PONV AND MH
| NEW MECHANISMS, MODALITIES, AND METHODS FOR MANAGEMENT OF POSTOPERATIVE NAUSEA
AND VOMITING —Anthony L. Kovac, MD, Professor of Anesthesiology, University of Kansas School of
Medicine, Kansas City
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 | Historically: vomiting has been both remedy and symptom; Lewis and Clark expedition treated nausea and vomiting
by bloodletting or giving emetogenic agents or cathartics; in ether era, postoperative nausea and vomiting
(PONV) as high as 75% to 80%; Waters, in 1919, mentioned “PONV is a nuisance”; Kapur said, “it’s that big little
problem”
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| Currently: 25% to 30% of adults have PONV; without prophylactic antiemetic, ≤75% in high-risk group (eg,
women undergoing outpatient laparoscopy); PONV one of most common medical reasons for hospital admission;
multifactorial problem with no single solution
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| Incidence of postoperative vomiting (POV) in pediatrics: 45% to 50% in hospital, 50% to 55% at home; generally,
children <3 yr of age have lower incidence (25%); until boys and girls reach puberty, boys have same incidence;
after puberty, women have 3 times greater incidence than men
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| Hospital perspective: multidisciplinary action required, involving perianesthesia nursing (identify patient preoperatively
and care for patient postoperatively), pharmacist (gatekeeper of available medications), anesthesia provider,
and surgeon
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| Risk score for PONV in adults: important to determine baseline risk; Apfel found risk factors include female
sex, nonsmoker, history of PONV (also motion sickness), and postoperative opioids; 10% incidence without risk
factors
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| Risk factors for POV in pediatrics: include surgery >30 min, age >3 yr, strabismus surgery (also tonsillectomy),
and previous POV or PONV (patient or close relative)
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| New terms and definitions: include postdischarge nausea and vomiting (PDNV), opioid-induced nausea and
vomiting (OINV), and opioid-induced emesis (OIE); incidence of PDNV ≈30%; increased incidence (≈14%) after
discharge; orthopedic surgery generally low incidence of PONV (except shoulder surgery; perhaps due to interaction
of nerve plexus)
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| Opioid-induced nausea and vomiting: may be seen in postanesthesia care unit (PACU), on hospital floor, or at
home; incidence 10% to 60%; high incidence (60% to 90%) in gynecologic procedures; more emetogenic than regular
PONV; may require higher doses of traditional antiemetics for adequate management; start antiemetic regimen
as soon as possible; no advantage using one opioid over others
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| Consensus guidelines for management of PONV: use monotherapy prophylaxis for adults at moderate risk;
use double or triple antiemetic combinations for adult patients at high risk; alternatives to droperidol include dexamethasone
(4 mg; give early in case but after induction; may be effective in OINV), scopolamine patch (not approved
in pediatrics; not for patient with voiding problem or glaucoma; side effects include dry mouth; use with
caution in elderly; enhances efficacy when given in combination with dexamethasone or ondansetron; relatively inexpensive),
and haloperidol (0.5-4.0 mg; avoid repeated doses or use in treatment)
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| Current and upcoming antiemetic agents: neurokinin-1 (NK-1)—receptor antagonists and second-generation
serotonin-receptor antagonists; aprepitant (Emend) and palonosetron (Aloxi) have Food and Drug Administration approval
for use in chemotherapy-induced nausea and vomiting (especially useful for late emesis due to long half-lives)
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| Substance P and NK-1 receptor pathway: substance P receptors highly concentrated in central brainstem vomiting
center (nucleus tractus solitarius, area postrema) and peripheral gastrointestinal (GI) vagal nerve fibers; Hargreaves
looked at binding of positron-emission tomography (PET) tracer to NK-1 receptors before aprepitant dosing
and blockage of NK-1 receptors after aprepitant dosing
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| NK-1, pain, and PONV: substance P causes stimulation of type C fiber receptors; followed by complex mechanism
of calcium metabolism; opens voltage-gated calcium channels
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| Aprepitant vs ondansetron for prevention of PONV: 30-center, phase III study; oral aprepitant, 125 mg vs
aprepitant, 25 mg vs intravenous (IV) ondansetron, 4 mg; endpoint of study was number of patients who had complete
response (defined as no vomiting or emesis over 24-hr period); secondary endpoint looked at vomiting over
48-hr period; study found no difference between aprepitant and ondansetron as complete response; however,
aprepitant doses had better effect over 48 hr than ondansetron dose; randomized study of oral CP-122 ± ondansetron
vs ondansetron for prevention of PONV found incidence of emetic episodes significantly lower with CP-
122 vs ondansetron alone; effect not much greater when CP-122 combined with ondansetron; Diemunsch studied
IV GR205 on patients having major gynecologic surgery (eg, hysterectomy, oophorectomy); patients with nausea
or vomiting within 6 hr after recovery given medication or placebo; showed improvement in emesis or nausea with
use of GR205 vs placebo
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| Serotonin-receptor antagonists: palonosetron has longer-acting half-life (40 hr) but high receptor binding (30
times stronger than other serotonin-receptor antagonists); White study found 1 µg/kg better than placebo in abdominal
or vaginal hysterectomy (both complete or emetic response)
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| Pharmacogenomics: variations in CYP2D6 metabolism common and can lead to difference in drug clearance,
leading to therapeutic failure or increased adverse events; ultrarapid metabolizer phenotype—results in overactivity,
reduced effectiveness of drug, and more nausea and vomiting; more common in patients from Arabic countries
(eg, Saudi Arabia) than from Northern European countries; CYP2D6 deficiency—5% to 10% of whites; increased
potential for drug interactions and side effects; may result in accumulation; CYP2D6 metabolism in ethnic
groups—8% of whites poor metabolizers; 80% of Hispanic population extensive metabolizers; 66% of black population
extensive metabolizers
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| Summary: multifactorial etiology involves multiple receptors and stimuli; no single agent always effective; if one
antiemetic ineffective, do not repeat it (use antiemetic from another class); remember alternatives to droperidol (eg,
haloperidol, dexamethasone, scopolamine); think combination therapy for best effect in high-risk patients; pharmacogenetics
may help explain variations in antiemetic effectiveness of different populations
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| MALIGNANT HYPERTHERMIA DIAGNOSIS AND CRISIS MANAGEMENT —Harvey K. Rosenbaum, Clinical
Professor of Anesthesiology and Co-Director, Malignant Hyperthermia Program, David Geffen School of Medicine
at the University of California, Los Angeles
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| Elective facelift: woman, 48 yr of age, good general health; uncomplicated general anesthesia (sevoflurane and nitrous
oxide [N2 O]) 2 wk prior for different cosmetic surgical procedure; anesthesia induced with propofol and
maintained with sevoflurane and N2 O; laryngeal mask airway (LMA) used for airway management; liquid crystal
display (LCD) temperature strip used on thigh; first 2.5 hr uneventful; Bair-Hugger used for warming; progressive
increase in end-tidal CO2 (>70); considered possible LMA malpositioned; LCD temperature strip
indicates increase; electrocardiography shows wide-complex tachycardia
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| Malignant hyperthermia (MH) diagnosed: blood drawn but laboratory results not immediately available; anesthetic
turned off; given calcium chloride, glucose, insulin, and sodium bicarbonate; LMA changed to endotracheal
tube; patient hyperventilated; rectal temperature 107°F
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| MH treatment: given dantrolene, 2.5 mg/kg; cooling instituted with ice, cold IV saline, and cold cans of soda; temperature
decreased to 102°F; moderate hypotension noted; given ephedrine and low-dose dopamine; given additional
dose of dantrolene, 1 mg/kg
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| Transported to emergency department: initial potassium 7.8 mEq/L; pH 7.2; initial creatine kinase (CK) normal; no
gross myoglobinuria; temperature decreased to 97.6°F; unresponsive; computed tomography showed cerebral
edema
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| Hospital course: dantrolene for 48 hr; creatinine 1.2 mg/dL; responding to commands within 24 hr; CK 8000 U/L;
coagulopathy (hematomas evacuated); recovered without serious sequelae
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| Diagnosis of MH: hypermetabolism (increased CO2 despite minute ventilation >150 mL/kg per min; not difficult
to ventilate; inspired CO2 level not increased initially; hot CO2 absorbent canister; caused by any halogenated gas;
rigidity not necessary, even in life-threatening case of MH
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| Muscle injury: myoglobinuria; rigidity that does not abate with full dose of nondepolarizing muscle relaxant; hyperkalemia
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| Temperature monitoring: accurately monitoring temperature “not that difficult”; methods include LCD strips
(2°C offset; inaccurate if skin flushed or mottled); more accurate sites include distal esophagus and nasopharynx;
rectum and axilla (arm tucked; not under Bair-Hugger; not under rapidly flowing warm or cool IV fluid) considered
sites of intermediate accuracy; oral temperature can be reasonably accurate (also posterolateral LMA cuff in
future)
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| MH treatment: vaporizer off; inform surgeon; ask for help; high fresh gas flow of O2 ; do not change anesthesia machine;
hyperventilate using ventilator; give dantrolene
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| Freestanding center: arrange transport, but crucial to gain control over hypermetabolism before transport (give
enough dantrolene); dantrolene must be dissolved with sterile water (not saline) for injection; dissolves faster if
water heated to 40°C
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| Dantrolene: 20 mg per bottle; 3-yr shelf life; $75 per bottle; 3 g mannitol per bottle; 60 mL water per bottle required
to dissolve; initial recommended dose 2.5 mg/kg; full effect should be seen within 10 min; pooled dantrolene
supply (eg, 3 offices in building; 300 mg per office; total supply ≈50 bottles; acceptable with good
communication and cooperation)
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| Temperature >38.9°C: uncover patient; ice packs to groin, axillae, and neck; cool water on skin; fan with warm air;
cold IV fluid (reduces body temperature by 0.5°C per liter); cold circulating water mattress over and under patient;
orogastric lavage with cold saline
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| Temperature >40°C: rapid cooling with ice plus water bath (additional drop in temperature 1.5°-2.0°C after removal
from ice bath); strong plastic sheet under patient; if appropriate, peritoneal lavage with cool or cold saline
for irrigation; stop when temperature ≈38°C
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| Critical laboratory tests: blood gas (can be venous as long as no tourniquet); potassium; i-STAT device may be
solution to obtaining results in ambulatory setting; heparinized syringe on ice to hospital
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| Acidosis: respiratory (usually, but not always, accompanied by lactic acidosis); treatment includes hyperventilation,
dantrolene (to stop hypermetabolic process), and sodium bicarbonate (question benefit before gaining control of
hypermetabolic process); if giving sodium bicarbonate, limit boluses to 25 mL (acutely produces 500 mL CO2 )
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| Hyperkalemia: depolarization (closer to threshold); results in irritability manifest by premature ventricular contractions
(PVCs), ventricular tachycardia (or sinus tachycardia with wide QRS, no P wave), and ventricular fibrillation;
inactivates sodium channels, resulting in slower or impaired atrioventricular (AV) conduction, third-degree heart
block progression to junctional rhythm or asystole; typical signs—peaked T waves (base not broadened); increased
PR interval; P waves disappear; QRS widens; ST elevation in V1 and V2 or pseudoinfarction pattern; ECG changes
not always present until life-threatening
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| Wide-complex tachycardia: with hyperkalemia, use caution and avoid lidocaine; hyperkalemia increases sensitivity
to conduction block due to lidocaine; asystole may result; better to cardiovert unstable patient
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| Treatment: with positive ECG signs, give IV calcium chloride, 300 to 400 mg; hyperventilate; insulin, 10 U with
dextrose (D-50-W); alternatively, use β2 -agonist (eg, albuterol inhaler plus spacer; 40 to 50 puffs) or IV terbutaline
(1 mg diluted to 50 mL; dosed at either 0.1 µg/kg per min or 3 mL/10 kg per hr; studies do not confirm utility
of sodium bicarbonate in this setting
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| MH and hyperkalemia: only 4% reported cases (markedly underreported in this setting); contributing factors include
rhabdomyolysis, hypercarbia, and α-adrenergic agonists; plasma potassium may increase after resolution of
acidosis; treat if ECG signs indicate, if potassium >6.0 mEq/L, and with delayed diagnosis
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| Myoglobinuria: not acutely life-threatening
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| Sources of additional information: website www.mhaus.org; products include MH procedure manual (office-
based and outpatient surgery; cost ≈$200) and poster indicating emergency therapy for MH; Proctor & Gamble
(dantrolene) 800-448-4878
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Educational Objectives
| The goal of this program is to educate the listener about management of postoperative nausea and vomiting (PONV)
and malignant hyperthermia (MH). After hearing and assimilating this program, the participant will be better able to:
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| 1. List new terms and definitions related to PONV.
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| 2. Summarize the consensus guidelines for the management of PONV.
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| 3. Review current and upcoming antiemetic agents.
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| 4. Discuss pharmacogenetics in PONV.
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| 5. Review MH diagnosis and crisis management in the hospital and ambulatory setting.
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Discussed on This Program
Albuterol (salbutamol sulphate in United Kingdom) [several trade names]
Aprepitant [Emend]
Calcium chloride
Dantrolene sodium [Dantrium, Dantrium Intravenous]
Desflurane [Suprane]
Dexamethasone (several trade names)
Dextrose (D -glucose) [D-50-W, others]
Dopamine HCl [Intropin, Dopamine HCl in 5% Dextrose]
Droperidol [Inapsine]
Ephedrine sulfate [Pretz-D]
Haloperidol [Haldol, Haldol Decanoate 50, Haldol Decanoate 100]
Insulin injection, regular (several trade names)
Mannitol [Osmitrol, Resectisol]
Metoclopramide (several trade names)
Nitrous oxide (N2 O)
Ondansetron HCl [Zofran, Zofran ODT]
Palonosetron HCl [Aloxi]
Promethazine HCl [ Phenadoz, Phenergan]
Propofol [Diprivan]
Remifentanil HCl [Ultiva]
Scopolamine, oral [Scopace]
Scopolamine, transdermal [Transderm-Scop]
Sevoflurane [Ultane]
Sodium bicarbonate [Bell/ans, Neut]
Suggested Reading
Apfel CC et al: A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl
J Med 350:2441, 2004; Apfel CC et al: A simplified risk score for predicting postoperative nausea and vomiting:
conclusions from cross-validations between two centers. Anesthesiology 91:693, 1999; Apfel CC et al: Comparison
of predictive models for postoperative nausea and vomiting. Br J Anaesth 88:234, 2002; Carroll NV et al: Postoperative
nausea and vomiting after discharge from outpatient surgery centers. Anesth Analg 80:903, 1995; Chung F et
al: Ondansetron is more effective than metoclopramide for the treatment of opioid-induced emesis in post-surgical
adult patients. Ondansetron OIE Post-Surgical Study Group. Eur J Anaesthesiol 16:669, 1999; Davies PR et al: Antiemetic
efficacy of ondansetron with patient-controlled analgesia. Anaesthesia 51:880, 1996; Diemunsch P et al:
Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and
vomiting after major gynaecological surgery. Br J Anaesth 82:274, 1999; Eberhart LH et al: Applicability of risk
scores for postoperative nausea and vomiting in adults to paediatric patients. Br J Anaesth 93:386, 2004; Gan TJ et
al: Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 97:62, 2003; Gan TJ: Risk
factors for postoperative nausea and vomiting. Anesth Analg 102:1884, 2006; Hargreaves R: Imaging substance P
receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 63 Suppl 11:18,
2002; Kenny GN: Risk factors for postoperative nausea and vomiting. Anaesthesia 49 Suppl:6, 1994; Khalil SN et
al: A double-blind comparison of intravenous ondansetron and placebo for preventing postoperative emesis in 1- to
24-month-old pediatric patients after surgery under general anesthesia. Anesth Analg 101:356, 2005; Kovac AL: Is
there rationale to use an antiemetic in the same class for the treatment of patients who experience postoperative nausea
and vomiting despite prophylaxis? Anesth Analg 97:1857, 2003; Kovac AL: Meta-analysis of the use of rescue antiemetics
following PONV prophylactic failure with 5-HT3 antagonist/dexamethasone versus single-agent therapies.
Ann Pharmacother 40:873, 2006; Kovac AL: Prevention and treatment of postoperative nausea and vomiting. Drugs
59:213, 2000; Kovac AL: Prophylaxis of postoperative nausea and vomiting: controversies in the use of serotonin 5-
hydroxytryptamine subtype 3 receptor antagonists. J Clin Anesth 18:304, 2006; Plattner O et al: Efficacy of intraoperative
cooling methods. Anesthesiology 87:1089, 1997; Sinclair DR et al: Can postoperative nausea and vomiting
be predicted? Anesthesiology 91:109, 1999; White PF: Consensus guidelines for managing postoperative nausea
and vomiting: is there a conflict of interest? Anesth Analg 98:550; author reply 550, 2004; White PF: Treatment of
postoperative nausea and vomiting with dolasetron versus ondansetron: is there a conflict of interest? Anesth Analg
101:1887; author reply 1887, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Kovac is on the Speakers’ Bureau or Advisory Board of Merck & Co., Inc., GlaxoSmithKline,
and Baxter International Inc., and has received research grants from Organon and Helsinn Healthcare. His presentation
may also reference unlabeled use of dexamethasone and haloperidol.
Dr. Kovac was recorded at the 56th Annual Postgraduate Symposium on Anesthesiology, presented March 31, April
1-2, 2006, by the University of Kansas Medical Center Department of Anesthesiology and University of Kansas Continuing
Education, and held in Kansas City, MO; Dr. Rosenbaum, at Anesthesiology Update 2005, presented November
12, 2005, by the Office of Continuing Medical Education, David Geffen School of Medicine at the University of
California, Los Angeles, and held in Los Angeles, CA. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
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