivefold greater affinity for a1A-adrenoceptors compared to xylometazoline [9]. However, oxymetazoline’s potency is 1000-fold lower than its affinity at this receptor [9]. Oxymetazoline exhibits full agonist activity at the a2B-adrenoceptor, where it is also demonstrates potency, and is therefore, predominantly a nasal venoconstrictive agent [9,18]. Oxymetazoline enters the nasal mucosa rapidly (within 5–10 min) and is released slowly with a duration of action of up to 12 hours [19,20]. In particular, mucosal vasoconstriction persists for 5–6 hours and th en gradually declines over the ensuing 6 hours [19].
Conclusion Imidazolines demonstrate higher affinities for the a-adrenoceptors compared to epinephrine [9]. However, imidazolines have a lower potency at these receptors compared to epinephrine [9]. As a result, imidazolines may potentially antagonize the action of epinephrine, a more potent vasoconstrictor agent. Animal studies have demonstrated that imidazolines inhibit adrenalinepotentiated platelet aggregation [23]. Imidazolines appear to exhibit the greatest effect on a2B-adrenoceptors and are primarily venoconstrictive agents. Their efficacy in pre-operative vasoconstriction is probably limited. In fact, their greatest benefit may be in pre-operative decongestion, providing the surgeon with a better initial intra-operative view. However, topical epinephrine will also achieve decongestion. We postulate that use of imidazolines before epeinephrine may result in poorer intra-operative vasoconstriction and less platelet aggregation than if epinephrine is used alone. Reduced intra-operative haemostasis places the patient at risk for complications such as orbital injury, major vascular and intracranial injury or incomplete surgery. Further research is required to determine the optimal vasoconstrictor regimen for sinus surgery. In the interim we would suggest that the administration of pure a agonists is not preceded by partial agonists of this receptor. Conflict of interest statement Drs. Campbell, Nair and Douglas have no financial disclosures. Professor Sacks is a consultant to Medtronic. This paper received no funding or financial support. References [1] Drettner B, Aust R. Plethysmographic studies of the blood flow in the mucosa of the human maxillary sinus. Acta Otolaryngol 1974;78(3–4):259–63. [2] Panda N, Verna RK, Panda NK. Efficacy and safety of high-concentration adrenaline wicks during functional endoscopic sinus surgery. J Otolaryngol Head Neck Surg 2012;41(2):131–7. [3] Jacobi KE, Bohm BE, Rickauer AJ, Jacobi C, Hemmerling TM. Moderate controlled hypotension with sodium nitroprusside does not improve surgical conditions or decrease blood loss in endoscopic sinus surgery. J Clin Anesth 2000;12(3):202–7. [4] Yang JJ, Wang QP, Wang TY, Sun J, Wang ZY, Zuo D, et al. Marked hypotension induced by adrenaline contained in local anaesthetic. Laryngoscope 2005;115(2):348–52. [5] Van Hasselt CA, Low JM, Waldron J, Gibb AG, Oh TE. Plasma catecholamine levels following topical application versus infiltration of adrenaline for nasal surgery. Anaesth Intensive Care 1992;20(3):332–6. [6] Dahlstrom A, Fuxe K. The adrenergic innervation of the nasal mucosa of certain animals. Acta Otorhinolaryngol 1965;59:65–72.
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R.G. Campbell et al. / Medical Hypotheses 82 (2014) 706–708
[7] Corboz MR, Rivelli MA, Varty L, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional a-adrenoceptors in human nasal mucosa. Am J Rhinol 2005;19(5):495–502. [8] Bylund DB, Bond RA, Clarke DE, et al. Adrenoceptors. In: The IUPHAR compendium of receptor characterization and classification. London, UK: IUPHAR Media; 1998. p. 58–74. [9] Haenisch B, Walstab J, Herberhold S, Bootz F, Tschaikin M, Ramseger R, et al. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol 2010;24(6):729–39. [10] Andersson KE, Bende M. Adrenoceptors in the control of human nasal mucosal blood flow. Ann Otol Rhinol Laryngol 1984;93(2 Pt 1):179–82. [11] Corboz MR, Rivelli MA, Mingo GG, McLeod RL, Varty L, Jia Y, et al. Mechanism of decongestant activity of a2-adrenoceptor agonists. Pulm Pharmacol Ther 2008;21(3):449–54. [12] Johannssen V, Maune S, Werner JA, Rudert JA, Ziegler A. a1-Receptors at precapillary resistance vessels of the human nasal mucosa. Rhinology 1997;35(4):161–5. [13] Aspen Pharmaceuticals Adrenaline Product Information. Available from:
[16] Orlandi RR, Warrier S, Sato S, Han JK. Concentrated topical epinephrine is safe in endoscopic sinus surgery. Am J Rhinol Allergy 2010;24(2):140–2. [17] Corboz MR, Varty LM, Rizzo CA, Mutter JC, Rivelli MA, Wan Y, et al. Pharmacological characterization of a2-adrenoceptor-mediated responses in pig nasal mucosa. Auton Autacoid Pharmacol 2004;23(4):208–19. [18] Horie K, Obika K, Foglar R, Tsuimoto G. Selectivity of the imidazoline aadrenoceptors agoniosts (oxymetazoline and cirazoline) for human cloned a1adrenoceptor subtypes. Br J Pharmacol 1995;116(1):1611–8. [19] Riegle EV, Gunter JB, Lusk RP, Muntz HR, Weiss KL. Comparison of vasoconstrictors for functional endoscopic sinus surgery in children. Laryngoscope 1992;102(7):820–3. [20] Medicines and Healthcare Products Regulatory Agency. Oxymetazoline Decongestant Nasal Spray 0.05% w/v. Available from: