Intraoperative nausea and vomiting during cesarean section under regional anesthesia

International Journal of Obstetric Anesthesia (2005) 14, 230–241 Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2004.12.004

REVIEW ARTICLE

Intraoperative nausea and vomiting during cesarean section under regional anesthesia M. Balki, J. C. A. Carvalho Department of Anesthesia, Mount Sinai Hospital, University of Toronto, Canada SUMMARY. Nausea and vomiting during regional anesthesia for cesarean section are very common and unpleasant events. They cause significant distress to the patient and also interfere with the surgical procedure. They have multiple etiologies, which include hypotension, vagal hyperactivity, visceral pain, i.v. opioid supplementation, uterotonic agents and motion. The obstetric anesthesia literature has addressed these causative factors for nausea and vomiting individually, making it difficult for the anesthesiologists to have a comprehensive understanding of these important complications. This review highlights the anesthetic and non-anesthetic causes of intraoperative nausea and vomiting during regional anesthesia for cesarean section and the appropriate prophylactic and therapeutic management. Intraoperative nausea and vomiting can be best prevented by controlling hypotension, optimizing the use of neuraxial and i.v. opioids, improving the quality of block, minimizing surgical stimuli and judicious administration of uterotonic agents. Although prophylactic antiemetics have been advocated during cesarean sections, strict adherence to these practices can effectively lower the incidence of intraoperative nausea and vomiting without the requirement of antiemetic agents. Antiemetics, therefore, should be reserved for the prevention of intraoperative nausea and vomiting in high-risk patients and for the treatment of nausea and vomiting not responding to routine measures. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Nausea; Vomiting; Cesarean section; regional anesthesia

Comprehensive reviews on postoperative but not on intraoperative nausea and vomiting are widely available in the literature.1–5 This is particularly true in obstetric anesthesia. This review highlights the predisposing anesthetic and non-anesthetic factors responsible for IONV during regional anesthesia for cesarean section and the appropriate prophylactic and therapeutic management. We have reviewed articles from Pubmed, MEDLINE 1966 to present, EMBASE 1988 to present, Cochrane database and MDConsult using the key words cesarean, caesarean, regional anesthesia, nausea, vomiting and their combination. Additional pertinent references from relevant articles have also been included.

INTRODUCTION Regional anesthesia has been shown to be effective, safe and the anesthetic of choice for elective and emergency cesarean sections. Despite major advances in spinal, epidural and combined spinal-epidural anesthesia techniques, intraoperative nausea and vomiting (IONV) are still present in a significant number of patients. These symptoms can be distressing and uncomfortable for patients and may have a negative impact on their overall birthing experience. Most of the factors predisposing to IONV during regional anesthesia for cesarean section overlap with those involved in other surgical procedures, but some are unique to this operation.

OUTLINE Accepted December 2004

      

M. Balki, MBBS, MD, Assistant Professor, Department of Anesthesia, Mount Sinai Hospital, University of Toronto, Canada. J.C.A. Carvalho, MD, PhD, FANZCA, FRCPC, Associate Professor and Director of Obstetric Anesthesia, Department of Anesthesia, Mount Sinai Hospital, University of Toronto, Canada. Correspondence to: M. Balki, MBBS, MD, Assistant Professor, Tel.: +416 586 5270; Fax: +416 586 8664; E-mail: [email protected] 230

Incidence of IONV Physiology of nausea and vomiting Risk factors Causes and related prophylactic measures Additional prophylaxis Treatment Conclusion

Nausea and vomiting during cesarean section 231 Table 1. Incidence of intraoperative nausea and vomiting during cesarean section Study

Anesthesia

Nausea

Vomiting

Pan PH (2001)7 Harmon D (2000)8 Carvalho JCA (2000)9

Epidural N = 51 Spinal N = 47 Spinal N = 40

57% 36.2% 30-35% (Pre)

25% 17% 15% (Pre)

Albouleish EI (1999)10

Spinal N = 38

55.3% (Pre) 79% (Post)

42.1% (Pre) 58% (Post)

Ure D (1999)11 Stain DJ (1997)12

Spinal N = 25 Spinal N = 19

68% 76%

16% 24%

Lussos SA (1992)13

Spinal N = 21

57% (Pre) 57% (Post)

24% (Pre) 24% (Post)

Chestnut DA (1987)14

Epidural N = 33

21% (Pre) 36% (Post)

0 (Pre) 15% (Post)

Santos A (1984)15

Spinal N = 25

40%

12%

Numbers reflect control groups in randomized controlled trials. Pre, pre-delivery; Post, post-delivery.

INCIDENCE

RISK FACTORS

The incidence of IONV during spinal anesthesia for nonobstetric surgery ranges from 7% to 42%.6 The overall incidence of IONV during regional anesthesia for cesarean section is extremely variable, up to 80%, depending on the anesthetic technique used (spinal, epidural or combined spinal-epidural) and on the preventive and therapeutic measures taken (Table 1).7–15 The incidence of IONV may also vary significantly according to the stages of the surgical procedure (e.g. pre-delivery vs. post-delivery), different factors being implicated in the etiology.10,13,14

The obstetric patient, due to the physiological changes of pregnancy, is prone to nausea and vomiting. This is attributed to impaired motility of the esophagus, stomach and small bowel as a result of smooth muscle relaxation fostered by increased levels of hormones particularly progesterone, perhaps primed by estrogen during pregnancy. Hormonal changes are postulated to alter lower esophageal sphincter (LES) function causing an incompetent sphincter. The large gravid uterus contributes to the manifestations of upper gastrointestinal symptoms by mechanically compressing the stomach. Alterations in small bowel transit times in the third trimester have also been investigated as potentially contributing to nausea and vomiting.17,18 Apart from these gastrointestinal effects, hormonal changes during pregnancy may influence the neurovestibular system and emetic center in the brainstem, further increasing the risk of IONV.17,18 A simplified risk score has been designed for predicting postoperative nausea and vomiting (PONV) in patients requiring general anesthesia for non-obstetric surgery. The predictors are female gender, history of motion sickness or PONV, non-smoking and the use of opioids.19 In non-obstetric patients, the variables conferring increased odds of IONV under spinal anesthesia include addition of vasoconstrictor to the local anesthetic, block height PT5, baseline heart rate P60 beats/min, history of car sickness and hypotension.6 The predictors for IONV have not been studied in obstetric patients undergoing regional anesthesia and there are no data to suggest that these predictors are applicable to obstetric patients.

PHYSIOLOGY OF NAUSEA AND VOMITING The central neural regulation of nausea and vomiting is vested in two separate units in the medulla, the chemoreceptor trigger zone (CTZ) and the vomiting center.3,16 The CTZ, located in the area postrema on the floor of the fourth ventricle, is a highly vascularized area where the blood-brain barrier is poorly developed. The vomiting center is located in the lateral reticular formation of the medulla and integrates the vomiting response. It receives many excitatory inputs from the nerve endings of vagal sensory fibers in the gastrointestinal tract, the labyrinth via the vestibular nuclei, higher centers in the cortex, CTZ and intracranial pressure receptors. These structures are rich in dopaminergic, muscarinic, tryptaminergic, histaminic and opioid receptors. Antiemetic drugs block these specific receptors.3 Efferent impulses from the emetic center are transmitted to the vagus, phrenic and spinal nerves of the abdominal muscles to cause the mechanical act of vomiting.

232 International Journal of Obstetric Anesthesia

Intraoperative nausea and vomiting

Anesthetic causes

Hypotension

Non-anesthetic causes

Neuraxial opioids

↓

↓

Left uterine displacement Preload Vasopressors

Optimum doses

Motion

Surgical stimuli

↓

↓

Avoid vigorous movements

Avoid excessive manipulation Parenteral opioids

↓ Avoid or use minimum doses Increased vagal activity

↓

Uterotonic Agent

↓ Slow administration Adequate doses

Vagolytics

Fig. 1 Causes and prevention of intraoperative nausea and vomiting during cesarean section under regional anesthesia.

CAUSES AND RELATED PROPHYLACTIC MEASURES IONV during regional anesthesia for cesarean section is a complex multifactorial problem arising from anesthetic and non-anesthetic causes (Fig. 1). Anesthetic causes include hypotension, increased vagal activity and administration of neuraxial or parenteral opioids. Non-anesthetic causes include surgical stimuli, surgical bleeding, medications such as uterotonic agents and antibiotics, and motion at the end of surgery. Both anesthetic and non-anesthetic causes may influence IONV either alone or in combination. Hypotension Hypotension occurring during neuraxial anesthesia is one of the most important etiological factors for IONV. It may lead to cerebral hypoperfusion and brainstem ischemia that may activate the circulatory, respiratory and vomiting centers in the medulla.1 It is also speculated that hypotension leads to gut ischemia and release of emetogenic substances such as serotonin from the intestine.1 Hypotension causing nausea and vomiting largely relates to spinal anesthesia. Untreated severe hypotension can also pose serious risks to both mother in the form of unconsciousness, pulmonary aspiration, apnea or even cardiac arrest, and baby leading to im-

paired placental perfusion causing hypoxia, fetal acidosis and neurological injury.20 Strategies to prevent rather than treat hypotension appear to be more likely to decrease the incidence of nausea and vomiting.20 Several measures such as lateral uterine displacement, fluid preloading, leg wrappings and prophylactic vasopressors have been advocated in order to avoid hypotension. Most data published in the obstetric anesthesia literature support the concept of the combined use of these measures for superior results. Acute hydration was once the cornerstone of prophylaxis of hypotension in obstetrics. Interestingly, there are very few studies in the literature on the effectiveness of acute hydration in which a control group has been included and, more importantly, in which such effectiveness has been compared with other therapeutic measures. In addition, the risks and benefits of administering large volume of fluids to a patient with an increased body water content, an expanded plasma volume and an overstressed cardiovascular system are controversial.21 Colloids and crystalloids, administered in different regimens, have shown limited efficacy in eliminating hypotension, nausea and vomiting.20–23 Carvalho and Mathias21 studied the influence of different volumes of Ringer’s lactate on plasma volume expansion in term pregnant patients. The most significant plasma volume increases were observed with the smallest volumes, with a trend toward a decrease in effectiveness with increasing volumes of

Nausea and vomiting during cesarean section 233 Table 2. Effect of the treatment of hypotension according to target blood pressure Study

Vasopressor

Target blood pressure% of baseline

IONV

Phenylephrine

100, 90, 80

4%, 14%, 40%

Cooper DW (2002)

Phenylephrine Ephedrine Combination

80 73 77

17% 66% 55%

Loughrey JPR (2002)29 Carvalho JCA (2001)33

Ephedrine Ephedrine

70 >80

33.3-40.9% 15-27.5%

Ngan Kee WD (2001)30

Ephedrine Metaraminol

90-100 90-100

20% 4%

Ngan Kee WD (2000)31 Carvalho JCA (2000)9 Datta S (1982)32

Ephedrine Ephedrine Ephedrine

>80 >80 100, >70, variable

25-65% Up to 50% 0, 66%, 10%

Ngan Kee WD (2004)26 28

crystalloid infusion. This fact could probably be explained by fluid shifts to the extravascular space. In this regard, colloid could be an interesting alternative, because its residence time in the vascular space is longer. Ueyama et al. studied the intravascular retention time of Ringer’s lactate and hydroxyethylstarch 6%, administered over 30 min, as part of acute preload at cesarean section. Upon completion of the infusion, only 28% of the infused crystalloid as opposed to 100% of the infused colloid was estimated to remain intravascular.24 The disadvantages of colloids, such as their cost and oddly enough the very long intravascular retention time, make their use still controversial. It is our opinion that crystalloids remain the most used and most appropriate solution, provided we understand the limits of their use. Our preload regimen consists of a moderate volume of Ringer’s lactate, no larger than 10 mL/kg, administered immediately before or during the induction of regional anesthesia, over the least period of time (pressurized bag if necessary). Vasopressors, once used i.v. only for the treatment of hypotension, are now being used more liberally for its prevention. Ephedrine, an indirectly acting a- and badrenergic agonist, is probably still the most commonly used vasopressor. However, in a dose-response metaanalysis, Lee et al. found that increasing doses of ephedrine reduce hypotension but do not reduce nausea. Also, the use of larger doses of ephedrine (>14 mg) does not completely eliminate hypotension but causes reactive hypertension and a minor decrease in umbilical arterial pH.25 Recent studies have consistently shown the superiority of pure a-agonists phenylephrine and metaraminol over ephedrine for the control of maternal hypotension and for improved fetal acid-base balance.25–28 Studies have shown that there is distinct association of IONV with maternal hypotension and strict control of blood pressure can dramatically reduce intraoperative emetic symptoms (Table 2).9,20,26–34 Datta et al.32 showed that, when the blood pressure dropped more

than 30% from baseline the incidence of IONV was 66%, but was <10% when the blood pressure was maintained at baseline values with ephedrine. Similarly, Ngan Kee et al.26 found that when phenylephrine was titrated with the aim of maintaining maternal blood pressure at 100% of baseline, the incidence of nausea and vomiting was only 4%, compared with 16% when the blood pressure is maintained at 90% and 40% when it was 80% of baseline, during spinal anesthesia for cesarean section. These studies clearly show that strict control of blood pressure can reduce intraoperative emetic symptoms. Several modifications of regional anesthetic techniques have been advocated to produce minimum hypotension. Epidural anesthesia, by virtue of its slower onset, might favor better hemodynamic control than spinal anesthesia. However, with the former technique, inadequate block of sacral roots and limited muscle relaxation may occur. Fan et al. successfully used a combined spinal-epidural technique with 2.5-, 5-, 7.5or 10-mg doses of spinal bupivacaine, supplemented with epidural lidocaine to improve the quality of block while maintaining hemodynamic stability. In their series, nausea and vomiting reduced dramatically when hypotension was minimized with the lower two spinal doses.35 Vagal hyperactivity Sympathetic block secondary to spinal or epidural anesthesia may result in nausea and vomiting induced by gastrointestinal hyperactivity due to relative overactivity of the vagus. The efficacy of vagolytic agents to relieve nausea during spinal anesthesia has been taken as evidence of support for this causation. Glycopyrrolate given before spinal anesthesia has been shown to reduce the frequency and severity of nausea and vomiting, without affecting neonatal outcome. When glycopyrrolate 200 lg was compared with

234 International Journal of Obstetric Anesthesia placebo, the frequency of nausea fell in the glycopyrrolate group from 68% to 42% and vomiting from 16% to 8%.1 However, pretreatment with glycopyrrolate can increase hypotension soon after establishing spinal blockade.36 Surgical stimuli Surgical stimuli that may be responsible for IONV include exteriorization of the uterus, intra-abdominal manipulation or exploration and peritoneal traction during closure. These maneuvers produce visceral pain that is mediated by unmyelinated C-fibers.37,38 Visceral pain is a potent stimulus for IONV during regional anesthesia. Its incidence can be as high as 50% under both spinal and epidural anesthesia during cesarean section with plain local anesthetic, despite high thoracic sensory block levels.37 Both the uterus and the peritoneum are widely innervated by vagal nerves that are unopposed by sympathetic activity during regional anesthesia.38 Handling of abdominal viscera can stimulate sensory vagal fibers and induce emesis by activating the vomiting center.37 Exteriorization of the uterus for surgical repair under regional anesthesia itself accounts for a higher incidence of IONV.39,40 Administration of neuraxial opioids has been shown to reduce visceral pain-induced nausea and vomiting.39 In a recent randomized controlled trial, yet to be submitted for publication, our group has studied, under strictly standardized conditions (drugs, dosages, prophylactic use of vasopressors and judicious use of oxytocin), the influence of the technique of uterine repair on the incidence of nausea and vomiting in 80 patients undergoing cesarean section. The incidence of nausea post partum, the primary outcome, was significantly reduced from 38% to 15% when the uterus was repaired in situ as opposed to after exteriorization. Vomiting was reduced from 18% to 5%, not statistically significant (Personal communication: Siddiqui M, Carvalho JCA, Goldszmidt E, Tharmaratnam U, Kingdom J, Windrim R.). It is our opinion that appropriate surgical technique is a key factor to reduce intraoperative nausea and vomiting and we strongly recommend that exteriorization of the uterus be avoided.

Quality of block and neuraxial adjuvants Pain sensation is carried by myelinated Ad- and unmyelinated C-fibers. Spinal- and d-opioid receptors have a significant role in modulation of visceral nociception. Local anesthetic agents block mainly Ad-fibers. Adequate blockade of C-fibers, which carry visceral pain,

may not be achieved during regional anesthesia when local anesthetics are used alone. Addition of lipophilic neuraxial opioids to the local anesthetic solution can effectively reduce visceral pain by depressing C-fiber mediated response. Addition of 50 lg of fentanyl to bupivacaine during epidural anesthesia for cesarean section has been shown to reduce the incidence of IONV from 47 to 7%.39 Several opioids and other adjuvants can be used with the local anesthetic solution to intensify the regional block, to improve the quality of intraoperative analgesia and to provide postoperative pain relief. Fentanyl, sufentanil, morphine, hydromorphone, diamorphine, meperidine, clonidine and neostigmine have been used through either the spinal or the epidural route for cesarean section. On the other hand, these adjuvants can also produce side effects, nausea and vomiting included, and therefore should be used in optimum doses. Several different mechanisms have been postulated for intrathecal and epidural opioid-induced IONV.41 Direct stimulation of the CTZ can occur as a result of cephalad spread of the drug in the cerebrospinal fluid (CSF) to the brainstem, secondary to vascular uptake and delivery to the vomiting center and CTZ, and to modulation of afferent input at the area postrema. Sensitization of the vestibular system to motion and decreased gastric emptying produced by intrathecal and epidural opioids may also play a role in inducing nausea and vomiting. Reduced motility of the gastrointestinal tract appears to be caused by interaction with opioid receptors located in the spinal cord. Opioid induced nausea is a centrally mediated effect that occurs in 30% of patients administered opioids and does not respond well to the existing antiemetics.41 Intrathecal adjuvants Fentanyl Adding fentanyl to intrathecal local anesthetic for cesarean section has not been shown to increase the incidence of IONV,42–51 but rather to reduce it. This has been attributed to a decrease in somatic and visceral pain, less requirement of supplemental i.v. opioids and lower incidence of hypotension.45 Hunt et al.43 established the minimum effective dose of intrathecal fentanyl to be 6.25 lg in patients undergoing cesarean section under spinal anesthesia with bupivacaine with no further increase in the quality and the duration of analgesia with increasing doses. The effectiveness of slightly larger doses of intrathecal fentanyl such as 10-20 lg in improving the quality of intraoperative anesthesia significantly, without the evidence of side effects has been supported by several other studies (Table 3).42,44–51 Doses above 25 lg are

Nausea and vomiting during cesarean section 235 associated with an increase in the incidence of pruritus, and respiratory changes.43,51 Sufentanil Dahlgren et al.44 showed that intrathecal sufentanil 2.5 and 5 lg added to hyperbaric bupivacaine during cesarean section, reduced the need for intraoperative antiemetic medication and produced superior analgesia compared with placebo (Table 3). A significantly higher incidence of pruritus with sufentanil P5 lg, but not of nausea and vomiting, has been reported when sufentanil is administered in a dose-dependent manner.42,44,52 Morphine Addition of morphine to local anesthetic solution for spinal anesthesia for cesarean section increased the incidence of nausea and vomiting in a dose-dependent manner postoperatively but not intraoperatively.53–56 Morphine may spread cephalad in the CSF to reach the fourth ventricle 3-6 h after intrathecal administration, hence morphine would not be expected to cause nausea or vomiting during the operative period for cesarean section which is usually about 1 to 1.5 h.41 Diamorphine The physicochemical properties of diamorphine, such as high lipid solubility, low pKa, and slow rate of deacetylation within neural tissues make it a suitable adjuvant for both intra- and postoperative periods. The optimum dose of intrathecal diamorphine to improve the quality of block with acceptable side effects for cesarean section has been found to be 0.3 mg.57 The incidence of side effects in the form of postoperative nausea, vomiting and pruritus increase in a dose-dependent manner.57–59 Meperidine Meperidine possesses local anesthetic as well as opioid properties.60 It can therefore be administered alone or with local anesthetics to provide operative analgesia. For cesarean section, it has not gained great popularity. The incidence of IONV increased from 15% to 55% when spinal meperidine 10 mg was added to bupivacaine for cesarean section.61 Clonidine Clonidine is thought to activate post-synaptic a2-adrenergic receptors in the dorsal horn of the spinal cord, which then inhibit substance P release and the firing of neurons carrying nociceptive stimuli. In animal models clonidine synergistically enhances analgesia from local anesthetics and opioids. In humans this interaction is less clear and appears to be additive rather than synergistic. Clonidine produces dose-dependent hypotension and sedation62 that may be responsible for emetic effects. Pan et al.63 documented a significantly higher incidence

of nausea and vomiting when clonidine 150 lg was added to bupivacaine for cesarean section. Clonidine has acquired a Food and Drug Administration (FDA) “Black Box” warning and is not approved for use in obstetric practice in the US. Neostigmine Neostigmine is an anticholinesterase that enhances analgesia by inhibiting CSF cholinesterase and indirectly increasing CSF and spinal cord levels of acetylcholine. A dose-dependent increase in nausea and vomiting was found in patients undergoing cesarean section under spinal anesthesia, with an incidence of 100% with a dose of 100 lg.64 The clinical value of spinal or epidural neostigmine is uncertain at this time.

Epidural adjuvants Fentanyl Fentanyl administered epidurally during cesarean section has been shown to improve the quality of anesthesia by decreasing the intraoperative pain scores and IONV during exteriorization of the uterus. Naulty et al.65 in a dose-response study in cesarean section patients, found the minimum effective dose of epidural fentanyl to be 50 lg. Doses of fentanyl above 50 lg exhibited a ceiling effect for analgesia. No dose-dependent IONV were observed with doses up to 100 lg.65 Sufentanil Madej and Strunin66 reported epidural sufentanil 20-30 lg to be equivalent to fentanyl 50-100 lg in its analgesic effects during cesarean section. The incidence of nausea, vomiting and pruritus was higher when patients received 30 lg or more of sufentanil. This may be related to rapid vascular uptake of the drug from the epidural space. While the minimum effective dose for postoperative analgesia remains unclear, sufentanil 30 lg has been shown to be highly effective.67 Morphine Epidural morphine used for post-cesarean section pain control can lead to nausea and vomiting in the postoperative but not in the intraoperative period due to its delayed onset of action. No correlation between the dose of epidural morphine and the incidence or severity of nausea and vomiting has been observed when administered after delivery in cesarean section patients.68,69 Diamorphine Epidural diamorphine 5 mg caused significantly higher postoperative nausea and vomiting than did intrathecal

236 International Journal of Obstetric Anesthesia diamorphine 0.25 mg (24% vs. 4%), while providing similar quality and duration of analgesia.70

Table 3. Recommended doses of lipophilic opioids with local anesthetic for neuraxial anesthesia Study

Hydromorphone Epidural hydromorphone 0.6 mg has shown to provide no clinical benefit over epidural morphine 3 mg for analgesia after cesarean section. The incidence and severity of pruritus and postoperative nausea and vomiting are the same for the two drugs. No increase in IONV has been associated with hydromorphone.71 Meperidine Epidural meperidine is not followed by undue nausea and vomiting during cesarean section, although a dose of 100 mg was found to cause more nausea than lower doses.72 Epidural clonidine and neostigmine The experience with intraoperative epidural clonidine and neostigmine in cesarean sections is limited. According to the data presented, the administration of lipophilic spinal and epidural opioids, when used in optimum doses, reduces intraoperative emetic symptoms by blocking visceral nociceptive afferents and improves the quality of the block. The optimum doses of lipophilic opioids that have been recommended by some authors to minimize side effects including nausea and vomiting in the intraoperative period are given in Table 3. In our clinical practice, the drug of choice for providing intraoperative analgesia with local anesthetic is fentanyl 10 lg for spinal and 50 lg for epidural anesthesia during cesarean section. Uterotonic agents Oxytocin The incidence of nausea has been reported to be 29% and vomiting 9% following an i.v. bolus of oxytocin 5 units during elective cesarean section under regional anesthesia; the incidence after carbetocin was similar.73 Nausea and vomiting mainly occur as a result of hypotension produced by oxytocin administration.74 The hypotensive action of oxytocin, as evidenced by animal models, is mediated via endothelial receptors causing nitric oxide release and also by the release of atrial natriuretic peptide from vasculature, heart, kidneys and other tissues.75–78 Slow administration and judicious use may reduce oxytocin-induced hypotension and IONV.74 Ergot alkaloids Ergonovine (ergometrine) may cause nausea and vomiting by interaction with dopaminergic and serotinonergic a-adrenergic receptors. The incidence is highest among the uterotonic agents, about 46% with 0.5-mg i.v. bolus.79 However, the drug is usually given intramuscu-

Hunt CO (1989)43 Dahlgren G (1997)44 Siddik-Sayyid SM (2002)45 Chu CC (1995)46 Shende D (1998)47 Palmer CM (1995)48 Cowan CM (2002)49 Manullang TR (2000)50 Belzarena SD (1992)51 Dahlgren G (1997)45 Braga AF (2003)52 Kelly MC (1998)58 Hallworth SP (1999)70 Cowan CM (2002)49 Skilton RWH (1999)57 Naulty JS (1985)65 Madej TH (1987)66 Madej TH (1987)66 Rosen MA (1988)67 Hallworth SP (1999)70

Route

Opioid

Optimum dose

Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Spinal Epidural Epidural Epidural Epidural Epidural

Fentanyl Fentanyl Fentanyl Fentanyl Fentanyl Fentanyl Fentanyl Fentanyl Fentanyl Sufentanil Sufentanil Diamorphine Diamorphine Diamorphine Diamorphine Fentanyl Fentanyl Sufentanil Sufentanil Diamorphine

6.25 lg 10 lg 12.5 lg 12.5 lg 15 lg 15 lg 20 lg 20 lg 20 lg 2.5 lg 5 lg 0.25 mg 0.25 mg 0.3 mg 0.3 mg 50 lg 100 lg 20 lg 30 lg 5 mg

larly which may produce less emesis. Methylergonovine lacks the adrenergic activity of many of the ergot alkaloids and produces comparatively less hemodynamic changes, nausea and vomiting. Prostaglandins 15-Methyl prostaglandin F2 (Carboprost or Hemabate) may cause nausea and vomiting by stimulating smooth muscles of the gastrointestinal tract.80 An overall incidence of nausea and vomiting of 10% has been reported following 250 lg of intramyometrial 15-methyl prostaglandin F2.80 Ergot alkaloids and prostaglandins are administered for postpartum hemorrhage; hypotension resulting from excessive blood loss can itself cause nausea and vomiting. Antibiotics Commonly used antibiotics such as cefazolin, cefotetan, clindamycin, ampicillin and gentamicin may be associated with mild nausea and vomiting, but an overall incidence of nausea and vomiting has not been reported.81 Motion There is a spectrum of susceptibility to vestibular-mediated sickness in a subset of women with pregnancyrelated stimulus, which lowers the threshold for nausea and vomiting with motion.82 Sudden motion, changes in position and transfer on stretcher at the end of surgery can stimulate afferent neural pathways that project to the vestibular nuclei, leading to activation of the brain stem nuclei, triggering the somatic and gastrointestinal

Nausea and vomiting during cesarean section 237 components of emesis. This activation is mediated primarily via histamine H1 and muscarinic cholinergic rather than dopaminergic or tryptaminergic pathways; antihistamines and anticholinergics have therefore assumed an important role in therapy.82,83 ADDITIONAL PROPHYLAXIS Appropriate management of the precipitating causes, as discussed above, should offer the best prophylaxis for IONV during cesarean section. However, some authors advocate additional prophylaxis in the form of antiemetic drugs and acupressure. Antiemetic agents There are several classes of drugs that constitute the mainstay of antiemetic therapy. These include benzamides (metoclopramide), antihistamines (dimenhydrinate), butyrophenones (droperidol), serotonin antagonists (ondansetron, granisetron, dolasetron, ramosetron and topisetron) and steroids (dexamethasone). Benzamides Metoclopramide is a benzamide that mediates its action by antagonism of dopamine receptors in the CTZ. It also acts by increasing the resting tone of the lower esophageal sphincter and in higher doses by antagonism of serotonin 5HT3 receptors. The onset of action after i.v. administration of 10-20 mg is 1-3 min. The more common side effects include dizziness, drowsiness and fatigue. Rarely, it can cause extrapyramidal reactions and acute dystonias. Metoclopramide crosses the placenta at term. Cord/maternal plasma ratios following prophylactic use during cesarean sections were found to be 0.57-0.84. No adverse neonatal effects were found as evaluated by Apgar scores, heart rate, systolic blood pressure and neurologic and adaptive capacity scores in the first 24 h of life.84 Metoclopramide is excreted in human milk. The American Association of Pediatrics has classified metoclopramide as a drug for which the effect on nursing infants is unknown but may be of concern. Metoclopramide apparently does not present a risk to the nursing infant in the maternal doses of 45 mg/ day.85 Doubts have been raised about the efficacy of the usual dose of metoclopramide as an antiemetic when used for prophylaxis of postoperative nausea and vomiting in non-obstetric patients.5 However, the obstetric anesthesia literature has revealed consistent efficacy of metoclopramide in preventing nausea and vomiting.13,14 Metoclopramide 0.15 mg/kg administered after cord clamping in patients undergoing cesarean section under epidural anesthesia reduced the incidence of intraoperative nausea from 36% to 12% and vomiting from 15% to 0%.14 Lussos et al.13 reported a significantly lower inci-

dence of intraoperative nausea from 81% to 14% and vomiting from 43% to 5% when metoclopramide 10 mg was administered before institution of spinal anesthesia for cesarean section. Antihistamines Dimenhydrinate is one of the most used antiemetics in the obstetric population. It exerts its antiemetic action by blocking H1 receptors and also by inhibiting the integrative function of vestibular nuclei. It is commonly used in the dose of 25-50 mg i.v. Side effects include drowsiness, dizziness, dry mouth, headache, restlessness and tachycardia. Dimenhydrinate has an oxytocic effect and can potentiate the effect of oxytocin.86 Controlled studies in animals do not indicate risk to the fetus. It has been widely used for the treatment of hyperemesis gravidarum, but there are no adequate and wellcontrolled studies of its use in women during cesarean section. Small amounts of dimenhydrinate are excreted in breast milk, hence caution should be exercised when it is used for nursing mothers, due to possible adverse reactions in infants.86 Butyrophenones Droperidol exerts its action on the dopamine receptors in the CTZ. This was the most popular and effective drug in the prophylaxis and treatment of nausea and vomiting during cesarean section for about 30 years. Droperidol 2.5 mg administered prophylactically for cesarean sections reduced the incidence of nausea from 40% to 12% when compared to placebo.15 Doses as low as 0.0625 mg have been found to be as effective as ondansetron 8 mg in reducing the incidence of intraoperative emetic symptoms without any untoward side effects and with cost-saving.87 However, at present, droperidol carries a “Black-Box” warning from the US FDA about the risk of sudden cardiac death based on 10 case reports of QTc prolongation and fatal arrhythmias. Its return to clinical practice remains uncertain. Serotonin antagonists Ondansetron and granisetron are newer antiemetics acting selectively on 5HT3 receptors at the CTZ and vagal nerve terminals. Prophylactic ondansetron 4 mg administered after clamping the umbilical cord has been shown to be more effective than metoclopramide 10 mg in the prevention of nausea (26% vs. 51%) and to be equally effective in the prevention of vomiting (15% vs. 18%).7 Abouleish et al. observed a reduced incidence of vomiting and severity of nausea with ondansetron compared to placebo during cesarean section under spinal anesthesia.10 Granisetron, in a minimum dose of 40 lg/kg, when administered after clamping the umbilical cord has been found to be effective for preventing nausea and vomiting during spinal anesthesia for

238 International Journal of Obstetric Anesthesia cesarean section.88,89 Dolasetron 12.5 mg administered after cord clamping does not significantly alter the incidence of nausea and vomiting in patients who received metoclopramide before cesarean section.90 The transfer of these drugs across the human placenta and into breast milk has not been studied. The use of other serotonin antagonists, topisetron and ramosetron,91 has not been reported during human pregnancy.

could be provided in the form of antiemetic agents. However, there are no data to support the efficacy of any antiemetic as rescue medication for IONV during cesarean section.

Steroids Dexamethasone modulates neurotransmitter or glucocorticoid receptor density in the nucleus of the solitary tract, the raphe nucleus and the area postrema. The onset of action after a single dose of 4-8 mg is about 2 h and the duration is about 12-24 h. Dexamethasone crosses the placenta to the fetus and is excreted in the breast milk.92 It has been safely used in the treatment of postoperative nausea and vomiting,93–95 but its role in the prevention of IONV in obstetric patients has not gained wide acceptance because of its pharmacokinetic properties and delayed onset of action.

Intraoperative nausea and vomiting are multifactorial and can be avoided by pre-emptive measures and prompt treatment of the offending factors. The strategy for prevention of IONV during cesarean section under regional anesthesia should include: (a) strict control of blood pressure (maintained at baseline levels throughout the procedure) by a combination of left uterine displacement, fluid preload and vasopressors, preferably a-agonists, either phenylephrine or metaraminol; (b) optimal use of neuraxial opioids and limited use of systemic opioids to improve the quality of anesthesia, thus reducing visceral pain without iatrogenic side effects; (c) improvement of the surgical technique, by avoiding exteriorization and excessive manipulation of the uterus; (d) judicious and slow administration of uterotonic agents; (e) finally at the end of surgery, avoiding vigorous movements and sudden transfer of patient on the stretcher. The optimal use of antiemetic agents in the management of IONV during cesarean section remains unclear. Antiemetic agents used prophylactically either before13 or after7,10,14,15,88,89,95 cord clamping during cesarean section under regional anesthesia have been shown to be highly effective. However, none of these studies assessed the efficacy of antiemetics with strict control of all the causative factors mentioned above. In fact, the use of opioids with local anesthetic for spinal anesthesia for cesarean section has been shown to be more effective than prophylactic administration of antiemetics for prevention of IONV.50 In our opinion, routine prophylactic administration of antiemetics during cesarean section under regional anesthesia is not indicated. Rescue antiemetic drugs should be reserved for the treatment of patients in whom the mutimodal approach for prevention of IONV has failed. The use of these drugs should be in accordance with assumed safety for mother and baby. Metoclopramide has been the most widely used drug intraoperatively13,14 and hence should be offered as first line treatment. Dimenhydrinate can be used as second line treatment as it has been safely used in the management of hyperemesis gravidarum.97 Ondansetron or granisetron should be the final option, as there are limited data on the use these drugs during pregnancy. In keeping with overall anesthesia practice, multidrug therapy could prove advantageous in the treatment of IONV.

Propofol Recently, the prophylactic antiemetic efficacy of propofol at subhypnotic dose (1.0 mg Æ kg 1h 1) administered after cord clamping, has been shown to be comparable to that of droperidol 1.25 mg and metoclopramide 10 mg in parturients undergoing cesarean section under regional anesthesia.96 The percentage of patients who were emesis-free in the intraoperative period was 80% with propofol, 80% with droperidol, and 78% with metoclopramide, compared with placebo (40%). This efficacy is attributed to a direct antiemetic property and a weak 5-HT3 antagonistic effect of propofol.96 However, this may not be a practical drug as most of our patients prefer to be fully awake after delivery. Acupressure Acupressure is a non-pharmacological and non-invasive method of preventing IONV. It acts by peripheral nerve stimulation and also by enhancing gastric motility.8 The incidence of intraoperative nausea and vomiting has been shown to be 14.9% and 8.5%, respectively, in the acupressure group compared to 36.2% and 17%, respectively, in the control group.8 Acupressure has also being shown to be comparable to metoclopramide in decreasing nausea but not vomiting during cesarean section.12

TREATMENT Management of IONV should essentially rely on prophylaxis. Should prophylactic measures fail, treatment

CONCLUSION

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