EDITORIAL
Oxymetazoline (Afrin®): maybe there is more that we need to know
Introduction
Adverse effects
Oxymetazoline is the active ingredient in the over-thecounter nasal spray decongestant, Afrinâ (Merck Schering-Plough Pharmaceuticals, North Wales, PA, USA). It was first sold as a prescription medication in 1966 and then became available as an over-the-counter medication in 1975. It is currently approved by the United States Food & Drug Administration for use in patients ≥6 years of age. The active component, oxymetazoline, is an a-adrenergic agonist with greater activity at the a2 than the a1 adrenergic receptor (1). Its action at the peripheral a2-adrenergic receptor on the smooth muscle of the vasculature results in vasoconstriction, thereby defining its clinical utility as both a decongestant and a topical hemostatic agent (1). Although used most commonly by the lay public to treat allergic and viralinduced rhinorrhea, it is also used in the operating room to prepare the nasal passages during nasal intubation and during ear, nose, and throat (ENT) surgery to improve visualization of the airway and to minimize postoperative bleeding (2,3).
Despite a long history of use and its potential advantages over other agents, there seems to be limited or no information regarding the pharmacokinetics of this medication including uptake when applied to mucosal membranes or the end-organ effects when used in average concentration and volume during the perioperative period. Although the package insert and various webbased programs clearly outline the potential for hypertension and cardiac effects related to the use of this product, we believe that there has not been effective emphasis placed on such information in the medical literature. Furthermore, we are unaware of guidelines regarding dosing or information regarding toxic plasma concentrations of this agent. Recently, there have been two case reports published regarding significant cardiovascular effects including bradycardia and prolonged hypertension related to inadvertent overdosing during the routine perioperative use of this medication in healthy children (6,7). These two case reports and others from the literature demonstrate the potential toxicity from this over-thecounter medication, which may be dosed without attention to the volume administered. Although used for its topical effects, vascular absorption of oxymetazoline can have profound systemic effects, most commonly hypertension related to its action on the a2-adrenergic receptors of the smooth muscle of the vasculature. When used in even larger doses in young children, oxymetazoline can activate central adrenergic receptors and lead to serious adverse effects including cardiovascular instability, respiratory depression, and sedation, which may be potentially life-threatening (8–11).
Clinical efficacy A superior efficacy and safety profile of oxymetazoline has been demonstrated when compared to other topical agents with vasoconstrictive properties, such as phenylephrine, epinephrine, or cocaine (2–4). Reigle et al. (3) compared the topical nasal mucosal application of oxymetazoline (0.05%), phenylephrine (0.25%), or cocaine (4%) during functional endoscopic sinus surgery in children. Phenylephrine was associated with an increase in blood pressure while subjective evaluation of bleeding and surgical visualization was best with oxymetazoline. The authors concluded that oxymetazoline was the preferred vasoconstrictor in children. Higgins et al. (4) reviewed the use of topical vasoconstrictors during ENT surgery. They compared the efficacy against the risks associated with the topical use of phenylephrine, cocaine, and oxymetazoline, and proposed recommendations to reduce the incidence of systemic complications caused by these agents in the operating room. Furthermore, during the days of halothane anesthesia, oxymetazoline was preferred given its decreased arrhythmogenic potential when compared to epinephrine (5). © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
Pharmacokinetics and dynamics: the known and unknown Imidazole derivatives such as oxymetazoline are rapidly absorbed across mucosal membranes in children. Hence, toxicity generally develops within minutes, while resolution may take up to 24 h (9,10). Giannakopoulos et al. studied the cardiovascular effects and pharmacokinetics of an intranasal 3% tetracaine/0.05% oxymetazoline spray at two different dose levels in adult dental patients (12). The authors administered to 12 volunteers, what they considered to be the maximum recommended dose 795
Editorial
(MRD) of 18 mg tetracaine and 0.3 mg oxymetazoline which was sprayed onto the nasal mucosa. One to three weeks later, twice the dose (36 mg tetracaine and 0.6 mg oxymetazoline) was administered. Physiological measures remained fairly stable throughout the 2-h period with no clinical concerns in the patients and no clinically significant differences between the two groups. However, the medications were administered over 8 and 20 min in the MRD and two-times-MRD groups, respectively, rather than the short-term instillation typically used for ENT surgery. This may explain the lack of changes in blood pressure and heart rate. Tetracaine plasma levels were undetectable in the majority of the participants while concentrations of oxymetazoline from the two-times-MRD administration were approximately 50% greater than those from the MRD administration. The plasma half-life of oxymetazoline was reported to vary from 1.72 to 2.32 h.
ery of oxymetazoline based on the position of the bottle. Their investigative and innovative work demonstrated a fact that had previously received no attention in the literature. There was up to a 75-fold increase in the volume of medication administered when the bottle was held inverted. Given the supine position of patients on the operating room table, it is common practice to hold the bottle inverted and squeeze it. While squeezing the bottle in the upright position resulted in a mist with the delivery of 28.9 6.8 ll of fluid; with the bottle inverted, the average volume delivered was 1037 527 ll (range: 473–2196 ll). With the bottle upright, the amount delivered is effort independent; however, it becomes effort dependent when the bottle is inverted and squeezed. Latham and Jardine also demonstrated that each surgical pledget could hold a significant volume (1511 184 ll), a fact which may further increase delivery during ENT surgery.
Delivery systems
Summary and recommendations
However, as the use of oxymetazoline has expanded for hemostasis, particularly for ENT surgical procedures, we postulate that various factors in the operating room may result in accelerated absorption of excessive dosing. Packing of the nasal cavity with oxymetazoline-soaked nasal pledgets is common practice by ENT surgeons and would theoretically speed and increase absorption in comparison with intranasal spraying. Absorption may be further increased by disruption of the nasal vasculature during surgical procedures and the out-fracturing of the turbinates with disruption of the nasal mucosa. Furthermore, the study of Latham and Jardine (6) provides alarming information regarding alteration of deliv-
Given these concerns and the recent reports in the literature, it seems that the time has come to develop guidelines for the dosing of oxymetazoline in infants and in children (13–16). Unfortunately, there are currently no pharmacokinetic studies on which to base such recommendations. We are left with the package insert, which recommends 2–3 sprays into each nostril for patients over the age of 6 years. Based on the data of Latham and Jardine, which demonstrate that each spray delivers 30 ll, this would be a total maximum dose of 180 ll, which is far less than the amount held by one pledget or the amount delivered by a single spray from an inverted bottle. In as much as there are not data correlating dose
Figure 1 Color-coded syringe for oxymetazoline administration as an aid to avoid syringe swaps.
Figure 2 Two commercially available atomizer devices (MAD NasalTM on the top and MADgicTM on the bottom from Teleflex, San Diego, CA 92122) for the administration of medications.
796
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
Editorial
and degree of hemostasis, there is no way to determine whether this dose would be sufficient to produce the desired vasoconstriction necessary to reduce bleeding. The key to the management of oxymetazoline-related adverse effects must start with prevention. However, when this strategy is not successful, the appropriate diagnosis must be made and treatment instituted. Oxymetazoline and other medications administered during intraoperative care should be considered as potential etiologic agents when perioperative hypertension occurs. Identifying the etiology guides therapy, as treatment regimens may be distinctly different from other causes of perioperative hypertension. Treatment should be directed at reducing the a-adrenergic receptor-induced vasoconstriction. Nonspecific b-adrenergic antagonists may result in further augmentation of the effect with unopposed a-adrenergic effects. In addition to hypertension, the increase in the peripheral vascular resistance shifts intravascular volume from the systemic to the pulmonary circulation, which is less sensitive to the vasoconstricting properties of the a-adrenergic agonists, resulting in pulmonary edema. The treatment of oxymetazoline-induced hypertension should include directly acting vasodilators (hydralazine or sodium nitroprusside) or selective a-adrenergic antagonists such as phentolamine. It is imperative that these medications be available at any site where oxymetazoline is administered. As an over-the-counter medication, the potential for morbidity related to oxymetazoline-containing products may be under-appreciated. Given its nasal delivery via a spray mechanism or soaked cotton pledgets, attention to exact dosing or limitation of the dose is frequently absent. Although there are limited reports of toxicity related to this agent, the morbidity can be significant and it appears that it is essential to establish a consensus for the appropriate dosing of oxymetazoline. Until further data are available, we would suggest the following:
1 Initiate the planning phases to perform the needed pharmacokinetic trials of oxymetazoline in the pediatric-aged patient. This could also include a clinical study to evaluate the hemostatic efficacy of a halfstrength concentration of the agent compared to fullstrength. 2 Measure the amount administered before administration, especially if pledgets are used. This would allow more effective dosing as well as calculation of the total dose that has been administered if adverse effects occur. This may allow for the estimation of a dose– response curve for systemic effects. 3 Measuring the amount administered would mandate that the medication be drawn up into a syringe. To avoid the potential for a syringe swap and inadvertent intravascular administration, we use color-coded syringes in our operating room (Figure 1). 4 To avoid the effort-dependent effect of the inverted bottle, Latham and Jardine recommend administration from an atomizer device that is not position dependent (Figure 2).
Disclosure and Acknowledgments Statement 1 Any necessary ethical approval – this is an editorial, no ethical approval required. 2 Source of funding – none. 3 Conflict of interest – none for any of the authors.
1
Joseph D. Tobias1,2,3, Richard Cartabuke1,2 & Thomas Taghon1,2 Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA E-mail: [email protected] 2 Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA 3 Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA doi:10.1111/pan.12399
References 1 Haenisch B, Walstab J, Herberhold S et al. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol 2009; 24: 729–739. 2 Katz RI, Hovagim AR, Finkelstein HS et al. A comparison of cocaine, lidocaine with epinephrine, and oxymetazoline for prevention of epistaxis on nasotracheal intubation. J Clin Anesth 1990; 2: 16–20. 3 Riegle EVE, Gunter JBJ, Lusk RPR et al. Comparison of vasoconstrictors for functional endoscopic sinus surgery in children. Laryngoscope 1992; 102: 820–823. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
4 Higgins TS, Hwang PH, Kingdom TT et al. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope 2011; 121: 422–432. 5 Maze M, Smith CM. Identification of receptor mechanism mediating epinephrine-induced arrhythmias during halothane anesthesia in the dog. Anesthesiology 1983; 59: 322–326. 6 Latham GJ, Jardine DS. Oxymetazoline and hypertensive crisis in a child: can we prevent it. Pediatr Anesth 2013; 23: 952–956. 7 Ramesh AS, Cartabuke R, Essig C et al. Oxymetazoline-induced postoperative
hypertension. Pediatr Anesth Crit Care J 2013; 1: 72–77. 8 Fabi M, Formigari R, Picchio FM. Are nasal decongestants safer than rhinitis? A case of oxymetazoline-induced syncope. Cardiol Young 2009; 19: 633–634. 9 Higgens GL, Campbell B, Wallace K et al. Pediatric poisoning from over-the-counter imidazoline-containing products. Ann Emerg Med 1991; 20: 655–658. 10 Mahieu LM, Rooman RP, Goossens E. Imidazoline intoxication in children. Eur J Pediatr 1993; 152: 944–946.
797
Editorial
11 Jensen P, Edgren B, Hall L et al. Hemodynamic effects following ingestion of an imidazoline-containing product. Pediatr Emerg Care 1989; 5: 110–112. 12 Giannakopoulos H, Levin LM, Chou JC et al. The cardiovascular effects and pharmacokinetics of intranasal tetracaine plus oxymetazoline: preliminary findings. J Am Dent Assoc 2012; 143: 872–880.
798
13 Eddy O, Howell JM. Are one or two dangerous? Clonidine and topical imidazolines exposure in toddlers. J Emerg Med 2003; 25: 297–302. 14 Liebelt EL, Shannon MW. Small doses, big problems: a selected review of highly toxic common medications. Pediatr Emerg Care 1993; 9: 292–297.
15 Thrush DN. Cardiac arrest after oxymetazoline nasal spray. J Clin Anesth 1995; 7: 512– 514. 16 Glazener F, Blake K, Gradman M. Bradycardia, hypotension, and near-syncope associated with Afrinâ (oxymetazoline) nasal spray. N Engl J Med 1983; 309: 731.
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
Oxymetazoline (Afrin®): maybe there is more that we need to know
Introduction
Adverse effects
Oxymetazoline is the active ingredient in the over-thecounter nasal spray decongestant, Afrinâ (Merck Schering-Plough Pharmaceuticals, North Wales, PA, USA). It was first sold as a prescription medication in 1966 and then became available as an over-the-counter medication in 1975. It is currently approved by the United States Food & Drug Administration for use in patients ≥6 years of age. The active component, oxymetazoline, is an a-adrenergic agonist with greater activity at the a2 than the a1 adrenergic receptor (1). Its action at the peripheral a2-adrenergic receptor on the smooth muscle of the vasculature results in vasoconstriction, thereby defining its clinical utility as both a decongestant and a topical hemostatic agent (1). Although used most commonly by the lay public to treat allergic and viralinduced rhinorrhea, it is also used in the operating room to prepare the nasal passages during nasal intubation and during ear, nose, and throat (ENT) surgery to improve visualization of the airway and to minimize postoperative bleeding (2,3).
Despite a long history of use and its potential advantages over other agents, there seems to be limited or no information regarding the pharmacokinetics of this medication including uptake when applied to mucosal membranes or the end-organ effects when used in average concentration and volume during the perioperative period. Although the package insert and various webbased programs clearly outline the potential for hypertension and cardiac effects related to the use of this product, we believe that there has not been effective emphasis placed on such information in the medical literature. Furthermore, we are unaware of guidelines regarding dosing or information regarding toxic plasma concentrations of this agent. Recently, there have been two case reports published regarding significant cardiovascular effects including bradycardia and prolonged hypertension related to inadvertent overdosing during the routine perioperative use of this medication in healthy children (6,7). These two case reports and others from the literature demonstrate the potential toxicity from this over-thecounter medication, which may be dosed without attention to the volume administered. Although used for its topical effects, vascular absorption of oxymetazoline can have profound systemic effects, most commonly hypertension related to its action on the a2-adrenergic receptors of the smooth muscle of the vasculature. When used in even larger doses in young children, oxymetazoline can activate central adrenergic receptors and lead to serious adverse effects including cardiovascular instability, respiratory depression, and sedation, which may be potentially life-threatening (8–11).
Clinical efficacy A superior efficacy and safety profile of oxymetazoline has been demonstrated when compared to other topical agents with vasoconstrictive properties, such as phenylephrine, epinephrine, or cocaine (2–4). Reigle et al. (3) compared the topical nasal mucosal application of oxymetazoline (0.05%), phenylephrine (0.25%), or cocaine (4%) during functional endoscopic sinus surgery in children. Phenylephrine was associated with an increase in blood pressure while subjective evaluation of bleeding and surgical visualization was best with oxymetazoline. The authors concluded that oxymetazoline was the preferred vasoconstrictor in children. Higgins et al. (4) reviewed the use of topical vasoconstrictors during ENT surgery. They compared the efficacy against the risks associated with the topical use of phenylephrine, cocaine, and oxymetazoline, and proposed recommendations to reduce the incidence of systemic complications caused by these agents in the operating room. Furthermore, during the days of halothane anesthesia, oxymetazoline was preferred given its decreased arrhythmogenic potential when compared to epinephrine (5). © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
Pharmacokinetics and dynamics: the known and unknown Imidazole derivatives such as oxymetazoline are rapidly absorbed across mucosal membranes in children. Hence, toxicity generally develops within minutes, while resolution may take up to 24 h (9,10). Giannakopoulos et al. studied the cardiovascular effects and pharmacokinetics of an intranasal 3% tetracaine/0.05% oxymetazoline spray at two different dose levels in adult dental patients (12). The authors administered to 12 volunteers, what they considered to be the maximum recommended dose 795
Editorial
(MRD) of 18 mg tetracaine and 0.3 mg oxymetazoline which was sprayed onto the nasal mucosa. One to three weeks later, twice the dose (36 mg tetracaine and 0.6 mg oxymetazoline) was administered. Physiological measures remained fairly stable throughout the 2-h period with no clinical concerns in the patients and no clinically significant differences between the two groups. However, the medications were administered over 8 and 20 min in the MRD and two-times-MRD groups, respectively, rather than the short-term instillation typically used for ENT surgery. This may explain the lack of changes in blood pressure and heart rate. Tetracaine plasma levels were undetectable in the majority of the participants while concentrations of oxymetazoline from the two-times-MRD administration were approximately 50% greater than those from the MRD administration. The plasma half-life of oxymetazoline was reported to vary from 1.72 to 2.32 h.
ery of oxymetazoline based on the position of the bottle. Their investigative and innovative work demonstrated a fact that had previously received no attention in the literature. There was up to a 75-fold increase in the volume of medication administered when the bottle was held inverted. Given the supine position of patients on the operating room table, it is common practice to hold the bottle inverted and squeeze it. While squeezing the bottle in the upright position resulted in a mist with the delivery of 28.9 6.8 ll of fluid; with the bottle inverted, the average volume delivered was 1037 527 ll (range: 473–2196 ll). With the bottle upright, the amount delivered is effort independent; however, it becomes effort dependent when the bottle is inverted and squeezed. Latham and Jardine also demonstrated that each surgical pledget could hold a significant volume (1511 184 ll), a fact which may further increase delivery during ENT surgery.
Delivery systems
Summary and recommendations
However, as the use of oxymetazoline has expanded for hemostasis, particularly for ENT surgical procedures, we postulate that various factors in the operating room may result in accelerated absorption of excessive dosing. Packing of the nasal cavity with oxymetazoline-soaked nasal pledgets is common practice by ENT surgeons and would theoretically speed and increase absorption in comparison with intranasal spraying. Absorption may be further increased by disruption of the nasal vasculature during surgical procedures and the out-fracturing of the turbinates with disruption of the nasal mucosa. Furthermore, the study of Latham and Jardine (6) provides alarming information regarding alteration of deliv-
Given these concerns and the recent reports in the literature, it seems that the time has come to develop guidelines for the dosing of oxymetazoline in infants and in children (13–16). Unfortunately, there are currently no pharmacokinetic studies on which to base such recommendations. We are left with the package insert, which recommends 2–3 sprays into each nostril for patients over the age of 6 years. Based on the data of Latham and Jardine, which demonstrate that each spray delivers 30 ll, this would be a total maximum dose of 180 ll, which is far less than the amount held by one pledget or the amount delivered by a single spray from an inverted bottle. In as much as there are not data correlating dose
Figure 1 Color-coded syringe for oxymetazoline administration as an aid to avoid syringe swaps.
Figure 2 Two commercially available atomizer devices (MAD NasalTM on the top and MADgicTM on the bottom from Teleflex, San Diego, CA 92122) for the administration of medications.
796
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
Editorial
and degree of hemostasis, there is no way to determine whether this dose would be sufficient to produce the desired vasoconstriction necessary to reduce bleeding. The key to the management of oxymetazoline-related adverse effects must start with prevention. However, when this strategy is not successful, the appropriate diagnosis must be made and treatment instituted. Oxymetazoline and other medications administered during intraoperative care should be considered as potential etiologic agents when perioperative hypertension occurs. Identifying the etiology guides therapy, as treatment regimens may be distinctly different from other causes of perioperative hypertension. Treatment should be directed at reducing the a-adrenergic receptor-induced vasoconstriction. Nonspecific b-adrenergic antagonists may result in further augmentation of the effect with unopposed a-adrenergic effects. In addition to hypertension, the increase in the peripheral vascular resistance shifts intravascular volume from the systemic to the pulmonary circulation, which is less sensitive to the vasoconstricting properties of the a-adrenergic agonists, resulting in pulmonary edema. The treatment of oxymetazoline-induced hypertension should include directly acting vasodilators (hydralazine or sodium nitroprusside) or selective a-adrenergic antagonists such as phentolamine. It is imperative that these medications be available at any site where oxymetazoline is administered. As an over-the-counter medication, the potential for morbidity related to oxymetazoline-containing products may be under-appreciated. Given its nasal delivery via a spray mechanism or soaked cotton pledgets, attention to exact dosing or limitation of the dose is frequently absent. Although there are limited reports of toxicity related to this agent, the morbidity can be significant and it appears that it is essential to establish a consensus for the appropriate dosing of oxymetazoline. Until further data are available, we would suggest the following:
1 Initiate the planning phases to perform the needed pharmacokinetic trials of oxymetazoline in the pediatric-aged patient. This could also include a clinical study to evaluate the hemostatic efficacy of a halfstrength concentration of the agent compared to fullstrength. 2 Measure the amount administered before administration, especially if pledgets are used. This would allow more effective dosing as well as calculation of the total dose that has been administered if adverse effects occur. This may allow for the estimation of a dose– response curve for systemic effects. 3 Measuring the amount administered would mandate that the medication be drawn up into a syringe. To avoid the potential for a syringe swap and inadvertent intravascular administration, we use color-coded syringes in our operating room (Figure 1). 4 To avoid the effort-dependent effect of the inverted bottle, Latham and Jardine recommend administration from an atomizer device that is not position dependent (Figure 2).
Disclosure and Acknowledgments Statement 1 Any necessary ethical approval – this is an editorial, no ethical approval required. 2 Source of funding – none. 3 Conflict of interest – none for any of the authors.
1
Joseph D. Tobias1,2,3, Richard Cartabuke1,2 & Thomas Taghon1,2 Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA E-mail: [email protected] 2 Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA 3 Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA doi:10.1111/pan.12399
References 1 Haenisch B, Walstab J, Herberhold S et al. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol 2009; 24: 729–739. 2 Katz RI, Hovagim AR, Finkelstein HS et al. A comparison of cocaine, lidocaine with epinephrine, and oxymetazoline for prevention of epistaxis on nasotracheal intubation. J Clin Anesth 1990; 2: 16–20. 3 Riegle EVE, Gunter JBJ, Lusk RPR et al. Comparison of vasoconstrictors for functional endoscopic sinus surgery in children. Laryngoscope 1992; 102: 820–823. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
4 Higgins TS, Hwang PH, Kingdom TT et al. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope 2011; 121: 422–432. 5 Maze M, Smith CM. Identification of receptor mechanism mediating epinephrine-induced arrhythmias during halothane anesthesia in the dog. Anesthesiology 1983; 59: 322–326. 6 Latham GJ, Jardine DS. Oxymetazoline and hypertensive crisis in a child: can we prevent it. Pediatr Anesth 2013; 23: 952–956. 7 Ramesh AS, Cartabuke R, Essig C et al. Oxymetazoline-induced postoperative
hypertension. Pediatr Anesth Crit Care J 2013; 1: 72–77. 8 Fabi M, Formigari R, Picchio FM. Are nasal decongestants safer than rhinitis? A case of oxymetazoline-induced syncope. Cardiol Young 2009; 19: 633–634. 9 Higgens GL, Campbell B, Wallace K et al. Pediatric poisoning from over-the-counter imidazoline-containing products. Ann Emerg Med 1991; 20: 655–658. 10 Mahieu LM, Rooman RP, Goossens E. Imidazoline intoxication in children. Eur J Pediatr 1993; 152: 944–946.
797
Editorial
11 Jensen P, Edgren B, Hall L et al. Hemodynamic effects following ingestion of an imidazoline-containing product. Pediatr Emerg Care 1989; 5: 110–112. 12 Giannakopoulos H, Levin LM, Chou JC et al. The cardiovascular effects and pharmacokinetics of intranasal tetracaine plus oxymetazoline: preliminary findings. J Am Dent Assoc 2012; 143: 872–880.
798
13 Eddy O, Howell JM. Are one or two dangerous? Clonidine and topical imidazolines exposure in toddlers. J Emerg Med 2003; 25: 297–302. 14 Liebelt EL, Shannon MW. Small doses, big problems: a selected review of highly toxic common medications. Pediatr Emerg Care 1993; 9: 292–297.
15 Thrush DN. Cardiac arrest after oxymetazoline nasal spray. J Clin Anesth 1995; 7: 512– 514. 16 Glazener F, Blake K, Gradman M. Bradycardia, hypotension, and near-syncope associated with Afrinâ (oxymetazoline) nasal spray. N Engl J Med 1983; 309: 731.
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 795–798
