4/23/14 POST. Population POST POST POST POST. intervention. Comparison Outcome. Novel Preoperative Pharmacologic Methods of

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1 ovel Preoperative Pharmacologic Methods of David Kalil CRA, DAP Preventing Postoperative Sore Throat Sore throat and hoarseness after (GA) with tracheal intubation occurs in 30-70% of patients Usually is self-limiting Rated as one of the TOP 10 most undesirable postoperative outcomes Etiology: Mechanical injury during intubation Mucosal damage from endotracheal cuff Dehydration of the mucosa Postoperative Care Time 14 minute longer stay in PACU 25 minute longer stay in the Ambulatory Care Unit 51 minute later discharge from operative facility Reducing should Decrease length of stay Increase patient satisfaction on-pharmacologic factors to decrease Care during laryngoscopy Cuff pressure inflated to no more than cm H20 Laryngeal mask airway Pharmacologic interventions Local anesthetics or corticosteroids to the cuff of endotracheal tube (ETT) Population Comparison Outcome The PICO question: (P) Adult patients requiring endotracheal intubation (I) What is the efficacy of topical preoperative non-local anesthetic, non-steroid pharmacologic agents (O) Reducing the incidence of (C) All of the evidence addressed these agents and there was no comparison intervention in this question The search for evidence (1990 to 2012) Research Criteria on-local anesthetic and non-steroid pharmacologic treatments administered topically prior to intubation Excluded Sources examining combinations of drugs Supraglottic airway use Surgeries involving the oropharynx Pediatrics 1

2 117 potential evidence sources meeting inclusion criteria All sources were Random Controlled Trails (RCT) Ketamine 4 Benzydamine gargle.. 3 Azulene. 1 Aspirin 1 Dexpanethol. 1 Amyl-m-cresol.. 1 Licorice. 1 Magnesium 1 A total of 1078 subjects participated in the 11 investigations with study sample sizes ranging from 37 to 378 (median sample size of 58) There was subject withdrawal in 6 investigations All of the studies used blinded observers Subject blinding one in 3 investigations Questionable in one ot in one A placebo was used in all of the studies except for one PoST Endotracheal intubation performed by: Experienced staff anesthesiologist Experienced anesthesiology resident ot in one investigation Endotracheal tube size female male Intubation attempts limited to 1 or 2 ETT cuff pressure cm H2O ot always monitored or Other Bucking on extubation 2 studies excluded these subjects Suctioning of the posterior pharynx prior to extubation Oropharyngeal airway insertion prior to extubation Heat and moisture exchanger sometime used Anesthesia Intravenous induction ondepolarizers Opioids often administered (not always described) Fentanyl 2 mcg/kg Post-op opioid administration was not Postoperative Evaluation All of the investigators the incidence of All directly asked the subjects about rather than asking questions about their postoperative condition Subjects were usually assessed in the post care unit (often as 0 h ) and 2 to 24 hrs postoperatively. Severity was usually assessed using a 4 point visual or verbal analog scale anchored with 0 as no and 3 as severe with hoarseness or other voice changes One group assessed severity using a 7 point scale and another using a 100 point scale one of the investigators offered data describing the reliability or validity of the instruments used to measure Ketamine 4 group of investigators examined the effect of gargling 30 ml of water or saline containing mg of ketamine This is an n-methyl-d-aspartate (MDA) receptor antagonist Investigators have suggested MDA receptors are found not only in the central nervous system, but also in the peripheral nerves Moreover, experimental studies point out that peripherally administered MDA receptor antagonists are involved with antinociception and anti-inflammatory cascade This treatment probably resulted in the most promising results in reducing 2

3 Ketamine The incidence of early (in the post care unit) and late (measured at 24 h) was dramatically reduced For example: A group the incidence of at 24 h postoperatively was cut from 48% to 4% o authors side or systemic effects due to the ketamine It is not likely the results were due to systemic effects of the ketamine. Subjects ( = 22) gargled 40 mg of ketamine for 30 seconds Serum ketamine and norketamine levels were measured for five subjects at intervals up to 103 min after gargling. The authors both levels were below those described to produce analgesia Benzydamine It is a topical anti-inflammatory with local anesthetic properties Widely available outside of the United States May act on the prostaglandin system Has been used for mucositis due to radiation treatment Others ly used the drug treating lesions due to endotracheal intubation Benzydamine was examined as a 22.5 mg gargle and as an oral spray in 2.16 and 75mg doses The higher doses were ly more effective in reducing the incidence of While the treatment was usually well tolerated, two subjects in a study complained of oral numbing and a distorted sense of taste Sodium azulene sulfonate Derived from azulene, a chamomile extract, and available in Japan. The authors : Anti-inflammatory effects when used to treat chronic gastritis and ulcers They theorized that gargling with sodium azulene sulfonate might be a simple, effective way to prevent o side effects were Azulene is absorbed only in the small intestine and local tissue reactions are likely rare at the concentration used in the study Investigators (Japan) significant reduction of immediately postoperatively and at intervals up to 24 hours after surgery otably at 24 h postoperatively, no subjects in the treatment group while 45% of subjects in the group receiving the placebo Aspirin Widely-used anti-inflammatory has been used in a gargle to relieve pain due to oral lesions Gargling with 30 ml of distilled water containing 350 mg of aspirin was to significantly reduce the incidence of While the subject was in the post care unit at 2 hours, but not at 4 and 24 h postoperatively o side effects were. The widely-used anti-inflammatory has been used in a gargle to relieve pain due to oral lesions Dexpanthenol Applied topically is to have anti-inflammatory properties Acts as a moisturizer, improving skin hydration Subjects who preoperatively sucked on Pastilles containing 200 mg of dexpanthenol Investigators significantly less at all intervals up to 24 h when compared to both placebo and oral benxydamine spray The investigators theorized a greater positive effect would have been observed if a larger dose was administered (six rather than two pastilles). The drug is marketed for topical but not for oral use in the United States Licorice Licorice contains a number of ingredients Many of these including glycyrrhizin, liquilitin, and glabridin are to have anti-inflammatory and anti-allergic, peripheral and central antitussive properties, and ulcer-healing properties, respectively Subjects gargled with 0.5 g of licorice in 30 ml of water, The incidence of was to be reduced by more than half at all evaluation intervals Subjects all underwent lumbar laminectomy in the prone position. o severe side effects were 3

4 Amyl-m-cresol The researchers noted these lozenges have been used successfully to treat patients with oral inflammatory diseases and before oral surgery and suggest amyl-m-cresol produces an anti-inflammatory effect. Investigators examined the use of a lozenge commercially only available over-the-counter outside of the United States (Strepsils lozenges, Kingston-upon-Thames, UK) containing amyl-m-cresol 14% of subjects complained of in the PACU compared with 33% of subjects receiving a placebo (P <.05) A similar reduction was seen 24 h postoperatively The lozenges were well tolerated by all subjects. Magnesium (Magnesium-Diasporal lozenge, Med Ilac, Istanbul, Turkey) The researchers indicated the mechanism of action of magnesium for reducing inflammation is thought to be via reducing the release of mediators of inflammation including histamine, leukotrienes, and thromboxanes. Magnesium may also antagonize MDA receptors. They theorized the effect of magnesium was due to direct contact of magnesium ions with the pharyngeal wall There was a significantly decreased incidence of when subjects sucked on a lozenge containing magnesium ---preoperatively at 2 and 4 h, but not immediately or 24 h postoperatively Preoperatively at 2 and 4 h but not immediately or 24 h postoperatively Serum magnesium levels in subjects in the treatment group were unchanged compared with the control group 4 h after surgery Subjects no local or systemic side effects incidence in RESULTS Canbay et (2008) 40 Ketamine 40 mg (in 30 ml saline) gargled for 30 s, 5 min prior to induction of Saline gargle = 23 0 h c 17 (74%) 2 h 17 (74%) 4 h 13 (57%) 24 h 14 (61%) = 17 0 h 7 (41%) d 2 h 8 (47%) d 4 h 8 (47%) 24 h 6 (35%) d 3 subjects in treatment group withdrew, intention to treat Power analysis indicated need for 22 subjects per group All subjects underwent septorhinoplasty Gender of subjects not o significant difference between groups in age, height, weight, incidence of smoking, intraoperative remifentanil, and duration of surgery Unable to blind subjects, only mention of observer blinding ETT cuff pressure monitored intermittently G, OG, oral airway, ETT tube lubrication, ; incidence of coughing prior to extubation not a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperative or postextubation d P<.05 e umber of subjects in group receiving steroid ointment to ETT ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; OG, orogastric tube;, postoperative sore throat incidence in incidence in Rudra et (2009) 40 Ketamine 50 mg (in 30 ml drinking water) gargled for 40 s, 5 min prior Drinking water gargle = 20 4 h 17 (85%) 8 h 15 (75%) 24 h 12 (60%) = 20 4 h 8 (40%) d 8 h 7 (35%) d 24 h 5 (25%) d o significant difference in age, height, weight, gender and duration of surgery between groups Unable to blind subjects, only mention of observer blinding Smoking history not ETT cuff pressure monitoring not 2O used G, OG, oral airway use not Excluded if coughed or bucked prior to extubation Shrestha et (2010) 40 Ketamine 50 mg (in 30 ml drinking water) gargled for 30 s, 5 min prior Drinking water gargle = 20 4 h 15 (75%) 8 h 12 (60%) 24 h 10 (50%) = 20 4 h 7 (35%) 8 h 6 (30%) d 24 h 3 (15%) d o significant differences between groups in gender, weight, duration of surgery Smoking history not Method of sample size determination not Unable to blind subjects, only mention of observer blinding ETT cuff pressure and monitoring not G, OG, HME, oral airway used; coughing prior to extubation not a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperative or postextubation d P<.05 e umber of subjects in group receiving steroid ointment to ETT ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; OG, orogastric tube;, postoperative sore throat a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperative or postextubation d P<.05 e umber of subjects in group receiving steroid ointment to ETT ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; OG, orogastric tube;, postoperative sore throat 4

5 Shaaban and Kamal (2012) 50 Ketamine 40 mg (in 30 ml saline) gargled for 60 s, 5 min prior to induction of o placebo incidence in = 25 0 h 16 (64%) 2 h 15 (60%) 4 h 13 (52%) 24 h 12 (48%) e = 25 0 h 6 (24%) d 2 h 6 (24%) d 4 h 5 (20%) d 24 h 1 (4%) d Compared use of steroid ointment applied to ETT cuff with ketamine gargle 6 subjects withdrew, intention to treat Only blinding of subjects and observer f o significant differences between groups in age, weight, gender, duration of surgery Smoking history not ETT cuff pressure continuously monitored Oral airway use not Subject excluded if >2 intubation attempts Incidence of coughing prior to extubation not o significant difference in between groups receiving ketamine gargle and steroid ointment to ETT cuff Agarwal et (2006) 58 e Benzydamine 0.15%, 22.5 mg (in 30 ml distilled water) gargled for 30 s, 5 min prior Mineral water gargle control group b incidence in = 20 0 h 16 (80%) 2 h 12 (60%) 4 h 10 (50%) 24 h 4 (20%) =19 0 h 4 (21%) d 2 h 5 (26%) d 4 h 4 (21%) 24 h 1 (5%) All female subjects 2 subjects withdrew, intention to treat o significant difference between groups in age, height, weight, duration of surgery Incidence of smoking not Subject blinding not possible, intubator and observer were blinded ETT lubricated with water soluble jelly Maximum number of intubation attempts not ETT cuff pressure continuously monitored G, OG, oral airway use not Incidence of coughing prior to extubation not a Investigators only indicated gargled solutions was gargled, not swallowed b umber of subjects c 19 subjects were in group receiving aspirin gargle d Hours postoperative or post-extubation a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperative or postextubation d P<.05 e umber of subjects in group receiving steroid ointment to ETT ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; OG, orogastric tube;, postoperative sore throat e P<.05 f 60 subjects were in group receiving dexpanthenol pastilles g 94 subjects received benzydamine spray to both oral cavity and ETT cuff and 95 subjects who received benzydamine spray to ETT cuff and distilled water spray to oral cavity ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube control group b incidence in incidence in Gulhas et (2007) 180 f Benzydamine 4 puffs (2.16 mg) sprayed into mouth 30 and 5 min prior Distilled water sprayed into mouth = min 29 (48%) 6 h 40 (67%) 12 h 14 (23%) 24 h 16 (27%) = min 23 (38%) 6 h 37 (62%) 12 h 7 (12%) e 24 h 7 (12%) e o difference in age, weight, gender, smoking history, duration of surgery between groups ETT cuff pressure monitored every 10 min G tube not used ETT lubrication, oral airway and HME use, incidence of coughing prior to extubation not Maximum number of intubation attempts not Suctioned under direct visualization prior to extubation Significantly lower incidence of in group receiving dexpanthenol compared with group receiving benzydamine Huang et (2010) 378 g Benzydamine 5 puffs = 95 (75 mg) sprayed oropharyngeally 5 min 0 h 20 (21%) prior 2 h 38 (40%) and 4 h 30 (32%) 5 puffs distilled water 24 h 22 (23%) to sprayed on ETT cuff Distilled water sprayed oropharyngeally and to cuff of ETT = 94 0 h 6 (6%) e 2 h 22 (23%) 4 h 12 (13%) e 24 h 10 (11%) 2 subjects withdrew, intention to treat Statistical adjustments made for age, gender, smoking, duration of Subject blinding not, intubator and observer blinded ETT cuff pressure monitored hourly G, oral airway and HME use not Suctioned gently prior to extubation Incidence of coughing prior to extubation not a Investigators only indicated gargled solutions was gargled, not swallowed b umber of subjects c 19 subjects were in group receiving aspirin gargle d Hours postoperative or post-extubation e P<.05 f 60 subjects were in group receiving dexpanthenol pastilles g 94 subjects received benzydamine spray to both oral cavity and ETT cuff and 95 subjects who received benzydamine spray to ETT cuff and distilled water spray to oral cavity ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube a Investigators only indicated gargled solutions was gargled, not swallowed b umber of subjects c 19 subjects were in group receiving aspirin gargle d Hours postoperative or post-extubation e P<.05 f 60 subjects were in group receiving dexpanthenol pastilles g 94 subjects received benzydamine spray to both oral cavity and ETT cuff and 95 subjects who received benzydamine spray to ETT cuff and distilled water spray to oral cavity ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube control group b incidence in control group b incidence in Ogata et (2005) 40 Sodium azulene sulfonate 4 mg (in 100 ml tap water) gargled for unstated duration and time prior to induction of Tap water gargle = 20 0 h c 13 (65%) 2 h 18 (90%) 4 h 11 (55%) 24 h 9 (45%) = 20 0 h 5 (25%) d 2 h 8 (40%) d 4 h 2 (10%) d 24 h 0 (0%) d Method of sample size determination not o difference in age, height, weight, gender or duration of surgery between groups Smoking history not Subject excluded if >2 intubation attempts, if coughed or bucked prior to extubation Intermittent monitoring of ETT cuff pressure Oral airway use, HME method suctioning prior to extubation not Method of suctioning not Study drug was gift from manufacturer Agarwal et 58 e Aspirin 350 mg (in 30 (2006) ml distilled water) gargled a for 30 s, 5 min prior to induction of Mineral water gargle = 20 0 h 16 (80%) 2 h 12 (60%) 4 h 10 (50%) 24 h 4 (20%) =19 0 h 4 (21%) d 2 h 5 (26%) d 4 h 4 (21%) 24 h1 (5%) All female subjects 2 subjects withdrew, intention to treat o significant difference between groups in age, height, weight, duration of surgery Incidence of smoking not Subject blinding not possible, intubator and observer were blinded ETT lubricated with water soluble jelly Maximum number of intubation attempts not ETT cuff pressure continuously monitored G, OG, oral airway use not Incidence of coughing prior to extubation not a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperatively or post-extubation d P<.05 e 19 subjects were in group ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube;, postoperative sore throat; VAS, visual analog scale a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperatively or post-extubation d P<.05 e 19 subjects were in group ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube;, postoperative sore throat; VAS, visual analog scale 5

6 Gulhas et (2007) incidence in 180 f Dexpanthenol, 2 = 60 pastilles (200 mg) sucked 30 min prior 10 min 29(48%) 6 h 40 (67%) 12 h 14 (23%) 24 h 16 (27%) 4 puffs distilled water sprayed orally = min 15 (25%) d 6 h 22 (37%) d 12 h 5 (8%) d 24 h 7 (12%) d o difference in height, weight, gender, smoking history, duration of surgery between groups ETT cuff pressure monitored every 10 min G tube not used ETT lubrication, oral airway use, HME use, number of intubation attempts, incidence of coughing prior to extubation not Suction under direct visualization prior to extubation Overall dexpanthenol also more effective than benzydamine in preventing a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperatively or post-extubation d P<.05 e 19 subjects were in group ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube;, postoperative sore throat; VAS, visual analog scale Agarwal et (2009) 37 Licorice 0.5 g (in 30 ml water) gargled for 30 s, 5 min prior Water gargle control group b incidence in = 18 0 h 13 (72%) 2 h 14 (78%) 4 h 10 (56%) 24 h 8 (44%) = 19 0 h 4 (21%) d 2 h 4 (21%) d 4 h 3 (17%) d 24 h 2 (11%) d 3 subjects withdrew, intention to treat All subjects underwent lumbar laminectomy in prone position o difference in age, height, weight, gender, duration of surgery between groups Unable to blind subjects ETT cuff pressure continuously monitored measured using 100 point VAS differences with subjects at rest, similar differences upon swallowing a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperatively or post-extubation d P<.05 e 19 subjects were in group ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube;, postoperative sore throat; VAS, visual analog scale incidence in incidence in Ebneshahidi et (2010) 145 Lozenge containing amyl-m-cresol 0.6 mg, sucked on for 45 min prior to induction of Placebo lozenge = 72 0 h 24 (33%) 24 h 13 (18%) = 73 0 h 10 (14%) d 24 h 5 (7%) d 5 subjects withdrew and intention to treat o differences in age, height, weight, gender, length of laryngoscopy and duration of surgery between groups Smoking history, intubator experience, ETT lubrication, ETT cuff pressure monitoring, intubation attempts, HME use not Oral airway used on all subjects Borazan et (2012) 70 Lozenge containing 610 mg magnesium citrate salt, sucked 30 min prior to induction of Placebo lozenge = 35 0 h 16 (46%) 2 h 20 (57%) 4 h 14 (40%) 24 h 10 (29%) = 35 0 h 6 (17%) 2 h 8 (23%) d 4 h 5 (14%) d 24 h 3 (9%) Subjects with smoking history excluded o difference in age, weight, gender, duration of laryngoscopy and surgery, intraoperative opioids use between groups ETT lubricated with tap water ETT cuff pressure monitored every 30 min HME and oral airway use, method of suctioning and incidence in coughing prior to extubation not a Investigators only indicated gargled solutions were gargled, not swallowed b umber of subjects c Hours postoperatively or post-extubation d P<.05 e 19 subjects were in group ETT, endotracheal tube; HME, heat and moisture exchanger; G, nasogastric tube; orogastric tube;, postoperative sore throat; VAS, visual analog scale Postoperative sore throat, a usually self-limiting complication, continues to be an important concern for the surgical patient undergoing endotracheal intubation. Steps should be taken to help lessen the risk of including: avoiding a preoperative antisiaolgoue if possible avoiding trauma during laryngoscopy and intubation using an appropriate ETT size perhaps lubricating the cuff of the ETT with a water soluble jelly using the appropriate ETT cuff pressure and monitoring the cuff pressure avoiding the use of a naso- or orogastric tube if possible, carefully suctioning the oropharynx prior to extubation and taking steps to reduce the risk of the patient coughing or bucking prior to extubation Despite taking these steps, patients may suffer Local anesthetics and steroids might be considered to help decrease the incidence of Would be attractive to have an inexpensive, quick, convenient, and easy-to-administer medication that the patient could take immediately prior to help decrease this complication 6

7 Of the medications found for this review, preoperative ketamine and aspirin gargle are probably the most promising for providers practicing in the United States However before these agents are recommended for use, large muticenter trials should be done exploring not only efficacy but also dose-response relationships and potential side effects For those medications not available in the United States (Sodium azulene sulfonate), studies should continue and we should be aware of work being done with these agents Hopefully these drugs will be approved for use in the United States if found to be safe and effective 7