An overview of treatment options for postoperative nausea and vomiting after laparoscopic surgical procedures

Hüseyin C. Turgut1, Mustafa Arslan2
1Anesthesiology & Reanimation Specialist, Department of Maxillofacial Surgery, Faculty of Dentistry, Gazi University, Ankara (Turkey)

2Department of Anesthesiology & Reanimation, Faculty of Medicine, Gazi University, Ankara (Turkey)

Correspondence: Mustafa Arslan, Department of Anesthesiology & Reanimation, Faculty of Medicine, Gazi University, Ankara 06510 (Turkey); Tel: 90 312 202 41 66; (GSM) 90 533 422 85 77; E-mail: mustarslan@gmail.com

SUMMARY
Background: Postoperative nausea and vomiting (PONV) is a well-known entity following surgical procedures and may result in serious complications include aspiration of gastric contents, prolonged recovery period, impaired surgical wound healing. Laparoscopic surgery alone is a known risk factor for PONV and different treatment options with various agents are preferred for PONV prophylaxis and treatment.

Aim: We aimed to review advantages and disadvantages of various drugs and combination regimens for prophylaxis and treatment of PONV after different types of laparoscopic procedures.

Methodology: We made a comprehensive PubMed search using search terms PONV, laparoscopic surgery, prophylaxis, treatment, drug, without considering publication time period.

Findings: Relatively traditional anti-emetics, including anticholinergics, antihistamines and phenothiazines, have more prominent side effect profiles. Using different receptor antagonists (serotonin 5-HT3, neurokinin, dopamine receptor antagonists) especially when combined with agents of same group or from various different groups, e.g. dexamethasone - a strong corticosteroid, naloxone - an opioid receptor antagonist, or propofol – an intravenous anesthetic and hypnotic, effective anti-emesis can be achieved.

Conclusion: Combinations of antiemetic agents of different groups is more effective in prevention of postoperative nausea and vomiting.

Key words: PONV; Laparoscopic Surgery; Serotonin; Neurokinin; Opioid, Receptor Antagonist; Corticosteroid; Propofol; Anesthesia, Inhalation

Citation: Turgut HC, Arslan M. An overview of treatment options for postoperative nausea and vomiting after laparoscopic surgical procedures. Anaesth Pain & Intensive Care 2016;20(2):193-200

Received: 13 December 2015; Reviewed: 5 January, 11 April 2016; Corrected: 18 April, 31 May 2016; Accepted: 5 June 2016

INTRODUCTION
Postoperative nausea and vomiting (PONV) is a common complication of surgery and anesthesia protocols and reported incidence of PONV ranges between 12 and 38%.1 However, in special patient populations, incidence may be as high as 70%.2 PONV results in important undesirable clinical conditions such as prolonged hospital stay with patient discomfort, increased intracranial pressure, provoked bleeding, dehydration, electrolyte imbalance, impaired wound healing and stretching surgical sutures as well as aspiration of gastric contents that may result in serious pulmonary complications.3 Early PONV is described as nausea and vomiting in first two hours at postoperative period while late PONV is nausea and vomiting in first 24 hours postoperatively.4 There are many different agents and protocols in literature regarding PONV prophylaxis and treatment. However, there is no consensus on any one or more treatment modalities.

RISK FACTORS FOR PONV
Several risk factors for PONV have been identified such as female gender, previous PONV and/or motion sickness history, non-smoking status, certain agents used in perioperative period (volatile anesthetics, nitrous oxide, opioids, ketamine, parasympathomimetic drugs (neostigmine >2.5 mg), longer operating time, intraabdominal surgeries including gynecologic and laparoscopic surgeries.5-7
PHYSIOLOGICAL MECHANISMS
Central or peripheral emetogenic signals are generted by various receptors which are primary targets of anti-emetic drugs.8-10 Chemoreceptor trigger zone (CTZ) is placed at area postrema under the 4th ventricle and important for identifying noxious chemicals like volatiles, opioids and other emetogenics in body fluids, e.g. blood and cerebrospinal fluid. Serotonin type-3 (5-HT3), histamine type-1 (H1), muscarinic cholinergic type-1 (M1), dopamine type-2 (D2), neurokinin type-1 (NK1), and opioid receptors are located in CTZ. Toxins or drugs cause strong impulses at CTZ and, as an afferent center, newly generated afferent impulses from CTZ arrive nucleus tractus solitaries (NTS) in the brainstem. NTS is a key center for PONV and receives vagal impulses generated in vestibular and gastrointestinal system.11 And finally activated central pattern generator for vomiting center in lateral reticular formation of medulla oblongata results in vomiting.

Serotonin is the key neurotransmitter in gastrointestinal system and binds visceral 5-HT3 receptors at gastrointestinal canal activates vagal impulses result in CTZ activation and nausea vomiting.11 These receptors are primary targets of 5-HT3 receptor blocking agents.

Physiological Changes during Laparoscopic Surgery
Laparoscopic surgery has gained popularity among several surgical approaches and has many advantages, including less postoperative pain and hospital stay with early mobilization. Minimal wound size results in early wound healing with lower complication rates.12 In order to have a sufficient surgical sight and manipulation pneumoperitoneum is essential in laparoscopic surgery. However, various systemic changes occur dependent to the type of gas used and level of the intraabdominal pressure. Cardiopulmonary effects, systemic carbon dioxide absorbtion and venous gas embolism are major problems in laparoscopic surgery.13
Physiological changes occur related to pneumoperitoneum and patient position. Carbon dioxide (CO2) is the most commonly used gas and several chemical effects of CO2 may emerge during laparoscopic surgery.

In cardiovascular system increased sympathetic discharge, hypercarbia and decreased venous return lead to tachycardia. Additionally, sympathetic stimulation emerges secondary to decreased venous return and peritoneum stretching. Hypercarbia and acidosis lead to cardiac rhythm disturbances, including premature ventricular contractions, ventricular tachycardia and fibrillations. Vagal stimulations may lead to bradyarrhythmias. This vagal stimulation due to pneumoperitoneum, in addition to risk factors related to surgery itself, may cause PONV.

Physiological changes in respiratory system are primarily related with increased intraabdominal pressure. Elevated diaphragm and collapsed lung bases result in decreased functional residual capacity (FRC), ventilation perfusion mismatch and intrapulmonary shunting. Clinical outcomes of these physiological changes are hypoxemia and increased alveolar arterial oxygen gradient.

TREATMENT CHOICES FOR PONV
Various drug regimens are effective modalities in PONV. Its important to keep in mind that more than one receptors, serotonin (5-HT3), dopamine (D2), Mu (M1), histamine (H1) and NK1 (neurokinin), play integral role in PONV so that an agent blocks a special type of receptor may be inadequate for PONV prevention and treatment.14-16
Anticholinergics and Antihistamines
Anticholinergic agents (most commonly used agent is scopolamine) block muscarinic receptors and inhibit cholinergic impulses from the vestibular nuclei to the vomiting center 17. Anticholinergic agents have unfavorable adverse event profile that limits their use. Anti-cholinergic side effects include dry mouth and drowsiness, disorientation, memory disturbances, dizziness and hallucinations.18
Gan et al19 compared transdermal scopolamine and ondansetron combination with ondansetron alone in outpatient laparoscopic surgery or breast augmentation and showed less PONV incidence with decreased side effects in combination therapy.

Histamine-1 (H1) receptors induce nausea and vomiting via NTS. Antihistamines, such as cyclizine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine and promethazine, inhibit acetylcholine at vestibular apparatus and H1 receptors in NTS. Similar to anticholinergics, antihistamines have common side effects including dry mouth, constipation, and less commonly mental changes such as confusion; also secondary to muscarinic inhibition blurred vision and urinary retention.18
In a combination therapy investigation metoclopramide plus dimenhydrinate regimen resulted in effective PONV protection in laparoscopic gynecologic surgery although the findings of this study are questionable because of non-randomized and uncontrolled study design.20
Phenothiazines
Chemoreceptor trigger zone (CTZ) is rich in D2 receptors and receptor antagonists include the phenothiazines (e.g. chlorpromazine, fluphenazine), benzamides (e.g. domperidone, metoclopramide) and butyrophenones (e.g. droperidol, haloperidol) inhibit D2 receptors in CTZ.18 Serious and common adverse effect profiles of phenothiazines caused limited usage area for these drugs; while benzamides (especially metoclopramide) have extensive usage. Most common side effects of benzamides are sedation, restlessness, diarrhea, CNS depression and agitation. On the other hand several uncommon but serious side effects of these drugs, e.g. hypotension, supraventricular tachycardia, extrapyramidal side effects and neuroleptic malignant syndrome, have been reported.

Metoclopramide is the most commonly used agent in this group and various studies reported different results when compared with different agents in protection PONV during perioperative period of laparoscopic surgeries. In a study, similar protection rates for PONV with metoclopramide and ondansetron have been reported in laparoscopic cholecystectomy (LC).21 In contrast, Naguib et al22 showed adequate protection with ondansetron while no protection with metoclopramide at postoperative period of LC. In another study similar PONV protection rates were reported with metoclopramide 20 mg versus ondansetron 8 mg administered just before end of LC.23 Ko-Iam et al24 showed better protection rates with metoclopramide 5 mg plus dexamethasone 4 mg than metoclopramide 10 mg alone administered at 30 minutes before anesthesia induction. In accordance with previous study Nesek et al25 reported significantly effective protection profile with metoclopramide 10 mg + dexamethasone 8 mg than metoclopramide 10 mg alone.

Serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron)
Serotonin receptors are found in CTZ and/or vomiting center, thus serotonin plays important role in PONV.26 The most involved and effective receptor type is the 5-HT3 subtype that agents that work via receptor antagonism have significant effectiveness both for PONV protection and treatment.26 Usefulness of these drugs is particularly important in PONV due to their action profile, because the effectiveness is significant during early phase of PONV. In this group of anti-emetics ondansetron, granisetron, dolasetron, ramosetron and tropisetron are available. Particularly granisetron and dolasetron are highly specific for 5-HT3 receptor. All the agents in this group except granisetron are metabolized by the cytochrome P-450 (CYP) enzyme 2D6. And so patients with more than three CYP2D6 gene and/or ultra-metabolizer genotypes are resistant to ondansetron prophylaxis for PONV.27,28 Side effects of drugs in this group include headache, somnolence, ataxia, asymptomatic QTc interval prolongation, constipation, diarrhea, muscle pain and dizziness.26
Various studies investigating 5-HT3 RAs concluded different results in terms of PONV prophylaxis and treatment. In a study comparing various 5-HT3 receptor antagonists and metoclopramide in LC showed better PONV protection with ondansetron 4 mg than metoclopramide 10 mg while similar effectiveness levels with tropisetron 5 mg, granisetron 3 mg when compared with metoclopramide 10 mg.22 Similarly Farhat et al29 showed better PONV prophylaxis with ondansetron 4 mg than metoclopramide 10 mg administered at anesthesia induction in LC. In contrast two different placebo controlled studies showed equal efficacy with different doses of ondansetron and metoclopramide during LC.21,23 Another study showed better PONV prophylaxis with ondansetron 8 mg plus dexamethasone 8 mg than ondansetron alone in LC.30 In a prospective randomized and double blinded study three different 5-HT3 RAs (ondansetron 4 mg, ramosetron 0.3 mg and palonosetron 75 µg) were compared and better protection was found with palonosetron 75 µg.31 Bhattacharjee et al32 reported higher effectiveness levels with palonosetron 75 µg than granisetron 2.5 gr when administered before anesthesia induction in LC. Another study showed continuous infusion of ramosetron at postoperative period of laparoscopic gynecologic surgery was superior than single doses of either palanosetron or ramosetron.33 Ryu et al34 investigated different administration protocols of ramosetron and concluded that combination of oral and intravenous (0.1 mg and 0.3 mg respectively) administration provided better PONV protection. Also there are various studies reporting different results with 5-HT3 RA and corticosteroid regimens in PONV protection after different laparoscopic protocols.35-37.
Opioid Receptor Antagonists
Opioids have important modulatory effects on gastrointestinal system, including both inhibitory and excitatory effects. Opioids are not neurotransmitters in gastrointestinal system but there are at least 3 different opioid receptors — μ, δ and κ.38 Morphine and other exogenous opioid receptor agonists primarily effects intestinal motility via cholinergic transmission while decrease gastrointestinal motility and gastric emptying via Mu receptors.39
Reduced nausea and vomiting with lowered additional anti-emetic usage has been shown with low-dose naloxone (0.25 μg/kg/h) compared with placebo in adult patients,40 and significantly decreased opioid-related adverse effects such as nausea and vomiting in children and adolescents.41 In a study conducted in adult patients undergoing laparoscopic gynecological surgery two different combination regimens – naloxone+droperidol and naloxone+dexamethasone - were found significantly more effective than naloxone alone.42
Corticosteroids
There are increasing number of studies investigating the role of corticosteroids on PONV. Although the exact mechanism is unknown, anti-inflammatory or membrane-stabilising effects, both peripherally and/or centrally, are thought to be possible pathways on PONV protection.43 In summary decreasing available neurotransmitter levels44 and reducing the release of prostaglandin E,45 both well-known effects of corticosteroids, are possible steps induced by corticosteroids at cellular level. Increased gastric acid secretion, gastrointestinal distress, psychiatric disturbances, hyperglycemia with increased insulin resistance, immunosuppression, flushing and osteoporosis are common side effects of corticosteroids.

Bisgaard et al46 showed effective protection of PONV in LC with preoperatively administered dexamethasone 8 mg plus 4 mg ondansetron combination compared with placebo. Similarly in another study 8 mg dexamethasone added to 4 mg ondansetron provided more effective PONV protection compared with 4 mg ondansetron alone,30 In a study comparing palonosetron 0.075 mg + 8 mg dexamethasone with palonosetron alone in LC, combination therapy was found significantly more effective than palonosetron alone.35 However, another study couldn’t find any difference between 0.075 mg palonosetron+8 mg dexamethasone and palonosetron alone in LC.36
Amer et al47 compared metoclopramide 10 mg with metoclopramide 5 mg + dexamethasone 4 mg (administered 30 minutes before anesthesia induction) and concluded that combination therapy resulted significant PONV protection after LC. Similarly dexamethasone 8 mg added metoclopramide 10 mg was found more effective than metoclopramide alone for PONV after LC 25. Another study compared dexamethasone 8 mg with metoclopramide 10 mg alone has shown better PONV prophylaxis with dexamethasone after LC 48. In addition to listed treatment options above, various agents were investigated in different studies. Daabiss et al 49 showed that dexamethasone 5 mg plus ephedrine 0.5 mg/kg IM given ten minutes before the end of the LC was superior than control (saline) and dexamethasone 5 mg alone in protection PONV. Another randomized and placebo controlled study showed that methylprednisolone (125 mg iv) and methylprednisolone + etoricoxib (125 mg iv +120 mg orally) combination significantly reduced the incidence and severity of PONV 50.

Neurokinin (NK) Receptor Antagonists
The peptides belong to tachykinin family are widely distributed in different locations in the body and are excitatory neurotransmitters that have important roles within intercellular signaling pathways. Substance P is a well-known member of this family and has important role in afferent pathways of emesis.10 Enterochromaffin cells in gastrointestinal system and sensory neurons are thought to be the sources of substance P.10 Tachykinin peptides exert their activity via G-protein-coupled receptor subtypes found in the peripheral or central nervous tissue — NK1, NK2 and NK3. The NK1 receptors are distributed in the area postrema so that suspected roles of NK1 receptors in PONV (especially secondary to surgical trauma) are being investigated. In addition to NK1, NK2 receptors are located in gastrointestinal system and have important roles in visceral sensitivity, inflammation, regulation of motor functions and secretions. However, the exact mechanism of NK receptor antagonists in protection of PONV has not been identified.10 One of the potential advantage that the NK1 receptor antagonists have -compared with 5-HT3 receptor antagonists- is the protection of both acute and delayed emesis.10 Several studies conducted in laparoscopic gynecological surgery showed significant PONV protection with orally administered aprepitant (a novel NK1 receptor antagonist) compared with 5-HT3 RAs or controls.51-53
Propofol
Propofol is primarily an anesthetic agent with strong narcotic and hypnotic properties; however, clinical usage area is gradually increasing that includes antiemesis. Although the mechanisms of antiemetic properties has not been completely understood, a serotonin antagonistic effect and/or a blocking effect of glutamate and aspartate (excitatory amino acids in central nervous system) secretion are potential anti-emetic effects of propofol.54, 55
There are various studies comparing anti-emetic properties of propofol in combination with different agents or alone in laparoscopic surgery. Kim et al54 showed better PONV protection with low dose propofol infusion (0.5 and 1 mg/kg) 15 minutes before the anesthesia cessation compared with placebo in laparoscopic assisted vaginal hysterectomy. In contrast Scuderi et al55 showed equal PONV control with 0.1 mg/kg bolus administration followed by 0.1 mg/kg/hr propofol infusion compared with placebo in laparoscopic gynecological surgery. In another study conducted in laparoscopic prostatectomy, lower PONV incidence with profopol compared with desflurane was reported.56 Song et al57 investigated anti-emetic effects of propofol in two different inhalation anesthesia protocols and showed better PONV control with propofol (0.5 mg/kg) administered at the end of the LC in sevoflurane + N2O group than that in desflurane + N2O group. In another study sub-hypnotic dose of propofol (1 mg/kg/hr during operation) and dexamethasone (8 mg before anesthesia induction) were found equally effective compared to control (10% intralipid) in LC.58 Arslan et al59 compared sub-hypnotic dose (0.5 mg/kg) of propofol bolus combined with dexamethasone 8 mg versus propofol plus metoclopramide (0.2 mg/kg) at the end of the LC. They found better PONV protection with propofol + dexamethasone rather than propofol + metoclopramide administration. Also protective and anti-oxidant role of propofol has been shown against hypoperfusion–reperfusion phenomenon occurs in laparoscopic surgery.60
DIFFERENT ANESTHESIA PROTOCOLS & PONV
TIVA vs. Inhalation Anesthetics
Total intravenous anesthesia (TIVA) is a relatively new protocol for anesthesic management of patients. TIVA is generally accepted as a well-tolerated technique with rapid and early recovery with minimal residual anesthesia effects. Beyond its advantages listed above, low incidence of PONV, as compared to inhalational agents, have been reported in numerous studies. Propofol with remifentanil is the most common technique however various combinations of other drugs (dexmedetomidine, ketamine, midazolam) may be preferred. In a study conducted in laparoscopic gynecologic surgery, propofol + remifentanil combination was compared with sevoflurane + N2O + palonosetron 75 µg. Despite anti-emetic prophylaxis with palonosetron in second study group the authors reported similar PONV incidence between groups.56 Similar results were achieved when ondansetron was used for PONV protection.61 Another study comparing TIVA (propofol) vs. sevoflurane anesthesia indicated lower PONV incidence at postoperative first hour in TIVA group after laparoscopic gynecologic surgery.62 Akkurt et al63 showed better PONV protection with TIVA (propofol + alfentanyl (2-2.5 mg/kg and 20 μg/kg respectively) than inhalation anesthesia with desflurane + alfentanyl (4-6% and 20 μg/kg respectively).

CONCLUSION AND RECOMMENDATIONS
In this review we focused on PONV prophylaxis and treatment choices during laparoscopic surgical procedures. Based on different results regarding effectiveness of various anti-emetic agents presented in large number of different studies cited in the article, our investigation suggests that;
  1. Antiemetic prophylaxis after laparoscopic surgery is ineffective when a single antiemetic drug is used.
  2. Better antiemetic prophylaxis is achieved with combination regimens because different drugs act on different types of receptors and multi-receptor antagonism results in decreased PONV incidence and more effective treatment.
  3. There is insufficient evidence to recommend the most superior single antiemetic drug or a combination regimen for prophylaxis and treatment of postoperative laparoscopic surgery.
  4. A favorable side-effect profile of the selected agent and additional risks related to laparoscopic procedure should be kept in mind when selecting an agent for PONV prophylaxis.
REFERENCES
  1. Gan TJ. Mechanisms underlying postoperative nausea and vomiting and neurotransmitter receptor antagonist-based pharmacotherapy. CNS Drugs. 2007;21(10):813-33. [PubMed]
  2. Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999 Sep;91(3):693-700. [PubMed] [Free full text]
  3. Macario A, Weinger M, Carney S, Kim A. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg. 1999 Sep;89(3):652-8. [PubMed]
  4. Apfel CC, Roewer N, Korttila K. How to study postoperative nausea and vomiting. Acta Anaesthesiol Scand. 2002 Sep;46(8):921-8. [PubMed]
  5. Habib AS, Gan TJ. Pharmacotherapy of postoperative nausea and vomiting. Expert Opin Pharmacother. 2003 Apr;4(4):457-73. [PubMed]
  6. Habib AS, Gan TJ. Evidence-based management of postoperative nausea and vomiting: a review. Can J Anaesth. 2004 Apr;51(4):326-41. [PubMed]
  7. Gan TJ, Meyer T, Apfel CC, Chung F, Davis P J, Eubanks S, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg. 2003 Jul;97(1):62-71 [PubMed]
  8. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001 Dec 3,111 Suppl 8:106-112. [PubMed]
  9. Fortney JT, Gan TJ, Graczyk S, Wetchler B, Melson T, Khalil S, et al. A comparison of the efficacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures. S3A-409 and S3A-410 Study Groups. Anesth Analg. 1998 Apr;86(4):731-8. [PubMed]
  10. Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci. 2003 Feb;91(2):87-94. [PubMed] [Free full text]
  11. Andrews PL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its relevance to anti-emetic therapy. Consensus and controversies. Support Care Cancer. 1998 May;6(3):197-203. [PubMed]
  12. O'Malley C, Cunningham AJ. Physiologic changes during laparoscopy. Anesthesiol Clin North America. 2001 Mar;19(1):1-19. [PubMed]
  13. Volz J, Koster S, Weiss M, Schmidt R, Urbaschek R, Melchert F, et al. Pathophysiologic features of a pneumoperitoneum at laparoscopy: a swine model. Am J Obstet Gynecol,. 1996 Jan;174(1 Pt 1):132-40. [PubMed]
  14. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004 Jun 10;350(24):2441-51. [PubMed] [Free full text]
  15. Tramer MR, Reynolds DJ, Moore RA, McQuay HJ. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Anesthesiology. 1997 Dec;87(6):1277-89. [PubMed] [Free full text]
  16. Henzi I, Walder B, Tramer MR. Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth. 1999 Nov;83(5):761-71. [PubMed] [Free full text]
  17. Kranke P, Morin AM, Roewer N, Wulf H, Eberhart LH. The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg. 2002 Jul;5(1):133-43. [PubMed]
  18. Kranke P, Morin AM, Roewer N, Eberhart LH. Dimenhydrinate for prophylaxis of postoperative nausea and vomiting: a meta-analysis of randomized controlled trials. Acta Anaesthesiol Scand. 2002 Mar;46(3):238-44. [PubMed]
  19. Gan TJ, Sinha AC, Kovac AL, Jones RK, Cohen SA, Battikha JP, et al. A randomized, double-blind, multicenter trial comparing transdermal scopolamine plus ondansetron to ondansetron alone for the prevention of postoperative nausea and vomiting in the outpatient setting. Anesth Analg. 2009 May;108(5):1498-504 doi: 10.1213/ane.0b013e31819e431f.. [PubMed]
  20. Fatima N, Khan AR, Nasir KK. Role of metochlopramide and dimenhydrinate in prevention of postoperative nausea and vomiting in laparoscopic gynaecological surgery. JPMI 2008;22:136-9.
  21. Wilson EB, Bass CS, Abrameit W, Roberson R, Smith RW. Metoclopramide versus ondansetron in prophylaxis of nausea and vomiting for laparoscopic cholecystectomy. Am J Surg. 2001 Feb;181(2):138-41. [PubMed]
  22. Naguib M, el Bakry AK, Khoshim MH, Channa AB, el Gammal M, el Gammal K, et al. Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized, double-blind comparison with placebo. Can J Anaesth. 1996 Mar(3);43:226-31. [PubMed]
  23. Quaynor H, Raeder JC. Incidence and severity of postoperative nausea and vomiting are similar after metoclopramide 20 mg and ondansetron 8 mg given by the end of laparoscopic cholecystectomies. Acta Anaesthesiol Scand. 2002 Jan;46(1):109-13. [PubMed]
  24. Ko-Iam W, Sandhu T, Paiboonworachat S, Pongchairerks P, Junrungsee S, Chotirosniramit A, et al. Metoclopramide, versus its combination with dexamethasone in the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy: a double-blind randomized controlled trial. J Med Assoc Thai, 2015 Mar;98(3):265-72. [PubMed]
  25. Nesek-Adam V, Grizelj-Stojcic E, Rasic Z, Cala Z, Mrsic V, Smiljanic A. Comparison of dexamethasone, metoclopramide, and their combination in the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. Surg Endosc. 2007 Apr;21(4):607-12. [PubMed]
  26. Lee W.S, Lee KB, Lim S, Chang YG. Comparison of palonosetron, granisetron, and ramosetron for the prevention of postoperative nausea and vomiting after laparoscopic gynecologic surgery: a prospective randomized trial. BMC Anesthesiol. 2015 Sep;15(3):121. doi: 10.1186/s12871-015-0102-0 [PubMed] [Free full text]
  27. Janicki PK. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit, 2005 Oct;11(10):322-8. [PubMed]
  28. Candiotti KA, Birnbach DJ, Lubarsky DA, Nhuch F, Kamat A, Koch WH, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005 Mar;10(3):543-9. [PubMed] [Free full text]
  29. Farhat K, Pasha AK, Kazi WA. Comparison of Ondansetron and Metoclopramide for PONV Prophylaxis in Laparoscopic Cholecystectomy. . J Anesth Clinic Res, 2013;4:1-4. [Free full text]
  30. Elhakim M, Nafie M, Mahmoud K, Atef A. Dexamethasone 8 mg in combination with ondansetron 4 mg appears to be the optimal dose for the prevention of nausea and vomiting after laparoscopic cholecystectomy. Can J Anaesth. 2002 Nov;49(9):922-6. [PubMed]
  31. Kim SH, Hong JY, Kim WO, Kil HK, Karm MH, Hwang JH. Palonosetron has superior prophylactic antiemetic efficacy compared with ondansetron or ramosetron in high-risk patients undergoing laparoscopic surgery: a prospective, randomized, double-blinded study. Korean J Anesthesiol. 2013 Jun;64(6):517-23. [PubMed] [Free full text]
  32. Bhattacharjee DP, Dawn S, Nayak S, Roy PR, Acharya A, Dey R. A comparative study between palonosetron and granisetron to prevent postoperative nausea and vomiting after laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol. 2010 Oct;26(4):480-3. [PubMed] [Free full text]
  33. Kim SH, Oh CS, Lee SJ. Efficacy of palonosetron and ramosetron on postoperative nausea and vomiting related to intravenous patient-controlled analgesia with opioids after gynecological laparoscopic surgery (double-blinded prospective randomized controlled trial). J Anesth. 2015 Aug;29(4):585-92. doi: 10.1007/s00540-015-1981-4 [PubMed]
  34. Ryu JH, Jeon YT, Hwang JW, Oh AY, Moon JY, Ro YJ, et al. Intravenous, oral, and the combination of intravenous and oral ramosetron for the prevention of nausea and vomiting after laparoscopic cholecystectomy: a randomized, double-blind, controlled trial. Clin Ther. 2011 Sep;33(9):1162-72. [PubMed]
  35. Bala I, Bharti N, Murugesan S, Gupta R. Comparison of palonosetron with palonosetron-dexamethasone combination for prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Minerva Anestesiol. 2014 Jul;8(7):79-84. [PubMed]
  36. Blitz JD, Haile M, Kline R, Franco L, Didehvar S, Pachter HL, et al. A randomized double blind study to evaluate efficacy of palonosetron with dexamethasone versus palonosetron alone for prevention of postoperative and postdischarge nausea and vomiting in subjects undergoing laparoscopic surgeries with high emetogenic risk. Am J Ther. 2012 Sep;19(5):324-9. [PubMed] doi: 10.1097/MJT.0b013e318209dff1
  37. Hessami MA, Yari M. Granisetron versus dexamethasone in prophylaxis of nausea and vomiting after laparoscopic cholecystectomy. Anesth Pain Med. 2012 Fall;2(2):81-4. [PubMed] [Free full text] doi: 10.5812/aapm.6945
  38. Kojima Y, Takahashi T, Fujina M, Owyang C. Inhibition of cholinergic transmission by opiates in ileal myenteric plexus is mediated by kappa receptor. Involvement of regulatory inhibitory G protein and calcium N-channels. J Pharmacol Exp Ther, 1994 Feb;268(2):965-70. [PubMed]
  39. Tsuchida D, Fukuda H, Koda K, Miyazaki M, Pappas TN, Takahashi T. Central effect of mu-opioid agonists on antral motility in conscious rats. Brain Res. 2004 Oct 22;1024(1-2):244-50. [PubMed]
  40. Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology. 1997 Nov;87(5):1075-81. [PubMed] [Free full text]
  41. Maxwell LG, Kaufmann SC, Bitzer S, Jackson EV Jr. McGready J, Kost-Byerly S, et al. The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study. Anesth Analg, 2005 Apr;100(4):953-8. [PubMed]
  42. Kasagi Y, Hayashida M, Sugasawa Y, Kikuchi I, Yamaguchi K, Okutani R, et al. Antiemetic effect of naloxone in combination with dexamethasone and droperidol in patients undergoing laparoscopic gynecological surgery. 2013 Dec;27(6):879-84. doi: 10.1007/s00540-013-1630-8. [PubMed]
  43. Wang JJ, Ho ST, Uen YH, Lin MT, Chen KT, Huang JC, et al. Small-dose dexamethasone reduces nausea and vomiting after laparoscopic cholecystectomy: a comparison of tropisetron with saline. Anesth Analg. 2002 Jul;95(1):229-32. [PubMed]
  44. Golden GA, Mason PE, Rubin RT, Mason RP. Biophysical membrane interactions of steroid hormones: a potential complementary mechanism of steroid action. Clin Neuropharmacol. 1998 May-Jun;21(3):181-9. [PubMed]
  45. Floman Y, Zor U. Mechanism of steroid action in inflammation: inhibition of prostaglandin synthesis and release. Prostaglandins. 1976 Sep;12(3):403-13. [PubMed]
  46. Bisgaard T, Klarskov B, Kehlet H, Rosenberg J. Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial. Ann Surg. 2003 Nov;238(5):651-60. [PubMed] [Free full text]
  47. Amer M, Uddin S, Rasheed F. Comparison of Use of Metoclopramide Alone and in Combination with Dexamethasone for Prevention of Post Operative Nausea and Vomiting in Laparoscopic Cholecystectomy. Epub: pjmhsonline.com, 2012. [Free full text]
  48. Asadollah S, Vahdat M, Yazdkhasti P, Nikravan N. The influence of dexamethasone on postoperative nausea and vomiting in patients undergoing gynecologic laparoscopic surgeries: a randomised, controlled, double blind trial. J Turk Soc Obstet Gynecol. 2014;11:219-23. [Free full text]
  49. Daabiss M. Ephedrine-Dexamethasone Combination Reduces Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Cholecystectomy . Int J Anesth. 2007;18:1-6. [Free full text]
  50. Gautam S, Agarwal A, Das PK, Agarwal A, Kumar S, Khuba S. Evaluation of the Efficacy of Methylprednisolone, Etoricoxib and a Combination of the Two Substances to Attenuate Postoperative Pain and PONV in Patients Undergoing Laparoscopic Cholecystectomy: A Prospective, Randomized, Placebo-controlled Trial. Korean J Pain. 2014 Jul;27(3):278-84. doi: 10.3344/kjp.2014.27.3.278 [PubMed] [Free full text]
  51. Moon HY, Baek CW, Choi GJ, Shin HY, Kang H, Jung YH, et al. Palonosetron and aprepitant for the prevention of postoperative nausea and vomiting in patients indicated for laparoscopic gynaecologic surgery: a double-blind randomised trial. BMC Anesthesiol. 2014 Aug 10;14:68. doi: 10.1186/1471-2253-14-68 [PubMed] [Free full text]
  52. Jung WS, Kim YB, Park HY, Choi WJ, Yang HS. Oral administration of aprepitant to prevent postoperative nausea in highly susceptible patients after gynecological laparoscopy. J Anesth. 2013 Jun;27(3):396-401. doi: 10.1007/s00540-012-1529-9. [PubMed]
  53. Kakuta N, Tsutsumi YM, Horikawa YT, Kawano H, Kinoshita M, Tanaka K, et al. Neurokinin-1 receptor antagonism, aprepitant, effectively diminishes post-operative nausea and vomiting while increasing analgesic tolerance in laparoscopic gynecological procedures. J Med Invest. 2011 Aug;58(3-4):246-51. [PubMed] [Free full text]
  54. Kim EG, Park HJ, Kang H, Choi J, Lee H J. Antiemetic effect of propofol administered at the end of surgery in laparoscopic assisted vaginal hysterectomy. Korean J Anesthesiol. 2014 Mar;66(3):210-5. doi: 10.4097/kjae.2014.66.3.210 [PubMed] [Free full text]
  55. Scuderi PE, D'Angelo R, Harris L, Mims GR, Weeks DB, James RL. Small-dose propofol by continuous infusion does not prevent postoperative vomiting in females undergoing outpatient laparoscopy. Anesth Analg, 1997;84:71-5. [Free full text]
  56. Yoo YC, Bai SJ, Lee KY, Shin S, Choi EK, Lee JW. Total intravenous anesthesia with propofol reduces postoperative nausea and vomiting in patients undergoing robot-assisted laparoscopic radical prostatectomy: a prospective randomized trial. Yonsei Med J. 2012;53:1197-202. doi: 10.3349/ymj.2012.53.6.1197.[PubMed] [Free full text]
  57. Song D, Whitten CW, White PF, Yu SY, Zarate E. Antiemetic activity of propofol after sevoflurane and desflurane anesthesia for outpatient laparoscopic cholecystectomy. Anesthesiology. 1998 Oct;89(4):838-43. [PubMed] [Free full text]
  58. Celik M, Dostbil A, Aksoy M, Ince I, Ahiskalioglu A, Comez M et al. Is infusion of subhypnotic propofol as effective as dexamethasone in prevention of postoperative nausea and vomiting related to laparoscopic cholecystectomy? A randomized controlled trial. Biomed Res Int, 2015; 2015:349806 doi: 10.1155/2015/349806 [PubMed] [Free full text]
  59. Arslan M, Cicek R, Kalender HU, Yilmaz H. Preventing postoperative nausea and vomiting after laparoscopic cholecystectomy: a prospective, randomized, double-blind study. Curr Ther Res Clin Exp. 2011 Feb;72(1):1-12. [PubMed] [Free full text]
  60. Yagmurdur H, Cakan T, Bayrak A, Arslan M, Baltaci B, Inan N, et al. The effects of etomidate, thiopental, and propofol in induction on hypoperfusion-reperfusion phenomenon during laparoscopic cholecystectomy. Acta Anaesthesiol Scand, 2004 Jul;48(6):772-7. [PubMed]
  61. Purhonen S, Koski EM, Niskanen M, Hynynen M. Efficacy and costs of 3 anesthetic regimens in the prevention of postoperative nausea and vomiting. J Clin Anesth, 2006 Feb;18(1):41-5. [PubMed]
  62. Shinn HK, Lee MH, Moon SY, Hwang SI, Lee CS, Lim HK, et al. Post-operative nausea and vomiting after gynecologic laparoscopic surgery: comparison between propofol and sevoflurane. Korean J Anesthesiol. 2011 Jan;60(1):36-40. doi: 10.4097/kjae.2011.60.1.36 [PubMed] [Free full text]
  63. Akkurt BC, Temiz M, Inanoglu K, Aslan A, Turhanoglu S, Asfuroglu Z, et al. Comparison of recovery characteristics, postoperative nausea and vomiting, and gastrointestinal motility with total intravenous anesthesia with propofol versus inhalation anesthesia with desflurane for laparoscopic cholecystectomy: A randomized controlled study. Curr Ther Res Clin Exp. 2009 Apr;70(2):94-103. doi: 10.1016/j.curtheres.2009.04.002. [PubMed] [Free full text]