Postoperative Nausea and Vomiting Prevention and Treatment

Postoperative Nausea and Vomiting: Prevention and Treatment Phillip E. Scuderi, M.D. Department of Anesthesiology Wake Forest University School of Medicine Winston-Salem, NC 27157-1009 Postoperative Nausea and Vomiting: Prevention and Treatment http://www.wfubmc.edu/anesthesia pscuderi@wfubmc.edu Topics        Critical Evaluation of Data Risk factors Pharmacologic approaches to management Adjuvants (non-pharmacologic) Prevention versus treatment Multimodal management Postdischarge nausea and vomiting Evidence Based Medicine: Rating Scale Level of evidence based on study design I. Large randomized, controlled trial (n>100 per group) II. Systematic review III. Small randomized, controlled trial (n<100 per group) IV. Nonrandomized controlled trial or case report V. Expert opinion Strength of Recommendation based on expert opinion A. Good evidence to support the recommendation B. Fair evidence to support the recommendation C. Insufficient evidence to recommend for or against Measures of Treatment Consequences Relative Risk Reduction  The reduction of adverse events achieved by a treatment, expressed as a proportion of the control rate The traditional expression of the relative likelihood of an outcome expressed as P/(1 - P) where P = probability The difference in event rates between the control and treatment groups The number of patients who must be treated in order to prevent one adverse event. It is mathematically equivalent to the reciprocal of the absolute risk reduction. Laupacis et al. NEJM 1988;318:1728-1733 Odds Ratio  Absolute Risk Reduction  Numbers Needed to be Treated (NNT)  Measures of Treatment Consequences Rates of Adverse Events Placebo = 0.50 Treatment = 0.30 Relative Risk Reduction Odds Ratio [0.30 / (1 - 0.30)] [0.50 / (1 - 0.50)] = 0.43 0.5 - 0.30 = 0.40 0.50 Absolute Risk Reduction 0.5 - 0.3 = 0.20 Numbers Needed to be Treated 1 0.5 - 0.3 = 5 Laupacis et al. NEJM 1988;318:1728-1733 Risk Factors    Non-anesthetic factors Anesthetic related factors Postoperative factors Risk Factors Non-anesthetic Factors          Anesthetic Related Factors      Age Gender Body habitus Hx motion sickness Hx PONV Anxiety Concomitant disease Operative procedure Duration of surgery Preanesthetic medication Gastric distension Gastric suctioning Anesthetic technique Anesthetic agents Risk Factors Postoperative Factors      Pain Dizziness Ambulation Oral intake Opioids Risk Factors: Patient Specific Logistic Regression Palazzo M, Evans R. Logistic regression analysis of fixed patient factors for postoperative sickness: a model for risk assessment. Br J Anaesth 1993;70:135-40. Koivuranta M, Läärä E, Snåre L, Alahuhta S. A survey of postoperative nausea and vomiting. Anaesthesia 1997;52:443-49. Apfel CC, Greim CA, Haubitz I, et al. A risk score to predict the probability of postoperative vomiting in adults. Acta Anaesthesiol Scand 1998;42:495-501. Risk Factors: Patient Specific Logistic Regression       Younger age Nonsmoking history Female Hx of motion sickness Hx of PONV Increased duration of operation Risk Factors: Patient Specific Simplified Scoring System     Female Nonsmoking history Hx of motion sickness or PONV Use of postoperative opioids Incidence 10% 21% 39% 61% 79% Apfel CC et al. Anesthesiology 1999;91:693-700. Incidence of PONV Risk Factors 0 1 2 3 4 Risk Factors: Propofol and PONV *Analysis by NNT Nausea Induction Maintenance 9.3* 8* All Control Event Rates Early Vomiting 13.7* 9.2* Any 20.9 6.2* Nausea 50.1 5.8* Late Vomiting 14.9 10.1* Any NA 10 20% - 60% Control Event Rate Early Nausea Induction Maintenance 5.0* 4.7* Vomiting 7.0* 4.9* Any 14 4.9* Nausea 28 6.1* Late Vomiting 10 8.3* Any NA 7.1 Tramer et al. BJA 1997;78:247-255 Risk Factors: Anesthetic Related Volatile Anesthetics Risk Factors OR* CI Volatile anesthetics isoflurane sevoflurane enflurane 3.41 2.78 3.11 2.18; 5.37 1.79; 4.31 1.98; 4.88 * Compared to propofol Apfel et al. BJA 2002;88:659-668 Risk Factors: Anesthetic Related Nitrous Oxide and PONV Omission of Nitrous Oxide during Anesthesia Reduces the Incidence of Postoperative Nausea and Vomiting. A Meta-Analysis Divatia et al. Anesthesiology 1996;85:1055-1062 Twenty-Four of Twenty-Seven Studies Show a Greater Incidence of Emesis Associated with Nitrous Oxide than with Alternative Anesthetics Hartung. Anesth Analg 1996;83:114-116 Omitting Nitrous Oxide in General Anaesthesia: Meta-Analysis of Intraoperative Awareness and Postoperative Emesis in Randomized Controlled Trials Tramer et al. BJA 1996;76:186-193 Risk Factors: Anesthetic Related Nitrous Oxide and PONV Omitting nitrous oxide from general anesthesia:    Decreases POV significantly only if the baseline risk is high Does not affect nausea or complete control of emesis Increases the incidence of intraoperative awareness Tramer et al. BJA 1996;76:186-193 Risk Factors: Surgical Risk Factors Duration of Surgery Apfel et al. BJA 2002;88:659-668 Sinclair et al. Anesthesiology 1999; 91:109-118 Type of Surgery Sinclair et al. Anesthesiology 1999; 91:109-118 Apfel et al. BJA 2002;88:659-668 Fabling et al. Anesth Analg 2000;91:358-361 Gan et al. Anesthesiology 1996;85:1036-1042 Evidence Based Medicine: Risk Factors for PONV in Adults Patient-specific factors Female gender (II-A) Nonsmoking status (IV-A) History of PONV/motion sickness (IV-A) Anesthetic risk factors Use of volatile anesthetics (I-A) Nitrous oxide (I-A, II-A) Intraoperative opioids (II-A) Postoperative opioids (IV-A) Surgical risk factors Duration of surgery (IV-A) Type of surgery (IV-B) Gan et al. et al. Anesth Analg 2003; 97:62-71 Chemoreceptor Receptor Zone Pharmacologic Group Anticholinergics Scopolamine Antihistamines Cyclizine Dimenhydrinate Diphenhydramine Hydroxyzine Medizine Promethazine Antiserotonins Dolasetron Granisetron Ondansetron Ramosetron Benzamides Domperidone Metoclopramide Dopamine (D2) + + + + + + ++ – – – – ++++ +++ Muscarinic Cholinergic ++++ +++ ++ ++ ++ +++ ++ – – – – – – Histamine + ++++ ++++ ++++ ++++ ++++ ++++ – – – – – – Serotonin – – – – – – – ++++ ++++ ++++ ++++ + ++ Butyrophenones Droperidol Haloperidol Phenothiazines Chlorpromazine Fluphenazine Perphenazine Prochlorperazine Steroids Betamethasone Dexamethasone ++++ ++++ ++++ ++++ ++++ ++++ – – – – ++ + + ++ – – + + ++++ ++ ++ ++ – – + – + – + + – – Currently Available Medications        5HT3 (serotonin) antagonists - ondansetron Butyrophenones - droperidol Benzamides - metoclopramide Antihistamines - promethazine, dimenhydrinate Steroids - dexamethasone Phenothiazines- promethazine, prochlorperazine Anticholinergics – scopolamine Evidence Rating for Antiemetics Strength of Evidence Prevention Ondansetron 4 mg Ondansetron 1 mg Dolasetron 12.5 mg Granisetron 1 mg Droperidol Dexamethasone Dimenhydrinate Promethazine Metoclopramide Scopolamine patch *NNT Treatment Consequences* Prevention 5.5 – 6.5 4.0 – 5.0 3.1 – 4.2 4.3 – 5.0 4.3 – 7.1 4.8 – 8.0 ? 5.0 – 7.0 Treatment I-A I-A I-A I-A V-B V-B V-B - Treatment 3.2 – 3.9 3.8 – 4.8 3.6 – 4.2 3.1 – 3.8 ? ? ? ? ? I-A I-A I-A I-A II-A II-A III-B II-B Propofol and PONV Determination of Plasma Concentrations of Propofol Associated with 50% Reduction in Postoperative Nausea Gan TJ, Glass PSA, Howell ST, Canada AT, et al. Anesthesiology 1997;87:779-784    CACI devise targeted plasma concentrations of 100, 200, 400, and 800 ng/ml Median plasma concentration associated with antiemetic response - 343 ng/ml 17 mcg/kg/min propofol yields 400 - 540 ng/ml plasma concentration Propofol “PCA” Propofol Patient Controlled Antiemesis is a Safe and Effective Method for Treatment of Postoperative Nausea and Vomiting Gan TJ, El-Molem H, Ray J, Glass PSA, Anesthesiology 1999; 90:1564-1570 Three medications per delivery: propofol 20mg, propofol 40 mg, or placebo Lockout interval 5 min, no maximum dose limit Nausea scores were 34% and 40% less than placebo Placebo group had an 8 and 5 fold increase in risk of emesis and a 5 fold increase in incidence of rescue No differences in sedation Patients in treatment groups were more satisfied than those in placebo group Prevention of PONV: Ondansetron Versus Droperidol Complete Response Placebo Droperidol 0.625 mg Droperidol 1.25 mg Ondansetron 4 mg I-A *† 69 100 % of Patients 80 60 40 20 0 46 * 63 62 * * 48 36 *‡ 56 53 * 0 - 2 hr * p < 0 .05 compared to placebo † p < 0.05 compared to ondansetron 4 mg ‡ p ,<0.05 compared to droperidol 0.625 mg 0 - 24 hr Fortney et al. Anesth Analg 1998;86:731-738 Prevention of PONV: Ondansetron Versus Droperidol No Nausea 100 % of Patients * p < 0 .05 compared to placebo † p < 0.05 compared to droperidol 0.625 mg and ondansetron 4 mg I-A 80 60 40 20 0 23  29  † 43 29  0 - 24 hr Placebo Droperidol 0.625 mg Droperidol 1.25 mg Ondansetron 4 mg Fortney et al. Anesth Analg 1998;86:731-738 Prevention of PONV: Combination Therapy Which Combination? 5-HT3 + drop Event Early N Rate II-A 5-HT3 + dex N Rate P-value OR Nausea Vomiting Late Nausea Vomiting 138 318 17% 1% 260 419 11% 1% 0.12 1.00 1.6 1.0 358 443 27% 9% 623 813 21%* 9% 0.02 1.00 1.4 0.9 Ashraf et al. Anesthesiology 2001; 95:A-41 Prevention of PONV: Timing of Administration Ondansetron III-A  Sun et al. The effect of timing on ondansetron administration in outpatients undergoing otolaryngologic surgery. Anesth Analg 1997;84:331-336 Dolasetron III-A  Chen et al. The effect of timing of dolasetron administration on its efficacy as a prophylactic antiemetic in the ambulatory setting. Anesth Analg 2001;93:906-911 Dexamethasone III-A  Wang et al. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000;91;136139 Breakthrough PONV: Repeat Dosing With Ondansetron 100 Percent Complete Response * p = 0.074 80 60 43 40 20 0 0 - 2 hours Placebo 34 † p = 0.342 I-A * 32 † 28 0 - 24 hours Ondansetron 4 mg Kovac et al. J. Clin Anesth 1999;11:453-459 Droperidol FDA Box Warning Droperidol FDA Box Warning BOGUS! NK-1 Antagonists: Prevention III-A Emesis (24 hr) (%) Rescue antiemetics (%) Median emesis free time 75% of pts. (min) Nausea 8 hr (%) 24 hr (%) Satisfaction with nausea management (%) Ondansetron CP122,721 Combination (n=52) (n=52) (n=53) 18 6 2* 60 82 76 98 81 47 75 80 96 75 44 362* 80 98 80 Gesztesi Z, Scuderi PE, D’Angelo R, et al. Anesthesiology 2000;93:931-937 NK-1 Antagonists: Treatment III-A Complete Control of Emesis Placebo 100 % of Patients % of Patients Complete Control of Nausea Placebo 100 GR205171 GR205171 80 60 40 20 0 77 50 28 21 5 2 hr 6 hr 24 hr 80 60 40 20 0 55 21 16 20 0 2 hr 6 hr 31 5 31 10 0 10 72 hr 24 hr 72 hr Time After Treatment Time After Treatment Diemunsch et al. Anesth Analg 1998;86:S436 Prevention of PONV: Clonidine Effects of clonidine on postoperative nausea and vomiting in breast cancer surgery Oddby-Muhrbeck, Eksborg, Bergendahl, Muhrbeck, et al. Anesthesiology 2002; 96:1109-1111 III-A The efficacy of oral clonidine premedication in the prevention of postoperative vomiting in children following strabismus surgery Handa, Fujii. Paediatr Anaesth 2001; 11:71-74 Oral clonidine premedication reduces vomiting in children after strabismus surgery. Can J Anaesth 1995; 42: 977––81 Mikawa, Nishina, Maekawa, Asano, Obara. Can J Anaesth 1995; 42: 977-981 P-6 Acupuncture Point Stimulation  Zarate E, Mingus M, White PF, Chiu JW, Scuderi PE, et al. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001;92:629-35. P-6 Stimulation: Control of Nausea III-A TAES PACU 45 min 90 min 120 min 4 hr 6 hr 9 hr * compared to sham † compared to placebo Sham 17 51 51 40 52 47 42 Placebo 28 32 33 41 35 43 47 25 36 27* 27 26* 22*† 18*† Zarate E, et al. Anesth Analg 2001;92:629-35 P-6 Acupuncture Point Stimulation III-A TEAS n = 26 Nausea 2 h Emesis 2h 24 h Complete Response 2h 77 73 19 64 52 28 42 38 54 0.01 0.006 0.04 12 19 8 32 25 46 0.22 0.12 19 Ondansetron n = 25 40 Placebo n = 24 79 P value <0.0001 24 h Rescue Antiemetic All values in percent Gan et al. Anesth Analg 2004;99:1070-1075 Supplemental Oxygen    Greif R, Laciny S, Rapf B, et al. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999;91:1246-52. Goll V, Ozan A, Greif R, et al. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg 2001;92:112-17. Joris JL, Poth NJ, Djamandar AM, et al. Supplemental oxygen does not reduce postoperative nausea and vomiting after thyroidectomy. BJA 2003;91:857-861 Intravenous Fluid Therapy Incidence on Postop Nausea 20 High Infusion Incidence % Low Infusion 15 10 5 0 30 min 60 min Time DIS * Day 1 High Infusion = 20 ml/kg Low Infusion = 2 ml/kg Yogendran S, et al. Anesth Analg 1995;80:682-686 Intravenous Fluid Therapy 10 ml/kg n = 71 Cumulative 48 h 30 ml/kg n = 70 P value vomiting nausea, severe nausea, total antiemetic use 25.7 27.1 37.1 22.9 8.6 5.7 37.1 11.9 0.01 0.001 0.86 0.146 All values in percent Manger et al. BJA 2004;93:381-385 Management of PONV: Adjuvants (Nonpharmacologic)    P-6 acupuncture point stimulation III-A Supplemental oxygen III-C Aggressive perioperative rehydration III-A Prevention versus Treatment Prevention Versus Treatment IA, IIIA Routine administration of prophylactic antiemetics does reduce the incidence of emesis both before and after discharge; however, it did not improve any of the measures of outcome following outpatient surgery except in patients at the highest risk for symptoms. Scuderi et al. Anesthesiology. 1999;90:360-371 Multimodal Management of PONV: Hypothesis A multi-modal approach to the management of PONV can result in a zero incidence of vomiting (and perhaps nausea) in the immediate postoperative period (i.e., PACU) Scuderi at al. Anesth Analg 2000;91:408-414 Multimodal Management of PONV: Algorithm for Management I. PREOPERATIVE A. Anxiolysis - 10-30 mcg/kg midazolam B. Fluid - 10 ml/kg minimum II. INDUCTION A. PreO2 B. Droperidol 10 mcg/kg C. Decadron 8 mg D. Propofol - 2 mg/kg + 200 mcg/kg/min E. Remifentanil - 1 mcg/kg + 1 mcg/kg/min F. Intubate 90-120 seconds G. Gastric decompression Scuderi at al. Anesth Analg 2000;91:408-414 Multimodal Management of PONV: Algorithm for Management III. MAINTENANCE A. Propofol 200 mcg/kg/min x 5 min, then 150 mcg/kg/min x 5 min, then 100 mcg/kg/min x 5 min, then 75 mcg/kg/min until 10 minutes prior to end of surgery, then D/C B. Remifentanil 1 mcg/kg/min until intubated, then 0.5 mcg/kg/min until trocar, then 0.25 mcg/ kg/min titrated to effect or BIS D/C 2-3 minutes prior to end of surgery C. Ketorolac 30 mg IV after induction D. Ondansetron 1 mg at end of surgery E. Fentanyl 25 mcg IV 10 minutes prior to end of surgery Scuderi at al. Anesth Analg 2000;91:408-414 Multimodal Management of PONV: Algorithm for Management IV. PACU A. PONV rescue B. Pain rescue Dramamine 25 mg IV Fentanyl 25 mcg prn C. Fluids 25 ml/kg total for OSC stay Scuderi at al. Anesth Analg 2000;91:408-414 Multimodal Management: Results Group I Multimodal Patients Hx Risk Factors (%) Tx required (%) Vomiting before discharge (%) Group II Ondansetron Group III Placebo III-A P values 60 48 2 0 12 100 5 128 42 64 24 7 21 100 6 162 37 65 41 22 32 92 37 192 0.17*† <0.0001*† 0.67* 0.003† 0.27* 0.02† 0.05†‡ 1.00* 0.0013‡ 0.0015*; 0.0001† Vomiting after discharge (%) Satisfaction with PONV (%) Satisfaction score <10 (%) Time to discharge ready (mean) *Group I vs II; † Group I vs III; Group II vs III‡ Scuderi at al. Anesth Analg 2000;91:408-414 Multimodal Management of PONV: Simplified Algorithm I. INDUCTION A. PreO2 B. Propofol 2 - 4 mg/kg C. Opioid prn D. NMB prn C. Droperidol 10 mcg/kg D. Decadron 4 - 8 mg II. MAINTENANCE A. Propofol 50 mcg/kg/min B. Potent inhalation agent C. Nitrous oxide prn E. NMB reversal prn III. EMERGENCE A. Ondansetron 1 mg IV B. Suction oropharynx C. Extubate when awake Multimodal Management of PONV: Simplified Algorithm Cost Analysis COST ($) Case duration Droperidol (10 mcg/kg) Dexamethasone (8 mg) Ondansetron (1 mg) Propofol (50 mcg/kg/min) Total Cost 1 hour $2.10 $1.30 $4.00 $7.50 $14.90 2 hours $2.10 $1.30 $4.00 $15.00 $22.40 3 hours $2.10 $1.30 $4.00 $22.50 $29.90 PONV Risk Reduction I-A Intervention Ondansetron 4mg Dexamethasone 4mg % Relative Risk Reduction 26.0 26.4 Droperidol 1.25mg Propofol vs volatile Nitrogen vs Nitrous 24.5 18.9 12.1 Apfel, et al. NEJM 2004; 350:2441-2451 Post Discharge Symptoms Following Ambulatory Surgery Symptom Incidence (%) Pain Nausea Vomiting Headache 45 17 8 17 Drowsiness Dizziness Fatigue 42 18 21 Wu CL, et al. Anesthesiology 2002;96:994-1003 Postdischarge Vomiting: Ondansetron versus Placebo ODT Patients 30 Placebo 30 P-value Predischarge emesis Predischarge nausea Postdischarge emesis Postdischarge nausea * p<0.05 3% 40% 3%* 30% 0% 37% 23% 50% n.s n.s 0.02 0.11 Gan TJ, et al. Anesth Analg 2002;94:1199-1200 Postdischarge Vomiting: Ondansetron versus Placebo ODT Patients (n) PACU n or v Placebo 50 27% P-value n.s 46 34% 4 – 24 hr vomiting 4 – 24 hr nausea 24 – 72 hr vomiting 24 – 72 hr nausea 12% 48% 13% 35% 8% 28% 9% 21% n.s n.s n.s n.s Thagaard et al. Eur J Anesth 2003;20:153-157 PCA and Antiemetics Agent/Endpoint Droperidol Nausea 3 5.1 Trials (n) NNT II-A Vomiting N and/or V Ondansetron Nausea 5 3 2 3.1 2.8 - Vomiting N and/or V Promethazine N and/or V 2 2 1 5.1 2.9 2.5 Tramer et al. Anesth Analg 1999;88:1354-1361 Topics        Critical Evaluation of Data Risk factors Pharmacologic approaches to management Adjuvants (non-pharmacologic) Prevention versus treatment Multimodal management Postdischarge nausea and vomiting General Recommendations         Use generic drugs for “routine” prophylaxis Treat breakthrough symptoms with 5HT3 antagonists Don’t repeat dose with 5HT3 antagonists for failure Treat/prevent with different classes of antiemetics For “high risk” patients use combination prophylaxis Consider propofol infusion as part of anesthetic Prevent and control pain, hydrate aggressively Consider post-discharge therapy A foolish consistency is the hobgoblin of small minds Ralph Waldo Emerson Postoperative Nausea and Vomiting: Prevention and Treatment! http://www.wfubmc.edu/anesthesia pscuderi@wfubmc.edu